The total number of mutations (changes) found in the DNA of cancer cells. Knowing the tumor mutational burden may help plan the best treatment. For example, tumors that have a high number of mutations appear to be more likely to respond to certain types of immunotherapy. Tumor mutational burden is being used as a type of biomarker. Also called TMB.

Tumor Mutational Burden–High (≥10 Mutations/Megabase) Solid Tumors

Pembrolizumab

Indication. Pembrolizumab is indicated for adult and pediatric patients with unresectable or metastatic tumor mutational burden–high (TMB-H) solid tumors, whose disease progressed after prior treatment and who have no satisfactory alternative treatment options. TMB-H is defined as ≥10 mutations/megabase (mut/Mb), as determined by a U.S. Food and Drug Administration–approved test.

Evidence. Approval was based on a retrospective analysis of 10 cohorts of patients with various previously treated unresectable or metastatic TMB-H solid tumors enrolled in a multicenter, nonrandomized, open-label trial. Patients received 200 mg of pembrolizumab intravenously every 3 weeks until unacceptable toxicity or documented disease progression.

Efficacy. A total of 102 patients (13%) had tumors identified as TMB-H (defined as TMB ≥10 mut/Mb). The objective response rate for these patients was 29% (95% confidence interval, 21%–39%), with a 4% complete response rate and 25% partial response rate. The median follow-up was 13.4 months.

Identification of biomarker. The FoundationOne CDx assay is a companion diagnostic test for pembrolizumab.

Treatment of metastatic disease is palliative in intent. Goals of treatment include prolonging life and improving quality of life. Although median survival has been reported to be 18 to 24 months overall, survival varies according to subtype. The longest median survival outcomes have been observed in patients with human epidermal growth factor receptor 2 (HER2)–positive and hormone receptor–positive metastatic breast cancer, and less favorable outcomes have been observed in patients with metastatic triple-negative breast cancer (TNBC).

Treatment Option Overview for Metastatic Breast Cancer

Treatment options for metastatic breast cancer include the following:

1. Hormone therapy (tamoxifen, aromatase inhibitors, selective estrogen receptor [ER] degraders).
2. HER2-targeted therapy.
3. CDK4/6 inhibitors.
4. mTOR inhibitors.
5. PIK3CA inhibitors.
6. Chemotherapy.
7. Immunotherapy.
8. Surgery for patients with limited symptomatic metastases.
9. Radiation therapy for patients with limited symptomatic metastases.
10. Bone-modifying therapy for patients with bone metastases.

In many cases, these therapies are given in sequence and used in various combinations.

Cytological or histological documentation of metastatic disease, with testing of ER, progesterone receptor, and HER2 statuses, should be obtained at the time of metastatic presentation, if possible. If not possible, it is appropriate to consider liquid biopsy (via circulating tumor cell and/or circulating tumor DNA testing).

All patients with metastatic breast cancer are considered candidates for ongoing clinical trials.

Capecitabine and fluorouracil dosing

The DPYD gene encodes an enzyme that catabolizes pyrimidines and fluoropyrimidines, like capecitabine and fluorouracil. An estimated 1% to 2% of the population has germline pathogenic variants in DPYD, which lead to reduced DPD protein function and an accumulation of pyrimidines and fluoropyrimidines in the body. Patients with the DPYD*2A variant who receive fluoropyrimidines may experience severe, life-threatening toxicities that are sometimes fatal. Many other DPYD variants have been identified, with a range of clinical effects. Fluoropyrimidine avoidance or a dose reduction of 50% may be recommended based on the patient's DPYD genotype and number of functioning DPYD alleles. DPYD genetic testing costs less than $200, but insurance coverage varies due to a lack of national guidelines. In addition, testing may delay therapy by 2 weeks, which would not be advisable in urgent situations. This controversial issue requires further evaluation.

Hormone Receptor–Positive HER2-Negative Breast Cancer

Endocrine therapy and cyclin-dependent kinase (CDK) inhibitor therapy

CDK4 and CDK6 have been implicated in the continued proliferation of hormone receptor–positive breast cancer resistant to endocrine therapy. CDK inhibitors have been approved by the U.S. Food and Drug Administration (FDA) in combination with endocrine therapy in both first-line and later-line treatment of advanced hormone receptor–positive HER2-negative breast cancer. Three oral CDK4/6 inhibitors are currently available: palbociclib, ribociclib, and abemaciclib.

Overall, the addition of CDK4/6 inhibitors to endocrine therapy is associated with improved breast cancer outcomes and, in general, either maintained or improved quality of life. This benefit was observed across multiple clinicopathological subgroups of breast cancer.

First-line palbociclib and endocrine therapy

Evidence (first-line palbociclib and endocrine therapy):

1. PALOMA-2 (NCT01740427) confirmed the results of the phase II PALOMA-1 trial. This phase III, double-blind trial compared placebo plus letrozole with palbociclib plus letrozole as initial therapy for ER-positive postmenopausal patients with advanced disease (n = 666).
   • The primary end point was investigator-assessed progression-free survival (PFS). The median PFS was 24.8 months in the palbociclib-plus-letrozole group compared with 14.5 months in the placebo-plus-letrozole group (hazard ratio [HR], 0.58; 95% confidence interval [CI], 0.46–0.72; P .001).[Level of evidence B1]
   • Overall survival (OS) data are not yet mature.
   • Patients who received palbociclib experienced more frequent cytopenias (66.4% grade 3 to 4 in palbociclib-treated patients vs. 1.4% in placebo-treated patients). Other common adverse events included nausea, arthralgia, fatigue, and alopecia. The most common grade 3 to 4 adverse events other than neutropenia included leukopenia (24.8% vs. 0%), anemia (5.4% vs. 1.8%), and fatigue (1.8% vs. 0.5%).

First-line ribociclib and endocrine therapy

Ribociclib, another CDK4/6 inhibitor, has also been tested in the first-line setting for postmenopausal patients and premenopausal patients with hormone receptor–positive and HER2-negative recurrent or metastatic breast cancer.

Evidence (first-line ribociclib and endocrine therapy):

1. The phase III placebo-controlled MONALEESA-2 trial (NCT01958021) randomly assigned 668 patients to receive either first-line ribociclib plus letrozole or placebo plus letrozole.
   • The primary end point (investigator-assessed PFS) was met. A preplanned interim analysis was performed after 243 patients had disease progression or died, and median duration of follow-up was 15.3 months. After 18 months, the PFS rate was 63.0% (95% CI, 54.6%–70.3%) in the ribociclib group and 42.2% (95% CI, 34.8%–49.5%) in the placebo group.
   • OS was a secondary end point. A protocol-specified final analysis of OS was published after 400 deaths and a median follow-up of 6.6 years. Patients who received ribociclib plus letrozole had a significant OS benefit compared with patients who received placebo plus letrozole. Median OS was 63.9 months in the ribociclib group and 51.4 months in the placebo group (HR_death, 0.76; 95% CI, 0.63–0.93; two-sided P = .008).[Level of evidence A1]
   • Grade 3 to 4 neutropenia occurred in 63.8% of patients in the ribociclib group and 1.2% of patients in the placebo group. Grade 1 to 2 nausea, infection, fatigue, and diarrhea were also noted. Grade 3 to 4 hepatobiliary toxic effects occurred in 14.4% of patients who received ribociclib and 4.8% of patients who received placebo. Prolonged QTcF interval occurred in 4.5% of patients in the ribociclib group and 2.1% of patients in the placebo group.
2. Ribociclib has also been tested in combination with fulvestrant in postmenopausal patients with hormone receptor–positive and HER2-negative recurrent or metastatic breast cancer. The MONALEESA-3 trial (NCT02422615) included patients receiving first-line or second-line therapy. This phase III, placebo-controlled trial randomly assigned 726 patients in a 2:1 ratio to receive ribociclib plus fulvestrant or placebo plus fulvestrant.
   1. The primary end point (investigator-assessed PFS) was met. At the time of final analysis for PFS, the median PFS for the ribociclib group was 20.5 months versus 12.8 months in the placebo group (HR, 0.593; 95% CI, 0.480–0.732; P .001).[Level of evidence B1]
   2. OS was superior in the ribociclib group (HR, 0.724; 95% CI, 0.568–0.924; P = .004). The result crossed the prespecified stopping boundary (P = .011) for superior efficacy. Results were similar in all subgroups.[Level of evidence A1]
   3. Adverse events were similar to those in other studies of CDK4/6 inhibitors.
      • Grade 3 to 4 neutropenia occurred in 53.4% of patients in the ribociclib group and 0.0% of patients in the placebo group.
      • The rate of febrile neutropenia was 1.0% in the ribociclib group and 0% in the placebo group.
      • An increase in QTcF interval of more than 60 milliseconds from baseline was observed in 6.5% of patients in the ribociclib arm and 0.4% in the placebo arm.
3. Ribociclib was also assessed in the first-line setting in a study conducted solely in premenopausal or perimenopausal women receiving either tamoxifen or a nonsteroidal aromatase inhibitor (AI) plus goserelin. In the MONALEESA-7 trial (NCT02278120), 672 premenopausal patients with hormone receptor–positive and HER2-negative recurrent or metastatic breast cancer, who had not received endocrine therapy for advanced disease, were randomly assigned in a 1:1 ratio to ribociclib or placebo.
   1. The primary end point (investigator-assessed PFS) was met. At the time of final analysis for PFS, the median PFS for the ribociclib group was 23.8 months versus 13.0 months in the placebo group (HR, 0.55; 95% CI, 0.44–0.69; P .0001).[Level of evidence A3]
   2. OS was a secondary end point. The combination of ribociclib plus endocrine therapy was associated with longer OS than was endocrine therapy alone (42-month OS, 70.2% vs. 46%; HR_death, 0.71; 95% CI, 0.54−0.95, P = .01).[Level of evidence A1] The survival benefit was observed both in patients who received an AI plus goserelin and in those who received tamoxifen, but it was not statistically significant in the much-smaller tamoxifen group.
   3. Adverse events were similar to those in other studies of CDK4/6 inhibitors.
      • Grade 3 to 4 neutropenia occurred in 61% of patients in the ribociclib group and 4% of patients in the placebo group.
      • The rate of febrile neutropenia was 2.0% in the ribociclib group and 1.0% in the placebo group.
      • An increase in QTcF interval of more than 60 milliseconds from baseline was observed in 10.0 % of patients in the ribociclib arm and 2.0% in the placebo arm. Sixty-millisecond increases were more common in patients receiving tamoxifen (16% on ribociclib and 7% on placebo).

First-line abemaciclib and endocrine therapy

Abemaciclib, another CDK4/6 inhibitor, has also been tested in the first-line setting for postmenopausal patients with hormone receptor–positive and HER2-negative recurrent or metastatic breast cancer.

