Clinical Advances in Hematology & Oncology

January 2022 - Volume 20, Issue 1, Supplement 4

Highlights in Metastatic Breast Cancer From the 2021 San Antonio Breast Cancer Symposium

Joyce A. O’Shaughnessy, MD
Celebrating Women Chair in Breast Cancer Research, Baylor University Medical Center 
Chair, Breast Cancer Program, Texas Oncology
US Oncology 
Dallas, Texas

A Review of Selected Presentations From the 2021 SABCS 

December 7-10, 2021 San Antonio, Texas

Updated Data From AMEERA-1: Phase 1/2 Study of Amcenestrant (SAR439859), an Oral Selective Estrogen Receptor Degrader, Combined With Palbociclib in Postmenopausal Women With ER+/HER2– Advanced Breast Cancer

For patients with advanced breast cancer that is estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative, standard-of-care therapy consists of endocrine therapy in combination with an inhibitor of cyclin-dependent kinase 4/6 (CDK4/6).1,2 However, up to 40% of patients develop resistance to endocrine therapy. Amcenestrant is an oral selective estrogen receptor degrader (SERD). Arm 2 of the open-label phase 1/2 AMEERA-1 trial investigated the efficacy and safety of amcenestrant (200 mg/day) plus palbociclib (125 mg, 21 days on/7 days off) in patients with ER-positive/HER2-negative advanced breast cancer that had progressed during treatment with endocrine therapy in the adjuvant or advanced setting.3-5 

The 39 patients were a median age of 59 years (range, 33-86 years).5 Most patients (89.7%) had visceral metastases, and all patients had exhibited resistance to prior endocrine therapy. 

After a median follow-up of 14.8 months, the objective response rate (ORR) was 32.4% (11/34), and the clinical benefit rate was 73.5% (25/34; Table 1). The median progression-free survival (PFS) was 14.7 months, and the 12-month PFS rate was 59.4% (Figure 1). The median time to first response was 16.3 weeks (range, 8-32 weeks). Two patients experienced 100% shrinkage of their target lesions. ESR1 mutations were more common among patients whose most recent prior therapy was in the advanced setting (43.3% [13/30]) compared with patients whose most recent prior therapy was in the neoadjuvant setting (6.7% [1/15]). In most patients with the baseline ESR1 mutation, allele frequency decreased after 2 cycles of study treatment.

The median relative dose intensity was 99.6% for amcenestrant and 97.4% for palbociclib. Two patients discontinued treatment because of treatment-related adverse events (AEs). Treatment-related AEs of grade 3 or higher occurred in 12.8% (amcenestrant-related) and 48.7% (palbociclib-related) of patients. 

References

1. Cardoso F, Paluch-Shimon S, Senkus E, et al. 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5). Ann Oncol. 2020;31(12):1623-1649.

2. Manohar PM, Davidson NE. Updates in endocrine therapy for metastatic breast cancer. Cancer Biol Med. 2021. 2021;j.issn.2095-3941.2021.0255

3. Chandarlapaty S, Linden HM, Neven P, et al. AMEERA-1: phase 1/2 study of amcenestrant (SAR439859), an oral selective estrogen receptor (ER) degrader (SERD), with palbociclib (palbo) in postmenopausal women with ER+/ human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC) [ASCO abstract 1058]. J Clin Oncol. 2021;39(suppl 15).

4. Chandarlapaty S, Linden HM, Neven P, et al. AMEERA-1: subgroup analyses of phase I/II study of amcenestrant (SAR439859), an oral selective estrogen receptor (ER) degrader (SERD), with palbociclib in postmenopausal women with ER+/ human epidermal growth factor receptor 2-negative (HER2e) advanced breast cancer (aBC) [ESMO abstract 264P]. Ann Oncol. 2021;32(suppl 5).

5. Chandarlapaty S, Linden HM, Neven P, et al. Updated data from AMEERA-1: phase 1/2 study of amcenestrant (SAR439859), an oral selective estrogen receptor degrader, combined with palbociclib in postmenopausal women with ER+/HER2- advanced breast cancer. Abstract presented at: the 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract 1-17-11.

Overall Survival Subgroup Analysis by Metastatic Site From the Phase 3 MONALEESA-2 Study of First-Line Ribociclib + Letrozole in Postmenopausal Patients With Advanced HR+/HER2– Breast Cancer

The phase 3 MONALEESA-2 study investigated letrozole combined with ribociclib vs letrozole combined with placebo in postmenopausal women with hormone receptor–positive/HER2-negative advanced breast cancer.1,2 Enrolled patients had not received prior therapy for their advanced disease; however, prior use of adjuvant or neoadjuvant endocrine therapy was allowed. The trial randomly assigned 668 patients to receive ribociclib at 600 mg daily or placebo on a schedule of 3 weeks on, 1 week off, plus letrozole at 2.5 mg daily. The primary endpoint was PFS assessed locally and based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Overall survival (OS) was a key secondary endpoint.3 

After a median follow-up of 79.7 months, the median OS was 63.9 months in the ribociclib arm vs 51.4 months in the control arm (hazard ratio [HR], 0.76; 95% CI, 0.63-0.93; P=.004).2 The median OS achieved with ribociclib plus letrozole was the longest reported in any phase 3 clinical trial for advanced breast cancer and the first to exceed 5 years. The estimated 6-year OS rates were 44.2% with ribociclib vs 32.0% with placebo. 

Exploratory analyses evaluated outcomes in prespecified subgroups.1 In patients with metastases in the bone only, the 5-year survival rate was 58.6% with ribociclib vs 47.1% with placebo (Figure 2). Ribociclib also conferred a benefit over placebo in patients without bone-only metastases (5-year OS, 50.6% vs 43.0%; HR, 0.81; 95% CI, 0.54-1.24). Among patients with metastases in the liver only, the 5-year OS was 48.2% with ribociclib vs 45.4% with placebo. At 6 years, OS showed a greater difference between the groups: 40.5% with ribociclib vs 31.2% with placebo. Among patients without liver-only metastases, the 5-year OS was 55.2% with ribociclib vs 48.3% with placebo, and the 6-year OS was 46.8% vs 35.7%, respectively (HR, 0.77; 95% CI, 0.62-0.97). Among patients with metastases in the liver or lung, the 5-year OS was 48.2% with ribociclib vs 45.4% with placebo, and the 6-year OS rates were 40.5% vs 31.2%, respectively (HR, 0.81; 95% CI, 0.62-1.05). Among patients without liver or lung metastases, ribociclib also conferred a survival benefit (5-year OS, 57.1% vs 41.9%; 6-year OS, 48.6% vs 33.2%; HR, 0.71; 95% CI, 0.53-0.96). 

