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Breast Cancer: A Model Indication for Personalized Medicine

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The Heterogeneity of Breast Cancer

Since its conception almost two decades ago, the strategy to base treatment selection on HR- and HER2-status has stood the test of time. Based on the expression characteristics of breast cancer, hormonal agents and HER2-targeting agents have been successfully exploited. However, in recent years, novel biomarker-driven agents have been approved by the FDA in this space, namely, PARP inhibitors for germline BRCA1/2-mutation-positive, HER2-negative disease, Tecentriq for PD-L1-positive TNBC, and Piqray for PIK3CA-mutation-positive, HR-positive/HER2-negative disease.

Biomarker-Driven Data Continues to Drive Personalized Medicine

Data released at 2019 ASCO further demonstrates the success of personalized medicine approaches in breast cancer.

A plethora of key studies evaluating agents specifically for HER2-positive breast cancer was presented, alongside other interesting new data-sets for therapies targeting HR-positive/HER2-negative disease and TNBC.

  • Final analyses of the CLEOPATRA trial, which compared Perjeta+Herceptin+docetaxel with placebo+Herceptin+docetaxel in first-line HER2-positive metastatic breast cancer, were presented. MOS was 57.1 months vs. 40.8 months (HR = 0.69) and 8-year OS rates were 37% and 23%, respectively1. This regimen is the standard of care for this patient population in the major markets, and this impressive long-term data cements its position in HER2-positive disease.
  • The primary analysis of the SOPHIA study, which is evaluating the HER2-targeting agent margetuximab in combination with chemotherapy vs. Herceptin plus chemotherapy in HER2-positive breast cancer (second-to-fourth lines), was presented. In the ITT population, the mPFS was 5.8 months for the margetuximab arm compared to 4.9 months for the Herceptin arm (HR = 0.76; p = 0.033)2. Interestingly, the benefit of margetuximab was more pronounced in a predetermined subset analysis of patients harboring the CD16A-158F allele (a marker of poor response to Herceptin); mPFS was 6.9 months vs. 5.1 months, respectively (HR = 0.68; p = 0.005).
  • Data from the NALA trial comparing capecitabine plus either Nerlynx or Tykerb/Tyverb in third- and later-line HER2-positive breast cancer was presented. The study successfully demonstrated a statistically significant improvement in PFS for the Nerlynx arm over the Tykerb/Tyverb arm (HR = 0.76; p = 0.006), although the OS benefit did not reach statistical significance (MOS: 24.0 months vs. 22.2 months, respectively; HR = 0.88; p = 0.2086)3.
  • ASCO 2019 data showed Kisqali is the first CDK4/6 inhibitor to demonstrate not only a PFS benefit but also a statistically significant OS benefit in the MONALEESA-7 After a median follow-up of almost three years, the MOS in the arm assessing Kisqali plus an endocrine therapy had not been reached, and was 40.9 months in the placebo plus endocrine therapy arm (HR = 0.712; p = 0.00973)4.
  • Data from SOLAR-1 trial (which formed the basis of the recent FDA approval of Piqray for HR-positive/HER2-negative/PIK3CA-positive advanced/metastatic patients) were presented at ASCO 2019. Patients resistant to prior endocrine therapy received fulvestrant plus Piqray or placebo. mPFS in the Piqray and placebo arms in the first-line setting were 9.0 months and 4.7 months (HR = 0.69) and 10.9 months vs. 3.7 months in the second-line (HR = 0.61), respectively5.
  • Talzenna was the second-to-market PARP inhibitor for the treatment of germline BRCA1/2-mutation positive, HER2-negative breast cancer and was approved based on the EMBRACA trial, which compared the agent to the physician’s choice of chemotherapy. Data presented at ASCO 2019 demonstrated a mPFS and ORR benefit for Talzenna across each line of therapy6.
  • The IMpassion130 study is comparing the efficacy and safety of Tecentriq or placebo in combination with nab-paclitaxel for previously untreated locally advanced or metastatic TNBC. Second interim analysis of the OS data was presented at ASCO 2019; in patients selected for PD-L1-positive immune cells (≥1%), which accounted for approximately 40% of patients, the mPFS was 7.5 months vs. 5.0 months (HR = 0.62; p < 0.001) and the MOS was 25.0 months vs. 18.0 months (HR = 0.71) for the Tecentriq arm and control arm, repsectively7.

Increased Fragmentation and Complexity is Inevitable

The approval of the PARP inhibitors and Tecentriq for TNBC has further subdivided this population on biomarkers outside of classical PR, ER, and HER2, demonstrating not only greater subgroup heterogeneity, but also raising the question of the suitability of current segmentation in breast cancer.

Decision Resources Group’s suite of breast cancer solutions include:

  1. Swain SM, et al. End-of-study analysis from the phase III, randomized, double-blind, placebo (Pla)-controlled CLEOPATRA study of first-line (1L) pertuzumab (P), trastuzumab (H), and docetaxel (D) in patients (pts) with HER2-positive metastatic breast cancer (MBC). Journal of Clinical Oncology. 2019: 37 (suppl; abstr 1020).
  2. Rugo HS, et al. SOPHIA primary analysis: A phase 3 (P3) study of margetuximab (M) + chemotherapy (C) versus trastuzumab (T) + C in patients (pts) with HER2+ metastatic (met) breast cancer (MBC) after prior anti-HER2 therapies (Tx). Journal of Clinical Oncology. 2019: 37 (suppl; abstr 1000).
  3. Saura C, et al. Neratinib + capecitabine versus lapatinib + capecitabine in patients with HER2+ metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: Findings from the multinational, randomized, phase III NALA trial. Journal of Clinical Oncology. 2019: 37 (suppl; abstr 1002).
  4. Hurvitz SA, et al. Phase III MONALEESA-7 trial of premenopausal patients with HR+/HER2− advanced breast cancer (ABC) treated with endocrine therapy ± ribociclib: Overall survival (OS) results. Journal of Clinical Oncology. 2019: 37 (suppl; abstr LBA1008).
  5. Juric D, et al. Alpelisib (ALP) with fulvestrant (FUL) in patients (pts) with PIK3CA-mutated hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC): Primary or secondary resistance to prior endocrine therapy (ET) in the SOLAR-1 trial. Journal of Clinical Oncology. 2019: 37 (suppl; abstr 1038).
  6. Ettl J, et al. Outcomes of talazoparib (TALA) versus physician’s choice of chemotherapy (PCT) in patients (pts) with advanced breast cancer (ABC) and a germline BRCA (gBRCA) mutation by line of chemotherapy (CT) in the EMBRACA trial. Journal of Clinical Oncology. 2019: 37 (suppl; abstr 1071).
  7. Schmid P, et al. IMpassion130: updated overall survival (OS) from a global, randomized, double-blind, placebo-controlled, Phase III study of atezolizumab (atezo) + nab-paclitaxel (nP) in previously untreated locally advanced or metastatic triple-negative breast cancer (mTNBC). Journal of Clinical Oncology. 2019: 37 (suppl; abstr 1003).