Evidence (first-line abemaciclib and endocrine therapy):

1. MONARCH 3 (NCT02246621) was a randomized, double-blind, phase III trial that evaluated first-line abemaciclib or placebo plus a nonsteroidal AI in 493 postmenopausal women with hormone receptor–positive and HER2-negative advanced breast cancer.
   • The primary end point, investigator-assessed PFS, was met. After a median follow-up of 17.8 months, the PFS was not reached in the abemaciclib arm and was reached at 14.7 months in the placebo arm (HR, 0.54; 95% CI, 0.41–0.72; P = .000021).
   • OS data are not yet mature.
   • The side effect profile of abemaciclib differs from the other CDK4/6 inhibitors. Diarrhea was the most frequent adverse event in the abemaciclib arm, although most of the diarrhea cases were grade 1.
   • Neutropenia was more common in the abemaciclib arm; however, only 21.1% of participants experienced grade 3 to 4 neutropenia.

Second-line palbociclib and endocrine therapy

Evidence (second-line palbociclib and endocrine therapy):

1. PALOMA-3 (NCT01942135) was a double-blind, phase III trial of 521 patients with hormone receptor–positive, HER2/neu-negative, advanced breast cancer who had relapsed after or progressed on previous endocrine therapy and were randomly assigned to receive either fulvestrant plus placebo or fulvestrant plus palbociclib. Premenopausal and postmenopausal patients were eligible. Premenopausal patients received goserelin.[Level of evidence A3]
   • The final PFS analysis showed a median PFS of 9.5 months on the palbociclib-fulvestrant arm versus 4.6 months on the placebo-fulvestrant arm (HR, 0.46; 95% CI, 0.36–0.59; P .0001).[Level of evidence A3]
   • Cytopenias, particularly neutropenia, were much more frequent on the palbociclib-containing arm, but febrile neutropenia was very uncommon (1%) in both groups. Patients receiving palbociclib had more-frequent fatigue, nausea, and headache.
   • A prespecified analysis of OS was made after 310 patients had died. A 6.9 month difference in median OS favoring the palbociclib-fulvestrant arm (34.9 months vs. 28.0 months) was found, which did not reach statistical significance (HR, 0.81; 95% CI, 0.64–1.03, P = .09).
   • In a preplanned subgroup analysis, improved OS was observed in patients who had demonstrated sensitivity to hormone therapy (HR, 0.72; 95% CI, 0.55−0.94), whereas in patients without sensitivity, OS was not improved in the palbociclib group (HR, 1.14; 95% CI, 0.71−1.84; P = .12 for interaction).

Second-line ribociclib and endocrine therapy

The MONALEESA-3 trial included patients receiving second-line therapy.

Second-line abemaciclib and endocrine therapy

Evidence:

1. The MONARCH 2 study (NCT02107703) tested abemaciclib (CDK4/6 inhibitor) in a phase III, placebo-controlled trial that randomly assigned 669 patients with hormone receptor–positive and HER2-negative advanced breast cancer (with previous progression on endocrine therapy) to receive abemaciclib plus fulvestrant or placebo plus fulvestrant.
   1. The primary end point (investigator-assessed PFS) was met, with median duration of follow-up of 19.5 months. The median PFS was 16.4 months for the abemaciclib-fulvestrant arm versus 9.3 months for the placebo-fulvestrant arm (HR, 0.55; 95% CI, 0.45–0.68; P .001).[Level of evidence B1]
   2. OS data are mature and demonstrate an improvement in OS for patients receiving abemaciclib, and showed a median OS of 46.7 months for abemaciclib plus fulvestrant versus 37.3 months for placebo (HR, 0.757; 95% CI, 0.606–0.945; P = .01).[Level of evidence A1]
   3. Adverse events included diarrhea in the abemaciclib group (86.4%) and in the placebo group (24.7%), neutropenia (46% and 4%), nausea (45.1% and 22.9%), fatigue (39.9% and 26.9%), and abdominal pain (35.4% and 15.7%).
      • These events were mostly grade 1 to 2. Grade 1 to 2 diarrhea occurred in 73% of the patients in the abemaciclib group and in 24.2% of the placebo group. Anti-diarrheal medicine effectively managed this symptom in most cases, according to the study report.
      • Grade 3 diarrhea occurred in 13.4% of patients in the abemaciclib group and 0.4% of patients in the placebo group. No grade 4 diarrhea was reported.
      • Grade 3 to 4 neutropenia occurred in 25.5% of patients in the abemaciclib group and 1.7% of patients in the placebo group. Febrile neutropenia was reported in six patients in the abemaciclib arm.

Single-agent CDK inhibitor therapy

Evidence (single-agent CDK inhibitor therapy)

1. Single-agent abemaciclib was approved by the FDA for use in hormone receptor–positive HER2-negative breast cancer with disease progression on or after endocrine therapy and chemotherapy on the basis of results of the MONARCH 1 trial (NCT02102490). Abemaciclib is the only CDK4/6 inhibitor approved as a single agent. MONARCH 1 was a single-arm phase II study of single-agent abemaciclib in 132 women with hormone receptor–positive and HER2-negative advanced breast cancer that had progressed on at least one line of previous endocrine therapy and at least two lines of previous chemotherapy. The study population was heavily pretreated, and most participants had visceral disease. Patients who had previous CDK inhibitors were excluded.
   • The primary end point, investigator-assessed objective response rate, was 19.7% at 12 months (95% CI, 13.3%–27.5%).
   • The clinical benefit rate was 42.4%.
   • Median PFS was 6.0 months (95% CI, 4.2–7.5).
   • The most common adverse event was diarrhea, which occurred in 90.2% of the participants. However, the majority was grade 1 to 2, and only 19.7% of participants experienced grade 3 diarrhea. There was no grade 4 diarrhea.
   • Neutropenia occurred in 97.7% of participants; however, the majority was grade 1 to 2, and only 26.9% of participants experienced grade 3 to 4 neutropenia.

Mammalian target of rapamycin (mTOR) inhibitor therapy plus endocrine therapy

Preclinical models and clinical studies suggest that mTOR inhibitors might overcome endocrine resistance.

Evidence (mTOR inhibitor therapy):

1. The Breast Cancer Trial of Oral Everolimus (BOLERO-2 [NCT00863655]) was a randomized, phase III, placebo-controlled trial in which patients with hormone receptor–positive metastatic breast cancer that is resistant to nonsteroidal aromatase inhibition were randomly assigned to receive either the mTOR inhibitor everolimus plus exemestane, or placebo plus exemestane.[Level of evidence B1]
   • At the interim analysis, median PFS was 6.9 months for everolimus plus exemestane and 2.8 months for placebo plus exemestane (HR, 0.43; 95% CI, 0.35–0.54; P .001).
   • The addition of everolimus to exemestane was more toxic than was placebo plus exemestane, with the most-common grade 3 or 4 adverse events being stomatitis (8% vs. 1%), anemia (6% vs. 1%), dyspnea (4% vs. 1%), hyperglycemia (4% vs. 1%), fatigue (4% vs. 1%), and pneumonitis (3% vs. 0%).
   • OS differences were not significant after further follow-up.
2. TAMRAD (NCT01298713) was an open-label, randomized, phase II trial comparing tamoxifen with tamoxifen plus everolimus in postmenopausal women whose disease had progressed after receiving an AI in the adjuvant or metastatic setting. The trial randomly assigned 57 women to receive tamoxifen and 54 women to receive the combination therapy.
   • Median time to progression was 8.6 months in the combination group and 4.5 months in the tamoxifen group (HR, 0.54; 95% CI, 0.56−0.81; P = .002).
   • Toxicities were greater on the everolimus arm and similar to those in the BOLERO2 trial.
   • In an exploratory analysis, OS was 32.9 months in the tamoxifen group and not reached in the combination group (HR, 0.45; 95% CI, 0.24−0.81; P = .007).[Level of evidence A1]
3. PrE0102 (NCT01797120) was a double-blind, randomized, phase II trial comparing fulvestrant with fulvestrant plus everolimus in postmenopausal women whose disease had progressed after receiving an AI in the adjuvant or metastatic setting. Sixty-six women were randomly assigned to the combination arm and 65 to fulvestrant alone.
   • Median PFS was 10.3 months on the combination arm and 5.1 months on the fulvestrant-alone arm (HR, 0.61; 95% CI, 0.40−0.92; P = .02).[Level of evidence B1]
   • Toxicities were similar to those in previous studies.
   • The was no observed difference in OS between the arms.
4. The single-arm SWISH trial (NCT02069093) assessed the efficacy of a dexamethasone oral solution (0.5 mg per 5 mL) in the prevention of stomatitis in women receiving exemestane plus everolimus. The incidence of grade 2 or worse stomatitis was 2% in the 85 evaluable patients in this study compared with 33% in the BOLERO-2 trial.

Alpelisib plus endocrine therapy

Activating mutations in PIK3CA are identified in approximately 40% of hormone receptor–positive and HER2-negative breast cancers. Alpelisib is an alpha-specific PI3K inhibitor.

Evidence (alpelisib plus endocrine therapy):

1. SOLAR-1 (NCT02437318) was a randomized phase III trial comparing alpelisib plus fulvestrant with placebo plus fulvestrant. The trial included 572 postmenopausal women with hormone receptor–positive and HER2-negative advanced breast cancer who had received previous endocrine therapy.[Level of evidence B1]

   PIK3CA mutations were confirmed in 341 participants. The primary end point was PFS in the cohort of patients with PIK3CA mutations.

   • In this cohort, median PFS was 11 months in the alpelisib-plus-fulvestrant arm compared with 5.7 months in the placebo-plus-fulvestrant arm (HR_progression or HR_death, 0.65; 95% CI, 0.50−0.85; P .001).
   • PFS did not differ between arms in the cohort of participants without PIK3CA mutations (median PFS, 7.4 months in the alpelisib-plus-fulvestrant arm vs. 5.6 months in the placebo-plus-fulvestrant arm).
   • OS in the cohort with PIK3CA mutations was a secondary end point. OS data are not yet mature.
   • Very few study participants had received previous CDK4/6 inhibitor therapy.
   • Common toxicities associated with alpelisib included hyperglycemia, diarrhea, nausea, anorexia, and rash. Careful monitoring and management of hyperglycemia are required during alpelisib use.

   The FDA approved alpelisib for use in combination with fulvestrant in advanced PIK3CA-mutated, hormone receptor–positive, HER2-negative breast cancer after previous endocrine therapy.

Elacestrant

Elacestrant is an oral selective ER degrader (SERD). It degrades ER alpha in a dose-dependent manner and inhibits estradiol-dependent ER-directed gene transcription and tumor growth, including in cells harboring ESR1 mutations. Mutations in ESR1 result in estrogen-independent ER activation and, consequently, resistance to AIs, but not necessarily to SERDs and selective ER modulators.