The analysis also showed an OS benefit with ribociclib vs placebo in the subset of patients with fewer than 3 metastatic sites and those with 3 or more metastatic sites; in patients who had received prior adjuvant or neoadjuvant chemotherapy, and in those who had not; in patients who had received prior aromatase inhibitor therapy; in patients who had received prior treatment with tamoxifen (with or without an aromatase inhibitor); and in patients with no prior endocrine therapy. Ribociclib has consistently demonstrated an OS benefit in the MONALEESA-2, -3, and -7 trials, irrespective of endocrine therapy partner, line of therapy, or menopausal status.4-6

References

1. O’Shaughnessy J, Stemmer SM, Burris HA, et al. Overall survival subgroup analysis by metastatic site from the phase 3 MONALEESA-2 study of first-line ribociclib + letrozole in postmenopausal patients with advanced HR+/HER2- breast cancer. Abstract presented at: the 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS2-01.

2. Hortobagyi G, Stemmer SM, Burris HA, et al. Overall survival (OS) results from the phase III MONALEESA-2 (ML-2) trial of postmenopausal patients (pts) with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2−) advanced breast cancer (ABC) treated with endocrine therapy (ET) ± ribociclib (RIB) [ESMO abstract LBA17_PR]. Ann Oncol. 2021;32(suppl 5).

3. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247.

4. Im SA, Lu YS, Bardia A, et al. Overall survival with ribociclib plus endocrine therapy in breast cancer. N Engl J Med. 2019;381(4):307-316.

5. Slamon DJ, Neven P, Chia S, et al. Overall survival with ribociclib plus fulvestrant in advanced breast cancer. N Engl J Med. 2020;382(6):514-524.

6. Yardley DA, Nusch A, Yap YS, et al. Overall survival (OS) in patients (pts) with advanced breast cancer (ABC) with visceral metastases (mets), including those with liver mets, treated with ribociclib (RIB) plus endocrine therapy (ET) in the MONALEESA (ML) -3 and -7 trials [ASCO abstract 1054]. J Clin Oncol. 2020;38(suppl 15).

Datopotamab Deruxtecan in Advanced/Metastatic HER2– Breast Cancer: Results From the Phase 1 TROPION-PanTumor01 Study

Few treatment options are available for patients with advanced triple-negative breast cancer (TNBC) that has progressed on systemic therapy. TROP2 is a calcium signal transducer that promotes the growth of tumor cells and is highly expressed in breast cancer and other malignancies.1,2 In breast and other tumors, increased TROP2 expression correlates with reduced OS. Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate that consists of a humanized, anti-TROP2, immunoglobulin G1 monoclonal antibody with a topoisomerase I inhibitor covalently attached by means of a cleavable, tetrapeptide-based linker.3 The antibody-drug conjugate delivers a high-potency payload with an optimized drug:antibody ratio and a short systemic half-life. TROPION-PanTumor01 is a phase 1 study that evaluated the safety and efficacy of Dato-DXd among patients with various solid tumor types and relapsed or refractory disease.4-6 Patients were not selected based on TROP2 expression. Enrolled patients were adults with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and measurable disease according to RECIST 1.1.7 The study included 44 patients with TNBC, and these patients were treated with Dato-DXd at a dose of 8 mg/kg (n=2) or 6 mg/kg (n=42) on day 1 of every 3-week cycle. The primary objectives were the safety and tolerability of the study treatment.

At baseline, the 44 patients with TNBC were a median age of 53 years (range, 32-82 years).5 Five patients (11%) had brain metastases. The median number of prior therapies was 3 (range, 1-10 prior therapies), and 30% of patients had received prior treatment with a topoisomerase I–based antibody-drug conjugate. After a median follow-up of 7.6 months (range, 4-13 months), the ORR was 34% by blinded independent central review, and the disease control rate was 77% (Figure 3). Among 27 patients without prior exposure to a topoisomerase I–based antibody-drug conjugate, the ORR was 52%, and the disease control rate was 81%. The median duration of response was not reached (range, 3.7-7.4+ months). 

Treatment-related AEs of grade 3 or higher were observed in 23% of patients, 18% required a dose reduction owing to an AE, and 2% discontinued treatment owing to an AE. No new safety signals emerged. A phase 3 trial of Dato-DXd in patients with TNBC is planned.  

References

1. Ambrogi F, Fornili M, Boracchi P, et al. Trop-2 is a determinant of breast cancer survival. PLoS One. 2014;9(5):e96993.

2. Zeng P, Chen MB, Zhou LN, Tang M, Liu CY, Lu PH. Impact of TROP2 expression on prognosis in solid tumors: a systematic review and meta-analysis. Sci Rep. 2016;6:33658.

3. Okajima D, Yasuda S, Maejima T, et al. Datopotamab deruxtecan, a novel TROP2-directed antibody-drug conjugate, demonstrates potent antitumor activity by efficient drug delivery to tumor cells. Mol Cancer Ther. 2021;20(12):2329-2340.

4. ClinicalTrials.gov. First-in-human study of DS-1062a for advanced solid tumors (TROPION-PanTumor01). https://clinicaltrials.gov/ct2/show/NCT03401385. Identifier: NCT03401385. Accessed January 7, 2021.

5. Krop I, Juric D, Shimizu T, et al. Datopotamab deruxtecan in advanced/metastatic HER2- breast cancer: results from the phase 1 TROPION-PanTumor01 study. Abstract presented at: the 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS1-05.

6. Bardia A. Datopotamab deruxtecan (Dato-DXd), a TROP2-directed antibody-drug conjugate (ADC), for triple-negative breast cancer (TNBC): preliminary results from an ongoing phase 1 trial [ESMO abstract LBA4]. Ann Oncol. 2021;32(suppl 2).

7. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247.