Evidence (elacestrant):

1. A randomized, open-label, phase III trial (EMERALD [NCT03778931]) enrolled patients with ER-positive HER2-negative metastatic breast cancer. Eligible patients had previously received one or two lines of endocrine therapy, a CDK4/6 inhibitor, and no more than one line of chemotherapy. A total of 477 patients were randomly assigned in a 1:1 ratio to receive either elacestrant 400 mg orally once daily or standard-of-care endocrine monotherapy. Primary end points were PFS by blinded independent central review in all patients and in patients with detectable ESR1 mutations. An ESR1 mutation was detected in 47.8% of patients, and 43.4% of patients had received two prior endocrine therapies. Twenty-nine percent of patients in the elacestrant arm and 31% of patients in the standard-of-care arm had received prior fulvestrant therapy. Less than 5% of patients in either arm had received prior mTOR inhibitor therapy.
   • PFS was prolonged in the elacestrant arm in all patients (HR, 0.70; 95% CI, 0.55–0.88; P = .002) and in elacestrant-treated patients with ESR1 mutations (HR, 0.55; 95% CI, 0.39–0.77; P = .0005). Among all patients, 6-month PFS rates were 34.3% for patients in the elacestrant arm and 20.4% for patients in the standard-of-care arm. Among patients with ESR1 mutations, 6-month PFS rates were 40.8% for patients in the elacestrant arm and 19.1% for patients in the standard-of-care arm. Similarly, for all patients, 12-month PFS rates were 22.3% for patients in the elacestrant arm and 9.4% for patients in the standard-of-care arm. For patients with ESR1 mutations, 12-month PFS rates were 26.8% for patients in the elacestrant arm and 8.2% for patients in the standard-of-care arm.[Level of evidence B1]
   • The most common adverse events observed with elacestrant versus standard-of-care therapy included nausea (35.0% vs. 18.8%), fatigue (19.0% vs. 18.8%), vomiting (19.0% vs. 8.3%), decreased appetite (14.8% vs. 9.2%), and arthralgia (14.3% vs. 16.2%). Grade 3 or 4 adverse events occurred in 64 patients (27.0%) who received elacestrant and 47 patients (20.5%) who received standard-of-care therapy. The most common grade 3 or 4 adverse events in the elacestrant arm were nausea (six patients, 2.5%), back pain (six patients, 2.5%), and increased alanine aminotransferase (five patients, 2.1%). The most common grade 3 or 4 adverse events in the standard-of-care arm were nausea, fatigue, diarrhea, and increased aspartate aminotransferase (each occurring in two patients, 0.9%). Adverse events led to treatment discontinuation in 15 patients (6.3%) in the elacestrant arm and 10 patients (4.4%) in the standard-of-care arm.

AKT inhibitor therapy

AKT1-activating mutations are found in 5% to 10% of advanced breast cancers. AKT is downstream from both PI3K and PTEN in the PI3K/AKT/PTEN pathway. Capivasertib is a selective inhibitor of all three AKT isoforms (AKT1, AKT2, and AKT3).

Capivasertib

Evidence (capivasertib):

1. The multicenter, double-blind, placebo-controlled, phase II FAKTION trial (NCT01992952) randomly assigned 140 postmenopausal women with metastatic breast cancer to receive fulvestrant with either capivasertib or placebo. No enrollees had received prior therapy with a CDK inhibitor.[Level of evidence A1]
   • The primary end point was PFS in the intention-to-treat (ITT) population. The median follow-up was 58.5 months for patients who received fulvestrant plus capivasertib and 62.3 months for patients who received fulvestrant plus placebo. The updated median PFS was 10.3 months in the fulvestrant-plus-capivasertib group and 4.8 months in the fulvestrant-plus-placebo group (two-sided P = .0023).
   • Secondary end points were OS and safety in the ITT population, as well as the effect of tumor PI3K/AKT/PTEN pathway status. The median OS was 29.3 months in the capivasertib group and 23.4 months in the placebo group (adjusted HR, 0.66; 95% CI, 0.45–0.97; two-sided P = .035).
   • An expanded biomarker panel identified an expanded pathway–altered subgroup of 76 participants (54% of the ITT population). The median PFS in the expanded pathway–altered subgroup was 12.8 months for patients who received capivasertib (n = 39) and 4.6 months for patients who received placebo (n = 37) (adjusted HR, 0.44; 95% CI, 0.26–0.72; two-sided P = .0014). The median OS for the expanded pathway–altered subgroup who received capivasertib was 38.9 months compared with 20.0 months for patients who received placebo (adjusted HR, 0.46; 95% CI, 0.27–0.79; two-sided P = .0047). There were no statistically significant differences in the PFS or OS of patients in the expanded pathway–nonaltered subgroups who received capivasertib (n = 30) or placebo (n = 34).

The FDA has not approved capivasertib.

HDAC inhibitor therapy

Epigenetic modification alters gene expression. This can lead to endocrine therapy resistance and may be reversed by epigenetic modifiers such as histone deacetylase (HDAC) inhibitors. Entinostat, an oral HDAC inhibitor, induces downregulation of estrogen-independent growth factor signaling pathways and normalization of estrogen receptor levels. Entinostat was evaluated in a phase III trial and showed no benefit.

Endocrine therapy alone

With the PFS and OS advantages associated with combination therapy with targeted agents and endocrine therapy as discussed above, single-agent endocrine therapy is less frequently used, especially in the first-line setting. However, its use remains appropriate in select cases as first-line therapy and in later-line therapy after progression on targeted therapies and before the use of chemotherapy in cases in which endocrine-sensitive disease is still thought to be present.

Commonly used single-agent endocrine therapies include tamoxifen, nonsteroidal AI (letrozole, anastrozole), the steroidal AI exemestane, and fulvestrant. In general, premenopausal women with metastatic breast cancer undergo ovarian suppression or ablation and are treated in the same manner as postmenopausal women.

Tamoxifen and AI therapy

While tamoxifen has been used for many years in treating postmenopausal women with newly metastatic disease that is ER positive, PR positive, or ER/PR unknown, several randomized trials suggest equivalent or superior response rates and PFS for the AI compared with tamoxifen.[Level of evidence B1]

Evidence (tamoxifen and AI therapy):

1. A meta-analysis evaluated patients with metastatic disease who were randomly assigned to receive either an AI as their first or second hormone therapy, or standard therapy (tamoxifen or a progestational agent).[Level of evidence A1]
   • Patients who received an AI as either their first or second hormone therapy for metastatic disease and were randomly assigned to receive a third-generation drug (anastrozole, letrozole, exemestane, or vorozole) lived longer (HR_death, 0.87; 95% CI, 0.82–0.93) than those who received standard therapy (tamoxifen or a progestational agent).

Fulvestrant

Fulvestrant is a selective estrogen receptor degrader that has been studied in the first-line and second-line setting in women with advanced or metastatic breast cancer.

First-line fulvestrant

Evidence (first-line fulvestrant):

1. FALCON (NCT01602380) was a phase III, double-blind, randomized trial that compared fulvestrant (500 mg) with anastrozole (1 mg) in patients with advanced or metastatic receptor-positive breast cancer who had not received previous endocrine therapy. The trial randomly assigned 230 patients to receive fulvestrant and 232 patients to receive anastrozole.
   • Median PFS was 16.6 months in the fulvestrant group and 13.8 months in the anastrozole group (HR, 0.797; 95% CI, 0.637−0.999; P = .049). [Level of evidence B1]
   • The frequency of adverse events was similar in the two groups, and there was no difference in quality of life.
   • OS results were not reported.

Second-line fulvestrant

Evidence (second-line fulvestrant):

1. Two randomized trials that enrolled 400 and 451 patients whose disease had progressed after they received tamoxifen demonstrated that fulvestrant yielded results similar to those of anastrozole in terms of its impact on PFS. The proper sequence of these therapies is not known.
2. EFECT (NCT00065325) was a phase III, double-blind, randomized trial that compared fulvestrant given in a loading-dose regimen (500 mg day 0, 250 mg days 14 and 28, and 250 mg every 28 days thereafter) with exemestane (25 mg) in women who had developed progressive disease after previous nonsteroidal AI (anastrozole or letrozole) therapy. The trial randomly assigned 351 women to receive fulvestrant and 342 women to receive exemestane.
   • Median time to progression was 3.7 months in both groups (HR, 0.93; 95% CI, 0.819−1.133; P = .65).[Level of evidence B1]
   • The frequency of adverse events was similar in both groups, and there was no difference in quality of life.
   • OS results were not reported.
3. CONFIRM (NCT00099437) was a double-blind phase III trial that compared two doses of fulvestrant (500 mg vs. 250 mg, each given in a loading-dose schedule) in 736 women whose disease had progressed on previous endocrine therapy.
   • PFS was significantly better on the higher-dose arm (HR, 0.80; 95% CI, 0.68–0.94; P = .006) [Level of evidence B1]
   • Adverse events and quality of life were similar on the two arms.

Combination endocrine therapy with an AI and fulvestrant

Conflicting results were found in two trials that compared the combination of the antiestrogen fulvestrant and anastrozole with anastrozole alone in the first-line treatment of hormone receptor–positive postmenopausal patients with recurrent or metastatic disease. For more information, see the Fulvestrant section. In both studies, fulvestrant was administered as a 500-mg loading dose on day 1; 250 mg was administered on days 15 and 29, and monthly thereafter; plus, 1 mg of anastrozole was administered daily. The Southwest Oncology Group (SWOG) trial included more patients who presented with metastatic disease; the Fulvestrant and Anastrozole Combination Therapy (FACT [NCT00256698]) study enrolled more patients who had previously received tamoxifen.

Evidence (combination endocrine therapy with an AI and fulvestrant):

1. The SWOG-0226 trial (NCT00075764), which enrolled 707 patients, demonstrated a statistically significant difference in PFS (HR, 0.80; 95% CI, 0.68–0.94; P = .007) and OS (HR, 0.81; 95% CI, 0.65–1.00; P = .05).[Level of evidence A1]
2. In an analysis done after 5 more years of follow-up, the observed benefits of combined therapy were still present, and the level of significance with respect to OS was greater (HR, 0.82; 95% CI, 0.69–0.98; P = .03).[Level of evidence A1]
3. In contrast, the FACT trial , which enrolled 514 patients, found no difference in either disease-free survival (DFS) (HR, 0.99; 95% CI, 0.81–1.20; P = .91) or OS (HR, 1.0; 95% CI, 0.76–1.32; P = 1.00).[Level of evidence A1]

Sequencing therapy for hormone receptor–positive metastatic breast cancer

The optimal sequence of therapies for hormone receptor–positive metastatic breast cancer is not known. In general, in the absence of a visceral crisis, most patients receive sequential endocrine-based regimens before transitioning to chemotherapy. On the basis of the PFS and OS improvements mentioned above, a combination of a CDK4/6 inhibitor therapy and endocrine therapy in the first line is an appropriate choice.