Correlative Analysis of Overall Survival by Intrinsic Subtype Across the MONALEESA-2, -3, and -7 Studies of Ribociclib + Endocrine Therapy in Patients With HR+/HER2− Advanced Breast Cancer

A retrospective, exploratory analysis investigated the association between intrinsic subtype and OS in patients treated with ribociclib plus endocrine therapy in the MONALEESA-2, -3, and -7 trials.1-4 Intrinsic subtyping was performed with a set of 152 genes selected through the original Prediction Analysis of Microarray 50 (PAM50) training set and based on the ability to identify the PAM50 subtype in 48 independent tumors. The retrospective analysis included 585 samples from patients treated with ribociclib plus endocrine therapy and 412 from patients treated with placebo plus endocrine therapy. Seventy-one percent (71%) of samples were from primary tumors. In the data set pooled from the 3 MONALEESA trials, subtypes included luminal A (54.4%), luminal B (27.9%), HER2-enriched (14.7%), and basal-like (3%).

Ribociclib showed an OS benefit in the 997 patients included in the retrospective analysis (HR, 0.75; 95% CI, 0.63-0.89; P=.0012), and a similar OS benefit among the intention-to-treat population of 2066 patients (HR, 0.76; 95% CI, 0.67-0.86; P<.0001).1 Results in the placebo arm reflected the strong association between intrinsic subtype and OS. In this group, the median OS was 54.6 months with the luminal A subtype, 44.9 months with the luminal B subtype, 29.4 months with the HER2-enriched subtype, and 21.2 months with the basal-like subtype. Compared with placebo, the median OS was prolonged with ribociclib treatment in patients with the luminal A (68.0 months), luminal B (58.8 months), and HER2-enriched (40.3 months) subtypes, but not the basal-like subtype (19.4 months). In multivariable models, the intrinsic subtype was associated with OS. Using luminal A as the referent population, the adjusted HR for death in the placebo arm was 1.47 for the luminal B subtype (95% CI, 1.08-2.00; P=.013), 2.87 for the HER2-enriched subtype (95% CI, 1.93-4.26; P<.0001), and 2.35 for the basal-like subtype (95% CI, 1.20-4.58; P=.012). In patients treated with ribociclib, the adjusted HR was 1.16 for the luminal B subtype (95% CI, 0.86-1.57; P=.32), 1.83 for the HER2-negative enriched subtype (95% CI, 1.33-2.52; P=.00023), and 7.06 for the basal-like subtype (95% CI, 3.73-13.40; P<.0001). Kaplan-Meier curves also demonstrated the benefit with ribociclib vs placebo in the subtypes of luminal A (HR, 0.75; P=.021; Figure 4), luminal B (HR, 0.69; P=.023), and HER2-enriched (HR, 0.60; P=.018), but not in the basal-like subtype (HR, 1.89; P=.148). The interaction test between tumor subtype and treatment arm was significant in the overall analysis (P=.016), but not when the basal-like subtype was removed (P=.47). 

References

1. Carey LA, Solovieff N, André F, et al. Correlative analysis of overall survival by intrinsic subtype across the MONALEESA-2, -3, and -7 studies of ribociclib + endocrine therapy in patients with HR+/HER2− advanced breast cancer. Abstract presented at: the 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS2-00.

2. Hortobagyi G, Stemmer SM, Burris HA, et al. Overall survival (OS) results from the phase III MONALEESA-2 (ML-2) trial of postmenopausal patients (pts) with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2−) advanced breast cancer (ABC) treated with endocrine therapy (ET) ± ribociclib (RIB) [ESMO abstract LBA17_PR]. Ann Oncol. 2021;32(suppl 5).

3. Im SA, Lu YS, Bardia A, et al. Overall survival with ribociclib plus endocrine therapy in breast cancer. N Engl J Med. 2019;381(4):307-316.

4. Slamon DJ, Neven P, Chia S, et al. Overall survival with ribociclib plus fulvestrant in advanced breast cancer. N Engl J Med. 2020;382(6):514-524.

Elacestrant, an Oral Selective Estrogen Receptor Degrader, vs Investigator’s Choice of Endocrine Monotherapy for ER+/HER2– Advanced/Metastatic Breast Cancer Following Progression on Prior Endocrine and CDK4/6 Inhibitor Therapy: Results of the EMERALD Phase 3 Trial

Most patients with ER-positive/HER2-negative metastatic breast cancer eventually progress on their first-line therapy. The poor median PFS associated with fulvestrant monotherapy as second-line and later treatment underscores the need for better endocrine therapy to treat this patient population.1-3 Elacestrant (RAD1901) is an oral SERD that reduces the downstream activity of the ER, inhibiting estradiol-dependent cellular proliferation more potently than fulvestrant.4 In a phase 1 study of postmenopausal women with ER-positive/HER2-negative metastatic breast cancer, elacestrant yielded confirmed partial responses (PRs) in heavily pretreated patients.5

The phase 3 EMERALD study compared elacestrant monotherapy vs the investigator’s choice of therapy in previously treated men and postmenopausal women diagnosed with advanced or metastatic, ER-positive/HER2-negative breast cancer.6 Eligible patients had progressed on or relapsed after treatment with 1 or 2 lines of endocrine therapy for advanced disease. Patients had experienced disease progression during treatment with a CDK4/6 inhibitor. Previous treatment with chemotherapy was limited to 1 line. Patients in the experimental arm received elacestrant at 400 mg daily. Patients in the control arm received fulvestrant, anastrozole, letrozole, or exemestane. The trial’s co–primary endpoints were PFS in all patients and PFS in patients with an ESR1 mutation according to independent review.

The trial enrolled 239 patients in the elacestrant arm (115 with the ESR1 mutation), and 238 in the control arm (113 with the ESR1 mutation).6 Patient characteristics were well balanced between the 2 arms. Approximately 70% of patients had visceral metastases, and approximately 22% had received 1 prior line of chemotherapy, reflecting the aggressive tumor biology. 

The trial met its primary endpoint, demonstrating a median PFS of 2.79 months with elacestrant vs 1.91 months with standard-of-care therapy (HR, 0.697; 95% CI, 0.552-0.880; P=.0018; Figure 5) in the entire study population. The risk of progression or death was also reduced with elacestrant vs the standard of care in the population of patients with the ESR1 mutation (HR, 0.54; P=.005). In the overall study population, 12-month PFS was 22.3% with elacestrant vs 9.4% with standard-of-care therapy. Among patients with the ESR1 mutation, 12-month PFS was 26.9% with elacestrant vs 8.2% with the standard of care therapy. The PFS benefit with elacestrant was observed in numerous prespecified subgroups, including those with visceral metastasis (HR, 0.665; 95% CI, 0.607-0.869) and those treated with 1 line of prior endocrine therapy (HR, 0.705; 95% CI, 0.527-0.959) or 2 lines of prior endocrine therapy (HR, 0.597; 95% CI, 0.423-0.841). Elacestrant was generally well tolerated, with a safety profile similar to that of other endocrine therapies. Treatment-emergent AEs required discontinuation of treatment in 6.3% of patients in the elacestrant arm vs 4.4% in the control arm. No treatment-related deaths occurred in either arm.

References

1. Lindeman GJ, Bowen R, Jerzak KJ, et al. Results from VERONICA: a randomized, phase II study of second-/third-line venetoclax (VEN) + fulvestrant (F) versus F alone in estrogen receptor (ER)-positive, HER2-negative, locally advanced, or metastatic breast cancer (LA/MBC) [ASCO abstract 1004]. J Clin Oncol. 2021;39(suppl 15).

2. André F, Ciruelos E, Rubovszky G, et al; SOLAR-1 Study Group. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med. 2019;380(20):1929-1940.

3. Turner NC, Kingston B, Kilburn LS, et al. Circulating tumour DNA analysis to direct therapy in advanced breast cancer (plasmaMATCH): a multicentre, multicohort, phase 2a, platform trial. Lancet Oncol. 2020;21(10):1296-1308.

4. Bihani T, Patel HK, Arlt H, et al. Elacestrant (RAD1901), a selective estrogen receptor degrader (SERD), has antitumor activity in multiple ER(+) breast cancer patient-derived xenograft models. Clin Cancer Res. 2017;23(16):4793-4804.

5. Bardia A, Kaklamani V, Wilks S, et al. Phase I study of elacestrant (RAD1901), a novel selective estrogen receptor degrader, in ER-positive, HER2-negative advanced breast cancer. J Clin Oncol. 2021;39(12):1360-1370.

6. Bardia A, Neven P, Streich G, et al. Elacestrant, an oral selective estrogen receptor degrader, vs investigator’s choice of endocrine monotherapy for ER+/HER2- advanced/metastatic breast cancer following progression on prior endocrine and CDK4/6 inhibitor therapy: results of EMERALD phase 3 trial. Abstract presented at: the 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS2-02.

Trastuzumab Deruxtecan (DS-8201a) vs Trastuzumab Emtansine in Patients With HER2+ Metastatic Breast Cancer: Subgroup Analyses From the Randomized Phase 3 Study DESTINY-Breast03

The multicenter, open-label, phase 3 DESTINY-Breast03 trial compared trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients with previously treated unresectable or metastatic breast cancer.1,2 Eligible patients had received prior treatment with trastuzumab and a taxane. Enrollment included patients with clinically stable, treated brain metastases. Stratification factors included hormone receptor status, prior treatment with pertuzumab, and history of visceral disease. The trial randomly assigned 524 patients to receive T-DXd at 5.4 mg/kg every 3 weeks or T-DM1 at 3.6 mg/kg every 3 weeks. The primary endpoint was PFS according to blinded independent review.

The baseline characteristics were generally well balanced between the 2 arms.2 Patients were a median age of 54 years (range, 20-83 years). Most patients (88%-90%) had a HER2 expression level of 3+ according to immunohistochemistry. A history of brain metastases was reported in 23.8% of the T-DXd arm and 19.8% of the T-DM1 arm. Baseline imaging showed brain metastases in 16.5% vs 14.8%, respectively. Prior pertuzumab therapy was noted in 62.1% of patients in the T-DXd arm and 60.1% of patients in the T-DM1 arm. 

After a median follow-up of 15.9 months, the median PFS was not reached (95% CI, 18.5 months to not estimable) in the T-DXd arm vs 6.8 months (95% CI, 5.6-8.2) in the T-DM1 arm (HR, 0.28; 95% CI, 0.22-0.37; P=7.8 × 10-22). The risk of disease progression or death was reduced by at least 67% in all subgroups, including those based on HR status, prior pertuzumab treatment, visceral disease, prior lines of therapy, and brain metastases. Across the same subgroups, the difference in the proportion of confirmed ORRs with T-DXd vs T-DM1 ranged from 39.1% to 51.6%, all favoring T-DXd. Among patients with confirmed brain metastases at baseline, the median PFS was 15.0 months with T-DXd vs 3.0 months with T-DM1 (HR, 0.25; 95% CI, 0.13-0.45; Figure 6). Among patients without brain metastases at baseline, the median PFS was not estimable in the T-DXd group vs 7.1 months in the T-DM1 group (HR, 0.30; 95% CI, 0.22-0.040).

In the overall study population, the confirmed ORR was 79.7% with T-DXd vs 34.2% with T-DM1, with complete response (CR) rates of 16.1% vs 8.7%, respectively. Among patients with brain metastases at baseline, the confirmed ORR was 67.4% with T-DXd vs 20.5% with T-DM1, with CR rates of 4.7% vs 0%. Thirty-six patients in each arm had brain metastases at baseline, and in these patients, intracranial responses with T-DXd vs T-DM1 included a CR rate of 27.8% vs 2.8% and a PR rate of 36.1% vs 30.6%, respectively. 

The median duration of treatment was 14.3 months (range, 0.7-29.8 months) with T-DXd vs 6.9 months (range, 0.7-25.1 months) with T-DM1. Owing to the large difference in exposure to study drug in the T-DXd arm compared with the T-DM1 arm, AEs were evaluated based on the exposure-adjusted incidence rate per patient-year (EAIR). Compared with the T-DM1 arm, patients in the T-DXd arm were less likely to experience a treatment-emergent AE of any grade (EAIR, 0.87 vs 1.43), a treatment-emergent AE of at least grade 3 (EAIR, 0.46 vs 0.72), or a serious treatment-emergent AE (EAIR, 0.17 vs 0.27). The rates of treatment-emergent AEs associated with treatment discontinuation, dose reduction, or death were similar in both arms based on EAIR analysis. The most common AEs of grade 3 or higher in the T-DXd arm were neutropenia (19.1%) and thrombocytopenia (7.0%), followed by leukopenia and nausea at 6.6% each. Rates of interstitial lung disease or pneumonitis were similar in patients from Asia and non-Asian regions.