Poly (ADP-ribose) polymerase (PARP) inhibitor therapy

Patients with hormone receptor-positive metastatic breast cancer and a germline BRCA mutation are eligible for PARP inhibitor therapy.

Sacituzumab govitecan

Sacituzumab govitecan is an antibody-drug conjugate that combines an anti–trophoblast cell-surface antigen 2 (TROP2) antibody with an active metabolite of irinotecan (SN-38). TROP2 is a transmembrane calcium signal transducer highly expressed in ER-positive HER2-negative breast cancer. Internalization of TROP2–bound sacituzumab govitecan delivers SN-38 into the tumor cell through hydrolysis of the linker.

Evidence (sacituzumab govitecan):

1. The global phase III TROPiCS-02 trial (NCT03901339) randomly assigned 543 patients to receive either sacituzumab govitecan or physician’s choice chemotherapy (eribulin, vinorelbine, capecitabine, or gemcitabine). Patients had locally recurrent inoperable or metastatic breast cancer that was endocrine-resistant, chemotherapy-treated, hormone receptor–positive, and HER2-negative. Patients had received three median lines of chemotherapy for advanced disease, and 99% of patients had previously received a CDK4/6 inhibitor.[Level of evidence B1]
   • The primary end point was PFS by blinded independent central review. An analysis noted a 34% reduction in the risk of progression or death (HR, 0.66; 95% CI, 0.53–0.83; P = .0003). The median PFS was 5.5 months in the sacituzumab govitecan group and 4.0 months in the chemotherapy group. The PFS at 6 and 12 months was 46% and 21% for patients who received sacituzumab govitecan and 30% and 7% for patients who received chemotherapy.
   • Median OS data are not yet mature.
   • Key grade 3 or greater treatment-related adverse events were neutropenia (occurring in 51% of patients who received sacituzumab govitecan and 38% of patients who received chemotherapy) and diarrhea (occurring in 9% of patients who received sacituzumab govitecan and 1% of patients who received chemotherapy). One patient in the sacituzumab govitecan group died of a treatment-related adverse event (septic shock related to neutropenic colitis).
   • The objective response rate by blinded independent central review was 21% in the sacituzumab govitecan group and 14% in the chemotherapy group. The clinical benefit rate was higher with sacituzumab govitecan than with chemotherapy (34% vs. 22%).

The FDA has approved sacituzumab govitecan for patients with metastatic unresectable breast cancer, including patients with TNBC who have received at least two systemic therapies, including at least one for metastatic cancer. It is also approved in patients with hormone receptor–positive and HER2-negative breast cancer who have received hormone therapy and at least two systemic therapies for metastatic cancer.

Chemotherapy

Chemotherapy may be appropriate for patients with hormone receptor–positive HER2-negative breast cancer.

HER2/neu-Low Breast Cancer

Sixty percent of HER2–negative metastatic breast cancers express low levels of HER2, defined as a score of 1+ on immunohistochemical (IHC) analysis or as an IHC score of 2+ and negative results on in situ hybridization. These are referred to as HER2-low tumors. Historically, HER2-directed therapies have not improved outcomes in these patients. Early-phase trials of trastuzumab deruxtecan showed potential efficacy in this subgroup. A subsequent randomized phase III trial showed OS benefit in this subgroup. Trastuzumab deruxtecan is an antibody-drug conjugate consisting of a humanized anti-HER2 monoclonal antibody linked to a topoisomerase-I inhibitor payload through a cleavable linker. This agent offers bystander effect to surrounding HER2-low cells via uptake into HER2-amplified cells, intracellular cleavage of payload, and release of payload into the surrounding tumor.

Evidence (trastuzumab deruxtecan for hormone receptor–positive and negative HER2-low tumors):

1. The DESTINY-Breast04 trial (NCT03734029) randomly assigned 557 women in a 2:1 ratio to receive either trastuzumab deruxtecan or the physician’s choice of chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel). Patients had received one or two prior lines of chemotherapy. The primary end point was PFS in the hormone receptor–positive group (88.7% of patients). The secondary end points were PFS in the total population, OS in the total population, and OS in the hormone receptor–positive group.
   • In the hormone receptor–positive cohort, the median PFS was 10.1 months for patients who received trastuzumab deruxtecan and 5.4 months for patients who received the physician’s choice of chemotherapy (HR_{disease progression or death}, 0.51; P .001). The OS was 23.9 months for patients who received trastuzumab deruxtecan and 17.5 months for patients who received the physician's choice of chemotherapy (HR_death, 0.64; P = .003).
   • Among all patients, the median PFS was 9.9 months in the trastuzumab deruxtecan group and 5.1 months in the physician’s choice group (HR_{disease progression or death}, 0.50; P .001). The OS was 23.4 months in the trastuzumab deruxtecan group and 16.8 months in the physician's choice group (HR_death, 0.64; P = .001).
   • Drug-related interstitial lung disease or pneumonitis occurred in 12.1% of the patients who received trastuzumab deruxtecan; 0.8% had grade 5 events.

Triple-Negative Breast Cancer

Chemotherapy plus immunotherapy

The standard-of-care treatment for first-line metastatic TNBC with a programmed death-ligand 1 (PD-L1) combined positive score (CPS) of 10 or more is chemotherapy plus pembrolizumab. This was evaluated in the KEYNOTE-355 trial.

Pembrolizumab

The phase III, randomized, placebo-controlled, double-blind, multinational KEYNOTE-355 trial (NCT02819518) evaluated the addition of pembrolizumab to first-line chemotherapy in patients with metastatic TNBC. This combination was approved for use in this patient population as a result of the trial.

Evidence (pembrolizumab):

1. Patients were randomly assigned in a 2:1 ratio to receive either pembrolizumab (200 mg every 3 weeks) and chemotherapy (nab-paclitaxel, paclitaxel, or gemcitabine plus carboplatin) or placebo and chemotherapy. Randomization was stratified by the type of on-study chemotherapy (taxane or gemcitabine/carboplatin), PD-L1 expression at baseline (CPS ≥1 or 1), and previous treatment with the same class of chemotherapy in the neoadjuvant or adjuvant setting (yes or no). Dual primary efficacy end points were PFS and OS assessed in the PD-L1 CPS of 10 or more, PD-L1 CPS of 1 or more, and ITT populations. Of the 847 patients assigned to treatment, 566 patients received pembrolizumab and chemotherapy and 281 patients received placebo and chemotherapy.
   • At the second interim analysis, the median follow-up was 25.9 months in the pembrolizumab-and-chemotherapy group and 26.3 months in the placebo-and-chemotherapy group. Among patients with CPS of 10 or more, the median PFS was 9.7 months with pembrolizumab and chemotherapy and 5.6 months with placebo and chemotherapy (HR_{progression or death}, 0.65; 95% CI, 0.49–0.86; one-sided P = .0012 [primary objective met]). Among patients with CPS of 1 or more, the median PFS was 7.6 months with pembrolizumab and chemotherapy and 5.6 months with placebo and chemotherapy (HR, 0.74; 0.61–0.90; one-sided P = .0014 [not significant]). Among the ITT population, the median PFS was 7.5 months and 5.6 months (HR, 0.82; 0.69–0.97 [not tested]). The pembrolizumab treatment effect increased with PD-L1 enrichment.
   • Based on the PFS data, the FDA approved pembrolizumab and chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10).
   • At time of final analysis, the median follow-up was 44.1 months. In the group with a CPS of at least 10, the median OS was 23 months in the pembrolizumab-and-chemotherapy group and 16.1 months in the placebo-and-chemotherapy group (HR, 0.73; 95% CI, 0.55–0.95; two-sided P = .0185 [significant]). In the group with a CPS of at least 1, the median survival was not significantly altered (17.6 vs. 16 months; P = .1125).
   • Grade 3 to 5 treatment-related adverse events occurred in 68.1% of patients in the pembrolizumab group and 66.9% of patients in the placebo group. Two deaths occurred in the pembrolizumab group (acute kidney injury and pneumonia). There were no deaths in the placebo group. Grade 3 to 4 immune-mediated adverse events occurred in 5.3% of patients in the pembrolizumab group, none of which led to death.

Atezolizumab

The addition of atezolizumab, a PD-L1–positive antibody, to first-line chemotherapy for patients with hormone receptor–negative and HER2-negative advanced breast cancer was evaluated in the phase III, randomized, placebo-controlled IMpassion130 trial (NCT02425891) Participants (N = 902) were randomly assigned 1:1 to atezolizumab plus nanoparticle albumin-bound (nab)-paclitaxel or to placebo plus nab-paclitaxel. Participants were stratified according to the presence of liver metastases (yes/no), receipt of previous taxane therapy (yes/no), and PD-L1 status (positive or negative). PD-L1 expression of 1% or greater was defined as positive. Co-primary end points included PFS and OS, both of which were evaluated in the ITT population and in the PD-L1–positive population (n = 369).

Based on the initial publication of PFS data from IMPassion130, the FDA granted accelerated approval for the use of atezolizumab in combination with protein-bound paclitaxel for patients with unresectable locally advanced or metastatic TNBC whose tumors express PD-L1. However, a 2021 final analysis revealed no OS benefit in the ITT population.

IMpassion131 (NCT03125902) was a phase III, randomized, placebo-controlled, double-blind trial of first-line paclitaxel with or without atezolizumab for patients with unresectable locally advanced or metastatic TNBC. The study included 651 patients, 45% of whom had PD-L1–positive TNBC. This trial also did not demonstrate a benefit from the addition of atezolizumab to paclitaxel in this population. Accordingly, the sponsor voluntarily withdrew this approval.

1. IMpassion130 reported PFS data with a median follow-up of 12.9 months.
   • In the ITT population, PFS was improved with the addition of atezolizumab (median PFS, 7.2 months vs. 5.5 months; HR, 0.80; 95% CI, 0.69–0.92; P = .0025).
   • In the PD-L1–positive population, PFS was improved with the addition of atezolizumab (median PFS, 7.5 months vs. 5 months; HR, 0.62; 95% CI, 0.49–0.78; P .001).
   • Adverse events occurred as expected. Adverse events that were potentially immune-related were more frequent in the atezolizumab arm.
2. The primary PFS analysis from IMpassion131 revealed that adding atezolizumab to paclitaxel did not improve investigator-assessed PFS in the PD-L1–positive population. The median PFS was 6.0 months for patients who received atezolizumab and paclitaxel compared with 5.7 months for patients who received placebo and paclitaxel (HR, 0.82; 95% CI, 0.60–1.12; P = .20).
   • The final OS results showed no difference between the treatment arms. The median OS was 22.1 months for patients who received atezolizumab and paclitaxel compared with 28.3 months for patients who received placebo and paclitaxel in the PD-L1–positive population (HR, 1.11; 95% CI, 0.76–1.64).
   • Results in the ITT population were consistent with the PD-L1–positive population. The safety profile was consistent with known effects of each study drug.

Sacituzumab govitecan

Sacituzumab govitecan is an antibody-drug conjugate that combines an anti–trophoblast cell-surface antigen 2 (TROP2) antibody with an active metabolite of irinotecan (SN-38). TROP2 is a transmembrane calcium signal transducer highly expressed in TNBC. Internalization of TROP2–bound sacituzumab govitecan delivers SN-38 into the tumor cell through hydrolysis of the linker..

Evidence (sacituzumab govitecan):

1. In a phase I/II trial, 108 women with TNBC who received at least two previous chemotherapy regimens (median, three) were treated with sacituzumab govitecan at a dose of 10 mg/kg intravenously on days 1 and 8 of a 21-day cycle.[Level of evidence C3]
   • A response rate of 33.3% (95% CI, 24.6%–43.1%) was observed.
   • The median duration of response was 7.7 months (95% CI, 4.9–10.8).
   • The main toxicity was neutropenia, and four deaths occurred during treatment.[Level of evidence C3]
   • The FDA granted accelerated approval to sacituzumab govitecan for patients with metastatic TNBC after at least two previous lines of therapy.
2. A phase III randomized trial (ASCENT [NCT02574455]) confirmed the efficacy of sacituzumab govitecan in patients with metastatic TNBC that was relapsed or refractory to two or more previous chemotherapy regimens. The trial randomly assigned 468 women without brain metastases to receive either sacituzumab govitecan or the physician's choice of single-agent chemotherapy (eribulin, vinorelbine, capecitabine, or gemcitabine). The primary end point was PFS. All patients had previous taxane exposure. Patients received sacituzumab govitecan at a dose of 10 mg/kg intravenously on days 1 and 8 of each 21-day cycle.
   • In the chemotherapy arm, 54% of patients received eribulin, 20% received vinorelbine, 13% received capecitabine, and 12% received gemcitabine.
   • The median PFS was 5.6 months (95% CI, 4.3–6.3; 166 events) in the sacituzumab govitecan arm and 1.7 months (95% CI, 1.5–2.6; 150 events) in the chemotherapy arm (HR_{disease progression or death}, 0.41; 95% CI, 0.32–0.52; P .001). [Level of evidence A1]
   • The median OS was 12.1 months (95% CI, 10.7–14.0) in the sacituzumab govitecan arm and 6.7 months (95% CI, 5.8–7.7) in the chemotherapy arm (HR_death, 0.48; 95% CI, 0.38–0.59; P .001).
   • The overall response rate was 35% in the sacituzumab govitecan arm and 5% in the chemotherapy arm.
   • Key treatment-related adverse events of grade 3 or higher occurred more often in patients who received sacituzumab govitecan than patients who received chemotherapy: neutropenia (51% vs. 33%), leukopenia (10% vs. 5%), diarrhea (10% vs. 1%), anemia (8% vs. 5%), and febrile neutropenia (6% vs. 2%).

PARP inhibitor therapy

Patients with TNBC and a germline BRCA mutation are eligible for PARP inhibitor therapy.

Chemotherapy

Chemotherapy may be appropriate for patients with TNBC.

Immunotherapy monotherapy

To date, immunotherapy monotherapy has not demonstrated an OS benefit for patients with metastatic TNBC.

Evidence (pembrolizumab):

1. KEYNOTE-119 (NCT02555657) was a phase III, randomized, open-label, multicenter, international trial that enrolled patients with metastatic TNBC. Patients had received one or two previous systemic treatments for metastatic disease and had previous treatment with an anthracycline or taxane. The trial randomly assigned 622 patients to receive intravenous pembrolizumab 200 mg once every 3 weeks for 35 cycles (pembrolizumab group), or to the investigator's choice of single-drug chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine). The primary end point was OS as assessed in each of the following groups: patients with a PD-L1 CPS of 10 or more, patients with a CPS of 1 or more, and all patients.
   • In patients with a PD-L1 CPS of 10 or more, the median OS was 12.7 months (95% CI, 9.9–16.3) in the pembrolizumab group and 11.6 months (95% CI, 8.3–13.7) in the chemotherapy group (HR, 0.78; 95% CI, 0.57–1.06; log-rank P = .057). [Level of evidence A1]
   • In patients with a CPS of 1 or more, the median OS was 10.7 months (95% CI, 9.3–12.5) in the pembrolizumab group and 10.2 months (95% CI, 7.9–12.6) in the chemotherapy group (HR, 0.86; 95% CI, 0.69–1.06; log-rank P = .073).
   • Among all patients, the median OS was 9.9 months (95% CI, 8.3–11.4) in the pembrolizumab group and 10.8 months (95% CI, 9.1–12.6) in the chemotherapy group (HR, 0.97; 95% CI, 0.82–1.15).

HER2/neu-Positive Breast Cancer

Antibody therapy targeting the HER2 pathway has been used since the 1990s and has revolutionized the treatment of HER2-positive metastatic breast cancer. Several HER2-targeted agents (e.g., trastuzumab, pertuzumab, trastuzumab emtansine, lapatinib) have been approved for treatment of this disease.

Monoclonal antibody therapy

Trastuzumab

Approximately 20% to 25% of patients with breast cancer have tumors that overexpress HER2/neu. Trastuzumab is a humanized monoclonal antibody that binds to the HER2/neu receptor. In patients previously treated with cytotoxic chemotherapy whose tumors overexpress HER2/neu, administration of trastuzumab as a single agent resulted in a response rate of 21%. [Level of evidence C3]

Evidence (trastuzumab):

1. In a phase III trial, patients with metastatic disease were randomly assigned to receive either chemotherapy alone (doxorubicin and cyclophosphamide or paclitaxel) or the same chemotherapy plus trastuzumab. [Level of evidence A1]
   • Patients treated with chemotherapy plus trastuzumab had an OS advantage over those who received chemotherapy alone (25.1 months vs. 20.3 months, P = .05). [Level of evidence A1]

Notably, when combined with doxorubicin, trastuzumab is associated with significant cardiac toxicity.

Clinical trials comparing multiagent chemotherapy plus trastuzumab with single-agent chemotherapy have yielded conflicting results.

• In one randomized study of patients with metastatic breast cancer treated with trastuzumab, paclitaxel, and carboplatin, patients tolerated the combination well and had a longer time to disease progression, compared with those treated with trastuzumab and paclitaxel alone. [Level of evidence B1]
• However, no difference in OS, time to disease progression, or response rate was shown in the Breast Cancer International Research Group’s phase III trial (BCIRG-007 [NCT00047255]) that compared carboplatin and docetaxel plus trastuzumab versus docetaxel plus trastuzumab as first-line chemotherapy for metastatic HER2-overexpressing breast cancer. [Level of evidence A1]

Outside of a clinical trial, standard first-line treatment for metastatic HER2-overexpressing breast cancer is single-agent chemotherapy plus trastuzumab.

Pertuzumab

Pertuzumab is a humanized monoclonal antibody that binds to a different epitope at the HER2 extracellular domain than does trastuzumab. The binding of pertuzumab to HER2 prevents dimerization with other ligand-activated HER receptors, most notably HER3.

Evidence (pertuzumab):

1. The phase III CLEOPATRA trial (NCT00567190) assessed the efficacy and safety of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel, in the first-line HER2-positive metastatic setting. [Level of evidence A1]
   • With a median follow-up of 50 months, the median OS was 40.8 months in the control group versus 56.5 months in the pertuzumab group (HR favoring pertuzumab group, 0.68; 95% CI, 0.56–0.84; P .001). Median PFS per investigator assessment was improved by 6.3 months by the addition of pertuzumab (HR, 0.68; 95% CI, 0.58–0.80).
   • Median OS was 56.5 months in the pertuzumab group compared with 40.8 months in the placebo group (HR, 0.68; 95% CI, 0.57–0.84; P .001).[76] Eight-year landmark OS rates were 37% with the addition of pertuzumab, compared with 23% in the placebo group.
   • The toxicity profile was similar in both treatment groups, with no increase in cardiac toxic effects seen in the pertuzumab combination arm.

Trastuzumab emtansine

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that incorporates the HER2-targeted antitumor properties of trastuzumab with the cytotoxic activity of the microtubule-inhibitory agent DM1. T-DM1 allows specific intracellular drug delivery to HER2-overexpressing cells, potentially improving the therapeutic index and minimizing exposure of normal tissue.

Evidence (T-DM1):

1. The phase III EMILIA or TDM4370g study (NCT00829166) was a randomized open-label trial that enrolled 991 patients with HER2-overexpressing, unresectable, locally advanced or metastatic breast cancer who were previously treated with trastuzumab and a taxane.[Level of evidence A1] Patients were randomly assigned to receive either T-DM1 or lapatinib plus capecitabine.
   • Median PFS was 9.6 months with T-DM1 versus 6.4 months with lapatinib plus capecitabine (HR, 0.65; 95% CI, 0.55–0.77; P .001).
   • Median OS was longer with trastuzumab emtansine versus lapatinib plus capecitabine (29.9 months vs. 25.9 months; HR, 0.75 [95% CI, 0.64–0.88]).
   • The incidences of thrombocytopenia and increased serum aminotransferase levels were higher in patients who received T-DM1, whereas the incidences of diarrhea, nausea, vomiting, and palmar-plantar syndrome were higher in patients who received lapatinib plus capecitabine.
2. Further evidence of T-DM1’s activity in metastatic HER2-overexpressed breast cancer was shown in a randomized phase II study of T-DM1 versus trastuzumab plus docetaxel. [Level of evidence B1] This trial randomly assigned 137 women with HER2-overexpressed breast cancer in the first-line metastatic setting.
   • At median follow-up of 14 months, median PFS was 9.2 months with trastuzumab plus docetaxel and 14.2 months with T-DM1 (HR, 0.59; 95% CI, 0.36–0.97).
   • Preliminary OS results were similar between treatment arms.
   • T-DM1 had a favorable safety profile compared with trastuzumab plus docetaxel, with fewer grade 3 adverse events (46.4% vs. 90.9%), adverse events leading to treatment discontinuations (7.2% vs. 40.9%), and serious adverse events (20.3% vs. 25.8%).
3. Evidence of activity of T-DM1 in heavily pretreated patients with metastatic, HER2-overexpressed breast cancer who had received previous trastuzumab and lapatinib was shown in the randomized phase III TH3RESA study (NCT01419197) of T-DM1 versus physician’s choice of treatment. [Level of evidence A1] This trial randomly assigned 602 patients in a 2:1 ratio (404 patients assigned to T-DM1 and 198 patients assigned to physician’s choice) and allowed crossover to T-DM1.
   • At a median follow-up of 7.2 months in the T-DM1 group and 6.5 months in the physician’s-choice group, median PFS was 6.2 months in the T-DM1 group and 3.3 months in the physician’s-choice group (HR, 0.528; 95% CI, 0.422–0.661; P .0001).
   • OS was significantly longer with trastuzumab emtansine versus the treatment of physician’s choice (median OS, 22.7 months vs. 15.8 months; HR, 0.68; 95% CI, 0.54–0.85; P = .0007).
4. The role of T-DM1 as first-line treatment of metastatic HER2-overexpressed breast cancer was evaluated in the phase III MARIANNE trial (NCT01120184). [Level of evidence B1] This study randomly assigned 1,095 patients to receive either trastuzumab plus taxane, T-DM1 plus placebo, or T-DM1 plus pertuzumab.
   • The median PFS for these treatment groups was 13.7 months for the trastuzumab-plus-taxane group, 14.1 months for the T-DM1-plus-placebo group, and 15.2 months for the T-DM1-plus-pertuzumab group.
   • There was no significant difference in PFS with T-DM1 plus placebo compared with trastuzumab plus taxane (HR, 0.91; 97.5% CI, 0.73–1.13), or with T-DM1 plus pertuzumab compared with trastuzumab plus taxane (HR, 0.87; 97.5% CI, 0.69–1.08).
   • Therefore, neither T-DM1 plus placebo nor T-DM1 plus pertuzumab showed PFS superiority over trastuzumab plus taxane.