References

1. Cortés J, Kim SB, Chung WP, et al. Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (pts) with HER2+ metastatic breast cancer (mBC): results of the randomized phase III DESTINY-Breast03 study [ESMO abstract LBA1]. Ann Oncol. 2021;32(suppl 5).

2. Hurvitz S, Kim SB, Chung WP, et al. Trastuzumab deruxtecan (DS-8201a) vs. trastuzumab emtansine in patients with HER2+ metastatic breast cancer: subgroup analyses from the randomized phase 3 study DESTINY-Breast03. Abstract presented at: the 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS3-01.

Fulvestrant-Palbociclib vs Continuing Aromatase Inhibitor-Palbociclib Upon Detection of Circulating ESR1 Mutation in HR+ HER2– Metastatic Breast Cancer Patients: Results of PADA-1, a UCBG-GINECO Randomized Phase 3 Trial

In patients with ER-positive metastatic breast cancer, mutations in ESR1 promote resistance to aromatase inhibitors while retaining sensitivity to ERα degradation by SERDs.1 Mutations in ESR1 can be detected by analyzing cell-free circulating DNA in the blood. Although these mutations are rare at diagnosis, they are more frequently detected in patients with disease that progresses during first-line treatment with an aromatase inhibitor. The phase 3 PADA-1 trial compared treatment with fulvestrant plus palbociclib vs an aromatase inhibitor plus palbociclib upon detection of an ESR1 mutation in the blood among patients with hormone receptor–positive/HER2-negative metastatic breast cancer.2 Eligible patients had received no prior therapy for their metastatic disease and had not relapsed within 12 months of adjuvant treatment with an aromatase inhibitor. Stratification factors included the time of inclusion to the detection of an increasing ESR1 mutation in the blood and the presence of visceral metastases. Patients with a rising ESR1 mutation in the absence of synchronous disease progression were randomly assigned into the 2 treatment arms. The co–primary endpoints were safety based on hematologic AEs of grade 3 or higher and investigator-assessed PFS based on RECIST 1.1.3 

The study enrolled 1017 patients who received treatment with an aromatase inhibitor plus palbociclib.2 An increasing level of ESR1 mutation in the blood was identified in 279 patients during the initial therapy. Among these patients, 172 patients had an increasing blood ESR1 mutation level and no synchronous disease progression. The patient characteristics were well balanced between the 2 arms. In the cohort of 84 patients who continued with an aromatase inhibitor plus palbociclib, the median age was 60 years (range, 30-80 years), and 49% had visceral metastasis. The time to rising blood ESR1 mutations was less than 12 months in 35% of patients and 12 months or longer in 65% of patients. For the 88 patients who were randomly assigned to treatment with fulvestrant plus palbociclib, the median age was 62 years (range, 23-88 years) and 48% had visceral metastasis. The time to rising blood ESR1 was less than 12 months in 39% of patients and 12 months or more in 61% of patients. After a median follow-up of 26 months, the median PFS was 11.9 months with fulvestrant plus palbociclib vs 5.7 months with an aromatase inhibitor plus palbociclib (stratified HR, 0.61; 95% CI, 0.43-0.86; P=.005; Figure 7). Few grade 3/4 AEs were observed, and no new safety signals were raised. 

References

1. Brett JO, Spring LM, Bardia A, Wander SA. ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer. Breast Cancer Res. 2021;23(1):85.

2. Bidard FC, Hardy-Bessard AC, Bachelot T, et al. Fulvestrant-palbociclib vs continuing aromatase inhibitor-palbociclib upon detection of circulating ESR1 mutation in HR+ HER2- metastatic breast cancer patients: results of PADA-1, a UCBG-GINECO randomized phase 3 trial. Abstract presented at: the 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS3-05.

3. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247.

Neratinib + Fulvestrant + Trastuzumab for Hormone Receptor-Positive, HER2-Mutant Metastatic Breast Cancer and Neratinib + Trastuzumab for Triple-Negative Disease: Latest Updates From the SUMMIT Trial

Breast cancer tumors that lack overexpression of HER2 as assessed by immunohistochemistry or fluorescence in situ hybridization may harbor HER2 mutations that can be targeted by tyrosine kinase inhibitors (TKIs).1,2 Xenograft studies suggest that tumor killing may be enhanced by treatment with a TKI plus an anti-HER2 antibody.3,4 The SUMMIT trial initially evaluated neratinib monotherapy in patients with a variety of tumor types, including breast tumors, with a documented HER2 mutation.5 The trial excluded patients who had received prior treatment with any pan-HER TKI.

In an initial analysis, neratinib monotherapy led to a median PFS of 3.6 months in 18 patients with hormone receptor–positive/HER2-negative, HER2-mutant metastatic breast cancer and of 2.0 months in 10 TNBC patients. Subsequently, fulvestrant was added to neratinib for the treatment of hormone receptor–positive/HER2-negative, HER2-mutant patients. The dual therapy yielded a PFS of 5.4 months in 39 patients. In the next stage of treatment for breast cancer patients in the trial, trastuzumab was added to neratinib plus fulvestrant. Inclusion criteria were updated to require prior treatment with a CDK4/6 inhibitor to reflect the current standard of care for patients with hormone receptor–positive disease. 

There were greater decreases in tumor size and longer treatment durations among the patients treated with neratinib, fulvestrant, and trastuzumab vs fulvestrant and trastuzumab (Figures 8 and 9). Thirty-three patients with hormone-receptor–positive breast tumors received neratinib, fulvestrant, and trastuzumab.5 The patients were heavily pretreated, with a median of 5 prior lines of therapy. Prior treatment with fulvestrant was reported in 82%. Triple-drug therapy yielded an ORR of 42.4%, including 1 CR (3.0%). The median PFS was 7.0 months (range, 4.2-12.7 months). Although patients were required to take loperamide as prophylaxis, diarrhea was the most common treatment-emergent AE among the 33 patients who received neratinib, fulvestrant, and trastuzumab. Any-grade diarrhea occurred in 90.9% of patients, and grade 3 diarrhea occurred in 45.5% of patients. (There were no cases of grade 4.) The median time to the first diarrhea event was 4 days (range, 1-68 days), and the median duration of each episode of grade 3 diarrhea was 2 days (range, 1-23 days). One patient (3.0%) discontinued study treatment owing to diarrhea, and 1 patient each discontinued owing to asthenia or nausea (6.0%). 