Trastuzumab deruxtecan

Trastuzumab deruxtecan is an antibody-drug conjugate that combines trastuzumab with a topoisomerase inhibitor. This drug has demonstrated antitumor activity in patients with advanced HER2-positive breast cancer.

Evidence (trastuzumab deruxtecan):

1. A phase III, multicenter, open-label, randomized trial (DESTINY-Breast03 [NCT03529110]) compared the efficacy and safety of trastuzumab deruxtecan with trastuzumab emtansine. The study included 524 patients with HER2-positive metastatic breast cancer previously treated with a taxane and trastuzumab. PFS was the primary end point.
   • At 12 months, 75.8% of patients who received trastuzumab deruxtecan were alive without disease progression, compared with 34.1% of patients who received trastuzumab emtansine (HR, 0.28; 95% CI, 0.22–0.37; P .001).
   • Secondary end points were OS, overall response rate, and safety. A total of 94.1% of patients who received trastuzumab deruxtecan were alive at 12 months, compared with 85.9% of patients who received trastuzumab emtansine (HR_death, 0.55; 95% CI, 0.36–0.86). The overall response rate was 79.7% versus 34.2%, favoring trastuzumab deruxtecan. Grade 3 to 4 drug-related adverse events occurred in 45.1% of patients who received trastuzumab deruxtecan and 38.9% of patients who received trastuzumab emtansine. Interstitial lung disease and pneumonitis occurred in 10.5% of patients who received trastuzumab deruxtecan and 1.9% of patients who received trastuzumab emtansine; none of these events were grade 4 to 5.
   • This trial led to a change in the standard of care for patients with HER2-positive metastatic breast cancer, such that patients with prior taxane/trastuzumab therapy proceed to trastuzumab deruxtecan, rather than trastuzumab emtansine, for second-line therapy.

Margetuximab

Margetuximab is an Fc-engineered anti-HER2 immunoglobulin G monoclonal antibody that targets the same epitope as trastuzumab, with similar antiproliferative effects. Compared with trastuzumab, margetuximab was designed to increase binding affinity (in vitro) for the activating Fc-gamma receptor and decrease binding affinity for the inhibitory Fc-gamma receptor.

Evidence (margetuximab):

1. The primary PFS analysis from the phase III SOPHIA study (NCT02492711) led to the FDA approval of margetuximab with chemotherapy in patients with HER2-positive metastatic breast cancer who have received as least two previous anti-HER2 regimens, at least one of which was for metastatic disease. The open-label SOPHIA trial randomly assigned 536 patients in the ITT population to receive either margetuximab or trastuzumab. Both groups received investigator's choice of chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine). Eligible patients had disease progression after two or more previous anti-HER2 therapies and one to three lines of therapy for metastatic disease. All patients had received previous trastuzumab, all but one had received previous pertuzumab, and 91.2% had received prior ado-trastuzumab emtansine.[Level of evidence B1]
   • The sequential primary end points were PFS by central review followed by OS. Margetuximab improved primary PFS over trastuzumab with a 24% relative risk reduction (HR, 0.76; 95% CI, 0.59–0.98; P = .03) (median PFS, 5.8 months vs. 4.9 months, favoring margetuximab).
   • The median follow-up was 20.2 months. The median OS in the ITT population was not statistically different between the two treatment groups: 21.6 months in the margetuximab group and 21.9 months in the trastuzumab group (HR, 0.95; 95% CI, 0.77–1.17; P = .620).
   • Grade 3 or greater adverse events that occurred in at least 5% of patients included decreased neutrophil count and anemia in both groups, fatigue in the margetuximab group, and febrile neutropenia in the trastuzumab group.

Tyrosine kinase inhibitor therapy

The FDA has approved several tyrosine kinase inhibitors for metastatic HER2-positive breast cancer.

Tucatinib

Tucatinib is an oral tyrosine kinase inhibitor highly selective for the kinase domain of HER2 that minimally inhibits the epidermal growth factor receptor. A phase Ib trial in pretreated patients demonstrated activity when tucatinib was combined with trastuzumab and capecitabine.

Evidence (tucatinib):

1. The HER2CLIMB trial (NCT02614794) compared trastuzumab, capecitabine, and tucatinib with trastuzumab, capecitabine, and placebo in 632 patients who had previously been treated with trastuzumab, pertuzumab, and trastuzumab emtansine. Patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients with and without brain metastases were included.[Level of evidence A1]
   • The analysis of the primary study end point, PFS, demonstrated a median PFS in the tucatinib combination group of 7.8 months and 5.6 months in the placebo combination group (HR, 0.54; 95% CI, 0.42–0.71; P .001)
   • In an interim analysis conducted at the time of the PFS analysis, median OS was 21.9 months in the tucatinib combination group and 17.4 months in the placebo combination group (HR, 0.66; 95% CI, 0.50–0.88; P = .005)
   • Patients with and without brain metastases benefited from the tucatinib combination.
   • Grade 3 adverse events including diarrhea, palmar-plantar erythrodysesthesia syndrome, and elevated aminotransferase levels were more common in the tucatinib combination group but occurred in fewer than 15% of patients.

Neratinib

Neratinib is an irreversible pan-HER tyrosine kinase inhibitor (HER1, HER2, and HER4), which is approved in combination with capecitabine for the treatment of patients with advanced or metastatic HER2-positive breast cancer after two or more prior anti–HER2-based regimens in the metastatic setting.

Evidence (neratinib):

1. In the phase III NALA trial (NCT01808573), neratinib and capecitabine were compared with lapatinib and capecitabine in 621 patients with HER2-positive metastatic breast cancer who received two or more HER2-directed regimens in the metastatic setting. PFS and OS were co-primary end points. Secondary end points were time to intervention for metastatic central nervous system (CNS) disease and duration of response. Patients with stable or asymptomatic CNS disease were included.[Level of evidence B1]
   • Patients who received neratinib and capecitabine had significantly improved PFS (HR, 0.76; 95% CI, 0.63–0.93). OS between the two arms was not different.
   • The cumulative incidence of intervention for CNS disease was 22.8% (95% CI, 15.5%–30.9%) for patients who received neratinib versus 29.2% (95% CI, 22.5%–36.1%) for patients who received lapatinib.
   • Duration of response was 8.5 months for patients who received neratinib versus 5.6 months for patients who received lapatinib.
   • Diarrhea, nausea, palmar-plantar erythrodysesthesia, and vomiting were the most common adverse events, with grade 3 diarrhea occurring in 24.4% of patients who received neratinib. Antidiarrheal medications were required in the neratinib arm and used by 98.3% of those patients.
   • Quality-of-life scores were similar between the two groups.

Lapatinib

Lapatinib is an orally administered tyrosine kinase inhibitor of both HER2/neu and the epidermal growth factor receptor. Lapatinib plus capecitabine has shown activity in patients who have HER2-positive metastatic breast cancer that progressed after treatment with trastuzumab.

Evidence (lapatinib):

1. A nonblinded randomized trial (GSK-EGF100151 [NCT00078572]) compared the combination of capecitabine and lapatinib with capecitabine alone in 324 patients with locally advanced or metastatic disease that progressed after therapies that included anthracyclines, taxanes, and trastuzumab][Level of evidence A1]
   • Median time-to-disease progression in the lapatinib-plus-capecitabine arm was 8.4 months compared with 4.4 months in the capecitabine-alone arm (HR, 0.49; 95% CI, 0.34–0.71; P .001).
   • There was no difference in OS (HR, 0.92; 95% CI, 0.58–1.46; P = .72).[Level of evidence A1]
   • Patients on combination therapy were more likely to develop diarrhea, rash, and dyspepsia. For more information, see the Diarrhea section in Gastrointestinal Complications.
   • No data are available on quality of life or treatment after disease progression.

mTOR inhibition

Evidence of mTOR inhibitor activity in HER2-positive breast cancer was shown in the double-blind, placebo-controlled, phase III BOLERO-3 trial (NCT01007942).

1. In the BOLERO-3 trial, 569 patients with HER2-positive trastuzumab-resistant breast cancer, who had received previous taxane therapy, were randomly assigned to receive either everolimus plus trastuzumab plus vinorelbine, or placebo plus trastuzumab plus vinorelbine.[Level of evidence B1]
   • At median follow-up of 20.2 months, median PFS was 7.0 months in the everolimus group versus 5.78 months in the placebo group (HR, 0.78; 95% CI, 0.65–0.95; P = .0067).
   • Serious adverse events were reported in 117 patients (42%) in the everolimus group and 55 patients (20%) in the placebo group.
   • Final OS outcomes for this trial have not yet been reported.

Germline BRCA-Mutated Breast Cancer

For patients with metastatic breast cancer who carry a germline BRCA mutation, oral PARP inhibitors have shown activity. BRCA1 and BRCA2 are tumor suppressor genes that encode proteins involved in DNA repair through the homologous recombination repair pathway. PARP plays a critical role in DNA repair and has been studied as therapy for patients with breast cancer who harbor a germline BRCA mutation.