Eighteen patients with TNBC in the SUMMIT trial received neratinib plus trastuzumab. The median number of prior lines of therapy was 3.5 (range, 1-7). The ORR was 33.3%, including 1 CR (5.6%), and the median PFS was 6.2 months (range, 2.1-8.2 months). The most common AE of any grade was diarrhea (88.9%). Grade 3 diarrhea was noted in 16.7% of patients, with no grade 4 diarrhea reported. 

References

1. Hyman DM, Piha-Paul SA, Won H, et al. HER kinase inhibition in patients with HER2- and HER3-mutant cancers. Nature. 2018;554(7691):189-194.

2. Smyth LM, Piha-Paul SA, Won HH, et al. Efficacy and determinants of response to HER kinase inhibition in HER2-mutant metastatic breast cancer. Cancer Discov. 2020;10(2):198-213.

3. Ivanova E, Kuraguchi M, Xu M, et al. Use of ex vivo patient-derived tumor organotypic spheroids to identify combination therapies for HER2 mutant non-small cell lung cancer. Clin Cancer Res. 2020;26(10):2393-2403.

4. Kavuri SM, Jain N, Galimi F, et al. HER2 activating mutations are targets for colorectal cancer treatment. Cancer Discov. 2015;5(8):832-841.

5. Jhaveri K, Park H, Waisman J, et al. Neratinib + fulvestrant + trastuzumab for hormone receptor-positive, HER2-mutant metastatic breast cancer and neratinib + trastuzumab for triple-negative disease: latest updates from the SUMMIT trial. Abstract presented at: the 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS4-10.

Highlights in Metastatic Breast Cancer From the 2021 San Antonio Breast Cancer Symposium: Commentary

Joyce A. O’Shaughnessy, MD

Presentations in metastatic breast cancer at the 2021 San Antonio Breast Cancer Symposium (SABCS) provided important insights into management. New data were presented for treatments such as the selective estrogen receptor degraders (SERDs) amcenestrant and elacestrant, ribociclib combinations, pembrolizumab, datopotamab deruxtecan, trastuzumab deruxtecan (T-DXd), fulvestrant regimens, and nivolumab plus ipilimumab, as well as strategies for genomic profiling.

SERDs 

The ongoing phase 1/2 AMEERA-1 trial is evaluating the oral SERD amcenestrant as monotherapy and in combination with targeted therapies in heavily pretreated postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. An analysis presented at the 2021 American Society of Clinical Oncology annual meeting provided data for the combination regimen of amcenestrant plus palbociclib.1 This analysis showed a clinical benefit rate of 74% and an objective response rate of 34% among 35 evaluable patients enrolled in the dose-escalation phase (part C) and the dose-expansion phase (part D). At the 2021 SABCS, Dr Sarat Chandarlapaty presented updated data.2 For the combination regimen, the dose of amcenestrant was reduced to 200 mg (vs 400 mg as monotherapy), given in combination with palbociclib at 125 mg, 21 days on, then 7 days off. The updated analysis showed that the combination was safe and effective. At a median follow-up of 14.8 months, the median progression-free survival (PFS) was 14.7 months (90% CI, 11.0-22.3). The objective response rate was 32.4%, and the clinical benefit rate was 73.5%.

These results underpin the ongoing phase 3 AMEERA-5 trial, which is comparing letrozole plus palbociclib vs amcenestrant plus palbociclib for the first-line treatment of patients with ER-positive/HER2-negative metastatic breast cancer.3 The trial quickly completed accrual. 

There were several posters that described different, ongoing arms of the AMEERA-1 trial. These arms are evaluating amcenestrant combination regimens in postmenopausal women with ER-positive/HER2-negative metastatic breast cancer. The regimen is amcenestrant plus alpelisib in arm 3 (parts F and G),4 amcenestrant plus everolimus in arm 4 (part H),5 and amcenestrant in combination with abemaciclib in arm 5 (parts J and K).6 There are no data yet available for these arms. Amcenestrant is being developed broadly in the ER-positive, HER2-negative metastatic setting in combination with the key agents typically used in this population. 

Elacestrant is another oral SERD. The phase 3 EMERALD study compared elacestrant vs investigator’s choice of fulvestrant, anastrozole, letrozole, or exemestane in patients with ER-positive, HER2-negative metastatic breast cancer.7 The study had 2 primary endpoints: PFS among all patients and PFS among patients with an ESR1 mutation. In the intention-to-treat population, elacestrant reduced the risk of progression or death by 30%. This rate was higher among patients with an ESR1 mutation, at 45%. Among all patients, elacestrant led to a statistically significant but modest improvement in median PFS of 2.79 months compared with 1.91 months with standard endocrine therapy. 

Among patients with an ESR1 mutation, the PFS rate at 12 months was 26.8% with elacestrant vs 8.2% with the standard of care. It appears that patients with mutant ESR1 breast cancers that are sensitive to endocrine therapy derive more benefit from elacestrant than fulvestrant, based on the results of this head-to-head study. Elacestrant does not appear to overcome resistance in patients whose breast cancers are resistant to endocrine therapy, but rather prolongs the duration of benefit with ER-targeted therapy. 

These encouraging results support the development of oral SERDs in breast cancer. These agents may be particularly helpful in patients whose breast cancers harbor an ESR1 mutation, who represent an unmet need. 

Ribociclib Combinations

I presented overall survival data in preplanned subsets from the randomized phase 3 MONALEESA-2 trial, which evaluated first-line ribociclib plus letrozole in postmenopausal patients with hormone receptor (HR)–positive, HER2-negative advanced breast cancer.8 The analyses showed similar survival advantages regardless of prior endocrine therapy and among clinically relevant subsets such as patients with liver metastases, bone metastases, or lung and liver metastases. There was no subgroup that did not benefit from the addition of ribociclib to letrozole. 

Dr Lisa Carey presented an analysis of the MONALEESA-2, -3, and -7 studies that focused on overall survival according to intrinsic subtype.9 These studies evaluated ribociclib plus endocrine therapy in patients with HR-positive, HER2-negative advanced breast cancer. The analysis showed that the addition of ribociclib to endocrine therapy was beneficial in patients with luminal A, luminal B, and HER2-enriched breast cancer. The addition of ribociclib was not beneficial in the small fraction of patients with ER-positive, HER2-negative basal-like breast cancer. 

It is not necessary to perform intrinsic subtyping on metastatic breast cancers, as this knowledge currently would not influence practice. However, these interesting data raise questions about how well the cyclin-dependent kinase 4/6 (CDK4/6) inhibitors work in patients with ER-positive, HER2-negative breast cancers that have the homologous recombination deficiency. Approximately 15% to 20% of HR-positive HER2-negative breast cancers may have this deficiency.

Pembrolizumab

A subgroup analysis of the phase 3 KEYNOTE-355 trial evaluated outcome according to patients’ combined positive score (CPS).10 A CPS of 10 or higher was reported in 38% of patients in the trial. The analyses showed that the addition of pembrolizumab to chemotherapy of physician’s choice conferred a survival benefit only in those patients with a CPS of 10 or higher. Therefore, it is necessary to limit this treatment to these patients.

Datopotamab Deruxtecan

The single-arm phase 1/1b TROPION study showed very promising results for datopotamab deruxtecan in patients with triple-negative breast cancer.11 This antibody-drug conjugate targets TROP2, and has the topoisomerase 1 payload (deruxtecan) for patients with triple-negative breast cancer. The objective response rate was 34% in a heavily pretreated population. Prior treatment with sacituzumab govitecan or another topoisomerase 1 inhibitor–based antibody-drug conjugate was reported in 30% of patients. When these patients were excluded from the analysis, the objective response rate increased to 54%. Datopotamab deruxtecan is therefore not fully cross-resistant with sacituzumab govitecan, an encouraging finding. An analysis of the overall population showed that the duration of disease control was not reached. The main adverse events were nausea, vomiting, stomatitis, and fatigue. The main toxicities seen with sacituzumab govitecan are myelosuppression and diarrhea. 

Datopotamab deruxtecan had an encouraging level of activity in these generally heavily pretreated patients. A phase 3 trial is planned to evaluate datopotamab deruxtecan in patients with triple-negative breast cancer earlier in the course of their metastatic disease. 

Trastuzumab Deruxtecan (T-DXd)

Dr Sara Hurvitz presented an update of data from the DESTINY-Breast03 trial that focused on patients with or without brain metastases.12 This phase 3 study compared T-DXd vs trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer. Enrollment included patients with stable, treated brain metastases. Among this population, the PFS advantage seen with T-DXd vs TDM1 was maintained, with a hazard ratio of 0.25. This improvement is dramatic. The intracranial objective response rate was 63.9% for T-DXd vs 33.4% for T-DM1. These interesting data show that T-DXd has very promising activity in the brain.

Fulvestrant Combinations

The PADA-1 trial explored whether it is helpful to detect subclinical progression of disease with the emergence of an ESR1 mutation in patients receiving an aromatase inhibitor plus palbociclib.13 It may be possible to learn at an early time point when cancer cells become resistant to an aromatase inhibitor. The trial evaluated whether patients with HR-positive metastatic breast cancer found to have mutant ESR1 on circulating tumor DNA (ctDNA) and no synchronous progressive disease would benefit if treatment with an aromatase inhibitor and palbociclib were switched to fulvestrant plus palbociclib. This strategy improved PFS by 6.2 months compared with continuing an aromatase inhibitor plus palbociclib until disease progression. However, the overall PFS improvement with the early-switch strategy was only 2.7 months compared with patients who switched to fulvestrant plus palbociclib when scans showed progression. This improvement is of questionable clinical utility. We await results of survival analyses from the PADA-1 trial, which should indicate whether an earlier change in therapy will improve survival. Currently, it is not clear whether the 2.7-month improvement in median PFS justifies an early switch to fulvestrant, while continuing the CDK4/6 inhibitor, upon the emergence of a ctDNA-detected ESR1 mutation.

Dr Komal Jhaveri presented updated results from the SUMMIT trial, which evaluated the combination of neratinib, fulvestrant, and trastuzumab in patients with HR-positive, HER2-mutant metastatic breast cancer and neratinib plus trastuzumab among patients with HER2-mutated metastatic triple-negative disease.14 The response rate was 42.4% in the HR-positive, HER2-negative, HER2-mutant cohort, with a median PFS of 7.0 months. Among patients with triple-negative breast cancer, which is associated with substantial intratumoral heterogeneity, the response rate was 33.3%, with a median PFS of 6.2 months. With such high levels of activity, these regimens will likely become a new standard of care for patients with HER2-mutant metastatic breast cancer.

Nivolumab Plus Ipilimumab

The phase 2 NIMBUS trial is evaluating nivolumab plus ipilimumab among patients with HER2-negative metastatic breast cancer, regardless of receptor status.15 Most patients (70%) were HR-positive, and the remainder had triple-negative breast cancer. All patients’ cancers had a tumor mutation burden of at least 9 mutations per megabase. Among all patients, the objective response rate was 16.7%. Among patients with very high tumor mutation burden (≥14 mutations per megabase) cancers, the response rate was 60%. PFS was also substantially improved among patients with very high tumor mutation burden. Among these patients with cancers that have very high tumor mutation burden, the median PFS was 9.5 months. In comparison, the median PFS was 1.4 months in patients with fewer than 14 mutations per megabase. The numbers of patients were small; only 5 patients had 14 or more mutations per megabase. The benefit with ipilimumab plus nivolumab seen in patients with high tumor-mutation–burden cancers raises the question of whether monotherapy with a checkpoint inhibitor would be equally effective. Pembrolizumab is approved for patients with metastatic breast cancer with high tumor-mutation–burden cancers. A randomized clinical trial would be needed to confirm whether the addition of the CTLA-4 agonist is additionally beneficial.