Olaparib

Evidence (olaparib):

1. The OlympiAD trial (NCT02000622) was a randomized, open-label, phase III trial that randomly assigned 302 patients, in a 2:1 ratio, to receive olaparib (300 mg bid) or standard therapy (either single-agent capecitabine, eribulin, or vinorelbine). All patients had received anthracycline and taxane previously in either the adjuvant or metastatic setting, and those with hormone receptor–positive disease had also received endocrine therapy previously.
   • Median PFS was significantly longer in the olaparib group than in the standard therapy group (7.0 months vs. 4.2. months; HR_{disease progression or death}, 0.58; 95% CI, 0.43–0.80; P .001).[Level of evidence A1]
   • OS did not differ between the two treatment groups with median time to death (HR_death, 0.90; 95% CI, 0.63–1.29; P = .57).
   • Olaparib was less toxic than standard therapy, with a rate of grade 3 or higher adverse events of 36.6% in the olaparib group and 50.5% in the standard therapy group, with anemia, nausea, vomiting, fatigue, headache, and cough occurring more frequently with olaparib; neutropenia, palmar-plantar erythrodysesthesia, and liver-function test abnormalities occurred more commonly with chemotherapy.
   • Of note, subset analysis suggested that PFS improvement with olaparib appeared greater in the TNBC subgroup (HR, 0.43; 95% CI, 0.29–0.63) than in the hormone receptor–positive subgroup (HR, 0.82; 95% CI, 0.55–1.26).

Talazoparib

Evidence (talazoparib):

1. The EMBRACA trial (NCT01945775) was a randomized, open label, phase III trial that assigned 431 patients with a deleterious germline BRCA or BRCA2 mutation and locally advanced or metastatic breast cancer in a 2:1 ratio to talazoparib (1 mg PO qd) or standard single-agent chemotherapy of the physician’s choice (eribulin, capecitabine, gemcitabine, or vinorelbine). All patients had received previous treatment with an anthracycline, taxane, or both. Patients had received three or fewer lines of cytotoxic chemotherapy for advanced breast cancer. Previous platinum therapy in the setting of early breast cancer was permitted if it was completed at least 6 months before progressive disease or if there was no objective progression while on platinum therapy in the advanced-disease setting. Hormone receptor–positive and hormone receptor–negative patients were enrolled.
   • Median PFS was significantly longer in the talazoparib group than in the standard therapy group (8.6 months vs. 5.6 months; HR_{disease progression or death}, 0.54; 95% CI, 0.41–0.71; P .001).
   • Benefits were observed in all subgroups, although CIs were wide in the subgroup of patients who had received previous platinum therapy.
   • Median OS did not differ between the two groups (22.3 months vs. 19.5 months; HR_death, 0.76; 95% CI, 0.55–1.06; P = .11), although survival data are not yet mature.
   • The primary toxicity observed with talazoparib was myelosuppression, especially anemia.
   • Patient-reported outcome data demonstrated more favorable effects of talazoparib than standard chemotherapy on quality-of-life measures.

High Tumor Mutational Burden

An established biomarker for checkpoint inhibitor immunotherapy is high somatic tumor mutational burden (TMB). TMB is the number of mutations within the coding region of a tumor genome and is reported as mutations per megabase (Mut/Mb). TMB is high (≥10) in approximately 5% of breast cancers. Highest median TMB is noted in triple-negative tumors and lowest median TMB is noted in ER-positive/HER2-negative patients.

Pembrolizumab

Evidence (pembrolizumab):

1. The FDA approved pembrolizumab for the treatment of metastatic solid tumors with a TMB of at least 10 Mut/Mb, based on the KEYNOTE-158 trial.]
   • KEYNOTE-158 (NCT02628067) was a multicohort, open-label, nonrandomized, phase II multinational study. Patients had metastatic solid malignancies, treated with at least one previous line of therapy. Participants received pembrolizumab 200 mg intravenously every 3 weeks for up to 35 cycles. TMB was assessed in formalin-fixed paraffin-embedded tumor samples using the FoundationOne CDx assay. A total of 105 of 805 evaluable patients had high TMB (≥10 Mut/Mb).
   • The primary outcome was objective response rate. Objective responses were observed in 30 of 102 patients (29%) in the TMB-high group and 43 of 688 patients (6%) in the non-TMB-high group. Grade 3 to 5 treatment-related adverse events occurred in 16 patients. One patient died of pneumonia that was assessed by the investigator to be treatment related.
2. The TAPUR study (NCT02693535) was a phase II basket trial done to identify the efficacy of commercially available targeted agents in patients with advanced cancers and genomic alterations known to be drug targets. TAPUR results from patients with metastatic breast cancer and high TMB have been reported.[Level of evidence C3]
   • The study enrolled 28 patients with metastatic breast cancer and high TMB. TMB ranged from 9 to 37 Mut/Mb.
   • The primary end point was disease control (objective response or stable disease for ≥16 weeks). Disease control was noted in 37% of patients, with objective response noted in 21% of patients.
   • The median PFS was 10.6 weeks and the median OS was 30.6 weeks.

Chemotherapy for Metastatic Breast Cancer

Patients receiving hormone therapy whose tumors have progressed are candidates for cytotoxic chemotherapy. There are no data suggesting that combination therapy results in an OS benefit over single-agent therapy. Patients with hormone receptor–negative tumors and those with visceral metastases or symptomatic disease are also candidates for cytotoxic agents.

Single agents that have shown activity in metastatic breast cancer include the following:

• Anthracyclines.
  • Doxorubicin.
  • Epirubicin.
  • Liposomal doxorubicin.
  • Mitoxantrone.
• Taxanes.
  • Paclitaxel.
  • Docetaxel.
  • Albumin-bound nanoparticle paclitaxel (ABI-007 or Abraxane).
• Alkylating agents.
  • Cyclophosphamide.
• Fluoropyrimidines.
  • Capecitabine.
  • Fluorouracil (5-FU).
• Antimetabolites.
  • Methotrexate.
• Vinca alkaloids.
  • Vinorelbine.
  • Vinblastine.
  • Vincristine.
• Platinum.
  • Carboplatin.
  • Cisplatin.
• Other.
  • Gemcitabine.
  • Mitomycin.
  • Eribulin mesylate.
  • Ixabepilone.

Combination regimens that have shown activity in metastatic breast cancer include the following:

• AC: Doxorubicin and cyclophosphamide.
• EC: Epirubicin and cyclophosphamide.
• Docetaxel and doxorubicin.
• CAF: Cyclophosphamide, doxorubicin, and 5-FU.
• CMF: Cyclophosphamide, methotrexate, and 5-FU.
• Doxorubicin and paclitaxel.
• Docetaxel and capecitabine.
• Vinorelbine and epirubicin.
• Capecitabine and ixabepilone.
• Carboplatin and gemcitabine.
• Gemcitabine and paclitaxel.

There are no data suggesting that combination therapy results in an OS benefit over single-agent therapy. An ECOG intergroup study (E-1193) randomly assigned patients to receive paclitaxel and doxorubicin, given both as a combination and sequentially. Although response rate and time to disease progression were both better for the combination, survival was the same in both groups.[Level of evidence A1]

The selection of therapy in individual patients is influenced by the following:

• Rate of disease progression.
• Presence or absence of comorbid medical conditions.
• Physician/patient preference.

Sequential use of single agents or combinations can be used for patients who relapse with metastatic disease. Combination chemotherapy is often given if there is evidence of rapidly progressive disease or visceral crisis. Combinations of chemotherapy and hormone therapy have not shown an OS advantage over the sequential use of these agents. A systematic review of 17 randomized trials found that the addition of one or more chemotherapy drugs to a chemotherapy regimen in the attempt to intensify the treatment improved tumor response but had no effect on OS.[Level of evidence A1]

Decisions regarding the duration of chemotherapy may consider the following:

• Patient preference and goals of treatment.
• Presence of toxicities from previous therapies.
• Availability of alternative treatment options.

The optimal time for patients with responsive or stable disease has been studied by several groups. For patients who attain a complete response to initial therapy, two randomized trials have shown a prolonged DFS after immediate treatment with a different chemotherapy regimen compared with observation and treatment upon relapse.[Level of evidence A1] Neither of these studies, however, showed an improvement in OS for patients who received immediate treatment; in one of these studies. survival was actually worse in the group that was treated immediately. Similarly, no difference in survival was noted when patients with partial response or stable disease after initial therapy were randomly assigned to receive either a different chemotherapy versus observation or a different chemotherapy regimen given at higher versus lower doses.[Level of evidence A1] However, 324 patients who achieved disease control were randomly assigned to maintenance chemotherapy or observation. Patients who received maintenance chemotherapy (paclitaxel and gemcitabine) had improved PFS at 6 months and improved OS. This was associated with an increased rate of adverse events.[Level of evidence A1] Because there is no standard approach for treating metastatic disease, patients requiring second-line regimens are good candidates for clinical trials.

Cardiac toxic effects with anthracyclines

The potential for anthracycline-induced cardiac toxic effects should be considered in the selection of chemotherapeutic regimens for selected patients. Recognized risk factors for cardiac toxicity include the following:

• Advanced age.
• Previous chest-wall radiation therapy.
• Previous anthracycline exposure.
• Hypertension and known underlying heart disease.
• Diabetes.

The cardioprotective drug dexrazoxane decreased the risk of doxorubicin-induced cardiac toxicity in patients in controlled studies. The use of this agent has permitted patients to receive higher cumulative doses of doxorubicin and has allowed patients with cardiac risk factors to receive doxorubicin. The risk of cardiac toxicity may also be reduced by giving doxorubicin as a continuous intravenous infusion. The American Society of Clinical Oncology guidelines suggest the use of dexrazoxane in patients with metastatic cancer who have received a cumulative dose of doxorubicin of 300 mg/m2 or more when further treatment with an anthracycline is likely to be of benefit. Dexrazoxane has a similar protective effect in patients receiving epirubicin.

Surgery

Surgery may be indicated for select patients. For example, patients may need surgery if the following issues occur:

• Fungating/painful breast lesions (mastectomy).
• Parenchymal brain or vertebral metastases with spinal cord compression.
• Isolated lung metastases.
• Pathological (or impending) fractures.
• Pleural or pericardial effusions.

Radiation Therapy

Radiation therapy has a major role in the palliation of localized symptomatic metastases. Indications for external-beam radiation therapy include the following:

• Painful bony metastases.
• Unresectable central nervous system metastases (i.e., brain, meninges, and spinal cord).
• Bronchial obstruction.
• Fungating/painful breast or chest wall lesions.
• After surgery for decompression of intracranial or spinal cord metastases.
• After fixation of pathological fractures.

Strontium chloride Sr 89, a systemically administered radionuclide, can be given for palliation of diffuse bony metastases.

Bone-Modifying Therapy

The use of bone-modifying therapy to reduce skeletal morbidity in patients with bone metastases should be considered. Results of randomized trials of pamidronate and clodronate in patients with bony metastatic disease show decreased skeletal morbidity.[Level of evidence A3] Zoledronate has been at least as effective as pamidronate.

The optimal dosing schedule for zoledronate was studied in CALGB-70604 (Alliance; NCT00869206), which randomly assigned 1,822 patients, 855 of whom had metastatic breast cancer, to receive zoledronic acid every 4 weeks or every 12 weeks. Skeletal-related events were similar in both groups, with 260 patients (29.5%) in the zoledronate every-4-week dosing group and 253 patients (28.6%) in the zoledronate every-12-week dosing group experiencing at least one skeletal-related event (risk difference of -0.3% [1-sided 95% CI, -4% to infinity]; P .001 for noninferiority).[Level of evidence B1] This study suggests that the longer dosing interval of zoledronate every 12 weeks is a reasonable treatment option.

The monoclonal antibody denosumab inhibits the receptor activator of nuclear factor kappa beta ligand (RANKL). A meta-analysis of three phase III trials (NCT00321464, NCT00321620, and NCT00330759) comparing zoledronate versus denosumab for management of bone metastases suggests that denosumab is similar to zoledronate in reducing the risk of a first skeletal-related event.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria.

A recent drug approval by the Food and Drug Administration (FDA) marks another milestone in the treatment of cancer. The action by FDA expands the growing list of approved uses for the immune checkpoint inhibitor pembrolizumab (Keytruda).

In this case, it is now approved to treat some adults or children with advanced cancer, regardless of the type of cancer they have, if the patient’s tumor has a large number of genetic mutations—also called a tumor mutational burden-high (TMB-H) cancer.

Because this is what is known as an accelerated approval, this new indication for pembrolizumab must be confirmed in additional studies. There also are a number of factors for oncologists to consider when deciding whether this treatment is a good option for their patients. I’ll return to those issues later.

But from a broader perspective, this new approval represents a continued march toward the use of genomics to guide cancer treatment, including for children with cancer.

It reinforces the idea that, as a routine matter, oncologists should be discussing tumor genomic testing (or biomarker testing) with their patients with advanced cancer, in particular those for whom there are no effective standard-of-care treatments. This applies to testing not only for biomarkers like TMB that might predict response to immunotherapies, but also for genetic biomarkers that identify those who might benefit from a specific targeted cancer treatment.

This type of biomarker testing has helped patients with many types of cancers, even hard-to-treat cancers such as brain and pancreatic, by identifying therapies that might be more effective and less toxic for them. But it’s important to note that biomarker testing has important limitations and, clearly, there are many patients who do not benefit from this testing.

This new approval for pembrolizumab marks the fourth time that FDA has approved a drug to be used in a “tissue-agnostic” manner—that is, for any cancer type—based solely on the results of biomarker testing. Given that there are now many approved cancer therapies whose use requires genomic biomarker testing (via what are known as “companion diagnostics”), I believe that genomic biomarker testing should be strongly considered for all patients with advanced cancers for which no known effective treatments currently exist.

Given this increasing role of genomic biomarker testing in cancer care, it is important to note that many patients do not benefit from molecularly targeted treatments because they are never offered that testing.

For example, a recent review in lung cancer, where genomic testing is particularly critical for selecting the most appropriate treatments, found that 10%–40% of patients are not being tested for molecular alterations that predict response to FDA-approved therapies, even though such testing is recommended by clinical guidelines.

This lack of biomarker testing, which can lead to the use of treatments with the potential to markedly improve how long patients live, is concerning. At NCI, we’re particularly worried about the possibility that less genomic biomarker testing in patients from underserved populations could further exacerbate existing cancer-related health disparities.

Learning about Cancer and Tumor Mutational Burden

Having a TMB-H tumor is not a guarantee that pembrolizumab will be effective, but it is an opportunity, based on a robust evidence base that was developed in part by NCI-supported research and investigators.

It’s also important to note that this is not the first tissue-agnostic FDA approval for pembrolizumab. In May 2017, it was approved to treat any cancer that has specific genetic alterations that affect a cell’s ability to repair damaged DNA, known as microsatellite instability high (MSI-H) tumors. MSI-H and TMB-H are related, with most MSI-H tumors also showing increased TMB. The converse, however, is not true—that is, many TMB-H tumors are not MSI-H.

Moreover, MSI status does not necessarily need to be established through extensive tumor genomic testing, whereas TMB status generally does. So having a drug approval based on TMB is important, because it is more common in tumors than MSI-H, and thus should promote far greater adoption of tumor genomic testing.

Cancer cells that are MSI-H or TMB-H tend to produce a large number of mutant proteins, which are then often displayed on the cells' surface as “neoantigens.” Since normal cells do not display such mutant proteins, the production of neoantigens can be a signal that draws the immune system’s attention. That, in turn, can increase the likelihood that treatments like pembrolizumab, which strengthen the anti-tumor immune response, will help immune cells kill those tumors.

In the clinical trial on which FDA based this new approval, called KEYNOTE-158, nearly 30% of patients with TMB-H tumors had a response to treatment—meaning they experienced at least 30% reduction in the size of their tumors—including some whose tumors disappeared completely. In contrast, only 6% of patients who were not TMB-H exhibited a response to pembrolizumab. In half of the participants who responded to the treatment, their tumors did not begin to grow again for at least 2 years!

Although patients on KEYNOTE-158 were not randomly assigned to an alternative therapy or placebo, these types of sustained treatment responses among patients with solid tumors are extremely rare with standard chemotherapies.

In addition, most participants in KEYNOTE-158 had received numerous other therapies and had no remaining treatment options known to be effective against their cancers. That’s an important point, because FDA’s new approval applies only to people with advanced cancer without any other standard treatment options.

In general, tumors in children and young adults with cancer do not have a large number of mutations and are therefore less likely to be TMB-H. But some tumors that arise in children are TMB-H, and this approval now means that such young patients have a new, potentially meaningful treatment option available to them as well.

Contribution of Genomics Research

The role of NCI-supported research in helping to identify TMB as a biomarker of immunotherapy response is particularly gratifying.

For example, although TMB did not even exist as a concept at the time that The Cancer Genome Atlas (TCGA) was launched, researchers used TCGA data to perform wide-scale analyses of the relationship between tumor mutation numbers and immunotherapy response in the first place. The finding is another example of how building large, high-quality, and diverse sets of research data and making them publicly available can yield unexpected insights that lead to meaningful advances in treatment.

In addition, NCI has had a sustained and successful partnership with Foundation Medicine, the company that developed FoundationOne CDx, the test used to identify patients with TMB-H tumors for this approval. NCI-supported researchers made important contributions to the development of the technologies used by this test.

As should be expected, though, this is an extremely complicated area of research. Even with the best tests, measuring TMB and deciding what that measurement means for individual patients—in particular, estimating their likelihood of response to immunotherapy—is far from straightforward.

So NCI has been working on other fronts to make further advancements that build on the use of TMB, MSI, and other biomarkers to help guide treatment decisions. For example, NCI has partnered with Friends of Cancer Research and several other organizations on the TMB Harmonization Project, which is working to standardize how mutational burden is measured in tumors using different technologies and approaches. This project will help to ensure that TMB is used in the most effective manner possible to guide decisions about patient care.

NCI is also supporting research through the Cancer MoonshotSM on the impact of TMB and other biomarkers on how patients respond to immunotherapy. That effort is being carried out by researchers who are part of the Moonshot-funded Cancer Immune Monitoring and Analysis Centers and through a large public–private partnership called the PACT initiative.

Good News, But More To Learn

This new approval is exciting, and it will have an immediate impact on patient care. However, it’s important to stress that TMB status is just one piece of information about a tumor. Its relevance to treatment may depend on a number of factors, including a patient’s physical ability and willingness to tolerate further treatment.

In KEYNOTE-158, most patients with TMB-H tumors didn’t benefit from pembrolizumab, and a small percentage of patients whose tumors had a low TMB did respond to treatment. This suggests we still have more to learn in order to predict who will respond to immunotherapy drugs.

There is evidence, for example, that the extent of TMB required to improve the likelihood of responding to immunotherapy may vary from cancer to cancer. Information such as whether cancer type influences treatment response is important, because no cancer treatment comes without side effects, including financial toxicity.

Larger studies of pembrolizumab, which are required by FDA as part of an accelerated approval, and other research being supported by NCI can hopefully provide answers to these questions. Those answers can then help patients and their doctors have informed discussions and engage in a true process of shared decision making. For patients with advanced cancer and their families, such discussions are vital.

Especially during these hectic times, one can become cynical. But as I’ve said previously, NCI is committed to addressing the challenges of the COVID-19 pandemic while also supporting the research required to address the most pressing needs for those with cancer and heralding important progress. The expanding role and value of immunotherapy as a cancer treatment is good news for patients, and that’s something I think is worth celebrating.

On June 16, 2020, the Food and Drug Administration granted accelerated approval to pembrolizumab (KEYTRUDA, Merck & Co., Inc.) for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.

Today, the FDA also approved the FoundationOneCDx assay (Foundation Medicine, Inc.) as a companion diagnostic for pembrolizumab.

Efficacy was investigated in a prospectively-planned retrospective analysis of 10 cohorts of patients with various previously treated unresectable or metastatic TMB-H solid tumors enrolled in a multicenter, non-randomized, open-label trial, KEYNOTE-158 (NCT02628067). Patients received pembrolizumab 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression.

The main efficacy outcome measures were overall response rate (ORR) and duration of response (DoR) in patients who have received at least one dose of pembrolizumab as assessed by blinded independent central review according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

A total of 102 patients (13%) had tumors identified as TMB-H, defined as TMB ≥10 mut/Mb. The ORR for these patients was 29% (95% CI: 21,39), with a 4% complete response rate and 25% partial response rate. The median DoR was not reached, with 57% of patients having response durations ≥12 months and 50% of patients having response durations ≥24 months.

Adverse reactions occurring in patients with TMB‑H cancer enrolled in KEYNOTE-158 were similar to those occurring in patients with other solid tumors who received pembrolizumab as a single agent. The most common adverse reactions to pembrolizumab are fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. Pembrolizumab is associated with immune-mediated side effects, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, and skin adverse reactions.

The prescribing information for pembrolizumab includes a “Limitation of Use” stating that the safety and effectiveness of pembrolizumab in pediatric patients with TMB-H central nervous system cancers have not been established.

The recommended pembrolizumab dosage regimen for TMB-H solid tumors is 200 mg every 3 weeks or 400 mg every 6 weeks for adults; 2 mg/kg (up to a maximum of 200 mg) every 3 weeks for pediatric patients.