Genomic Profiling

The phase 2 SAFIR02 study evaluated the clinical utility of genomic profiling among patients with triple-negative or HR-positive/HER2-negative metastatic breast cancer.16 Patients who were responding to standard chemotherapy were randomly assigned to continue the same chemotherapy or to switch to a targeted agent that, in some cases, matched a genomic alteration in the patients’ cancers. The study evaluated effectiveness based on categories established by the European Society for Medical Oncology Scale for Clinical Actionability of Molecular Targets (ESCAT), which separate genomic alteration–drug matches into tiers based on levels of evidence.17 There was an observed improvement in PFS in favor of switching to a targeted therapy, but only with agents categorized as ESCAT tier 1 (the alteration–drug match is associated with improved outcome in clinical trials) or tier 2 (the match is associated with antitumor activity, but the magnitude of benefit is unknown). In patients who received tier 1/2 agents, the median PFS improved from 2.8 months with maintenance chemotherapy to 9.1 months with targeted therapy. In the intention-to-treat population of patients, some of whom received non–tier 1/2 targeted therapies, there was no significant improvement in PFS. 

These results are interesting. When the treatment plan involves targeting a genomic alteration, oncologists should ensure there is a high level of evidence supporting effectiveness of the targeted agent in the metastatic setting.

Disclosure

Dr O’Shaughnessy has received honoraria for consulting and advisory boards from AbbVie, Agendia, Amgen Biotechnology, AstraZeneca, Daiichi Sankyo, Bristol Myers Squibb, Eisai, Genentech, Gilead, Lilly, Merck, Myriad Genetics, Exact Sciences, Novartis, Odonate Therapeutics, Pfizer, Puma Biotechnology, Roche, Tempus, Theranostics Health, and Seagen.

References

1. Chandarlapaty S, Linden HM, Neven P, et al. AMEERA-1: phase 1/2 study of amcenestrant (SAR439859), an oral selective estrogen receptor (ER) degrader (SERD), with palbociclib (palbo) in postmenopausal women with ER+/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC) [ASCO abstract 1058]. J Clin Oncol. 2021;39(suppl 15).

2. Chandarlapaty S, Linden HM, Neven P, et al. Updated data from AMEERA-1: phase 1/2 study of amcenestrant (SAR439859), an oral selective estrogen receptor degrader, combined with palbociclib in postmenopausal women with ER+/HER2- advanced breast cancer. Paper presented at: the 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract P1-17-11.

3. Bardia A, Cortes J, Hurvitz SA, et al. AMEERA-5: a randomized, double-blind phase III study of amcenestrant (SAR439859) + palbociclib versus letrozole + palbociclib for previously untreated ER+/HER2- advanced breast cancer [ASCO abstract TPS1104]. J Clin Oncol. 2021;39(suppl 15).

4. Campone M, Bardia A, Kabos P, et al. AMEERA-1: phase 1/2 study of amcenestrant (SAR439859), an oral selective estrogen receptor (ER) degrader (SERD), with alpelisib in postmenopausal women with ER+/human epidermal growth factor receptor 2-negative (HER2–) PIK3CA-mutated advanced breast cancer. Poster presented at: the 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract OT2-11-03.

5. Campone M, Neven P, Petráková K, et al. AMEERA-1 arm 4: phase 1/2 study of amcenestrant (SAR439859), an oral selective estrogen receptor (ER) degrader (SERD), with everolimus in postmenopausal women with ER+/human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer. Poster presented at: the 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract OT2-11-02.

6. Campone M, Chandarlapaty S, Bardia A, et al. AMEERA-1 arm 5: phase 1/2 study of amcenestrant (SAR439859), an oral selective estrogen receptor (ER) degrader (SERD), with abemaciclib in postmenopausal women. Poster presented at: the 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract OT2-11-04.

7. Bardia A, Neven P, Streich G, et al. Elacestrant, an oral selective estrogen receptor degrader, vs investigator’s choice of endocrine monotherapy for ER+/HER2- advanced/metastatic breast cancer following progression on prior endocrine and CDK4/6 inhibitor therapy: results of EMERALD phase 3 trial. Paper presented at: the 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS2-02.

8. O’Shaughnessy J, Stemmer SM, Burris HA, et al. Overall survival subgroup analysis by metastatic site from the phase 3 MONALEESA-2 study of first-line ribociclib + letrozole in postmenopausal patients with advanced HR+/HER2- breast cancer. Paper presented at: the 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS2-01.

9. Carey LA, Solovieff N, André F, et al. Correlative analysis of overall survival by intrinsic subtype across the MONALEESA-2, -3, and -7 studies of ribociclib + endocrine therapy in patients with HR+/HER2− advanced breast cancer. Paper presented at: the 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS2-00.

10. Cortes J, Cescon DW, Rugo HS, et al. Efficacy of pembrolizumab + chemotherapy vs placebo + chemotherapy by PD-L1 combined positive score 1-9, 10-19, and ≥20 for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer: KEYNOTE-355 subgroup analysis. Paper presented at: the 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS1-02.

11. Krop I, Juric D, Shimizu T, et al. Datopotamab deruxtecan in advanced/metastatic HER2-breast cancer: results from the phase 1 TROPION-PanTumor01 study. Paper presented at: the 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS1-05.

12. Hurvitz S, Kim SB, Chung WP, et al. Trastuzumab deruxtecan (DS-8201a) vs. trastuzumab emtansine in patients with HER2+ metastatic breast cancer: subgroup analyses from the randomized phase 3 study DESTINY-Breast03. Paper presented at: the 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS3-01.

13. Bidard FC, Hardy-Bessard AC, Bachelot T, et al. Fulvestrant-palbociclib vs continuing aromatase inhibitor-palbociclib upon detection of circulating ESR1 mutation in HR+ HER2- metastatic breast cancer patients: results of PADA-1, a UCBG-GINECO randomized phase 3 trial. Paper presented at: the 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS3-05.

14. Jhaveri K, Park H, Waisman J, et al. Neratinib + fulvestrant + trastuzumab for hormone receptor-positive, HER2-mutant metastatic breast cancer and neratinib + trastuzumab for triple-negative disease: latest updates from the SUMMIT trial. Paper presented at: the 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS4-10.

15. Barroso-Sousa R, Li T, Reddy S, et al. NIMBUS: a phase II study of nivolumab plus ipilimumab in metastatic hypermutated HER2-negative breast cancer. Paper presented at: the 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS2-10.

16. Andre F, Goncalves A, Filleron T, et al. Clinical utility of genomic profiling in patients with metastatic breast cancer: results of a randomized trial. Paper presented at: the 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS1-10.

17. Mateo J, Chakravarty D, Dienstmann R, et al. A framework to rank genomic alterations as targets for cancer precision medicine: the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT). Ann Oncol. 2018;29(9):1895-1902.