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Roche IMpassions Physicians to Treat TNBC Patients with Frontline Tecentriq plus Abraxane

by Katherine Stockstill | Oct 22, 2018
Co-authored by Madelyn Hanson

Triple negative breast cancer (TNBC) is defined by the absence of overexpression of the estrogen receptor (ER), the progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). Even though TNBC is a small portion of the total breast cancer patient population (around 11%1), it has one of the highest unmet needs due to the lack of effective, tolerable, and targeted agents; currently chemotherapeutic approaches are the only FDA-approved treatment options. This high unmet need has led to a great deal of development across all stages of TNBC and, as seen in many tumor types, immunotherapy appears to be leading the race.

Given the significant impact that immunotherapy has had on many tumor types, the potential use of PD-1/PD-L1 inhibitors is an exciting possibility for TNBC patients. Breast cancer has not been considered an immunogenic tumor type. However, TNBC has long been recognized as a highly heterogeneous disease due to high rate of genetic mutations within these tumors, a characterization often associated with increased response to immunotherapy2,3,4. Furthermore, studies have demonstrated PD-L1 expression as well as the presence of tumor-infiltrating lymphocytes (TILs) in TNBC tumors, additional factors which have also been shown to correlate with an increased response to PD-1/PD-L1 inhibitors 5,6,7. These findings support the hypothesis that immunotherapy, more specifically PD-1/PD-L1 inhibitors, may have therapeutic potential in TNBC.  

In June 2015, Roche initiated the global Phase III IMpassion130 trial (NCT02425891) combining the PD-L1 inhibitor Tecentriq (atezolizumab) with Abraxane (nab-paclitaxel, Celgene) versus placebo with Abraxane as treatment for previously untreated, metastatic TNBC. This Phase III trial is supported by a Phase Ib (NCT01633970) trial that examined Tecentriq with Abraxane in advanced solid tumors, including 33 patients with metastatic TNBC8. Responses were observed regardless of line of therapy or PD-L1 status with an objective response rate (ORR) of 39% across all TNBC patients.  Median progression free survival (mPFS) was 5.5 months and the median overall survival (mOS) was 14.7 months. Tecentriq plus Abraxane appeared to have more activity in first-line patients (n=13) compared to second-line and later patients (n=20; ORR =54% versus 30%, PFS= 8.6 months versus 5.1 months, OS= 24.2 months versus 12.4 months, respectively). The trial also found that patients with higher PD-L1 status (n=12), defined as immune cells expressing PD-L1 as a percentage of tumor area (IC ≥1%),  achieve a numerically greater ORR (42%), mPFS (6.9 months) and mOS (21.9 mos) compared to those patients (n=12) with IC<1% (33%, 5.1 months and 11.4 months, respectively)8. These data plus the fact that taxane-based therapy, including Abraxane, is currently standard of care in first-line TNBC9 supported the initiation of IMpassion130 in first-line TNBC.

IMpassion130 enrolled 902 patients with metastatic or inoperable locally advanced TNBC.  Patients were not allowed prior therapy for advanced TNBC, but chemotherapy in the curative setting was allowed if it was received at least 12 months prior to enrollment. An ECOG PS 0-1 was also required. Patients were stratified based on prior taxane exposure and the presence of liver metastases as well as PD-L1 status (IC; positive ≥1% versus negative <1%). Patients were then randomized (1:1) to receive Abraxane 100 mg/m2 on days 1, 8, and 15 combined with Tecentriq 840 mg on days 1 and 15 of a 28-day cycle or Abraxane combined with placebo. The trial assessed PFS and OS as co-primary endpoints as well as ORR, DOR, Health Related Quality of Life (HRQoL) and toxicities as secondary outcomes in the intent to treat (ITT) and PD-L1+ populations.

Data from the IMpassion130 trial were presented at the European Society for Medical Oncology (ESMO) 2018 Congress on October 20, 201810.  The trial met its co-primary endpoint of improving PFS.  In the ITT population, the experimental arm achieved a mPFS of 7.2 months versus 5.5 months in the control arm (n=451; HR= 0.80, p=0.0025). Forty-one percent of patients were determined to be PD-L1+ and the magnitude of PFS benefit was slightly larger in these patients (7.5 months vs 5.0 months, HR= 0.62, p<0.0001).  Interim OS data was also presented at the 2018 ESMO Congress. In the ITT population, Tecentriq plus Abraxane produced a mOS of 21.3 months while the control arm had a mOS of 17.6 months (HR=0.84, p=0.0840). In the PD-L1+ population, experimental arm reached a mOS of 25.0 months, while the control arm had a mOS of 15.5 months (HR=0.62). Since the OS improvement in the ITT population was not statistically significant, further analysis of OS in the PD-L1+ population was not conducted. Still, these results suggest that this regimen may provide a higher mOS benefit in PD-L1+ TNBC. Tecentriq plus Abraxane also produced numerically higher ORRs in the ITT (56% versus 46%) as well as PD-L1+ (59% versus 43%). Similarly, numerical increases in DOR were observed in both populations (ITT: 7.4 months versus 5.6 months; PD-L1+: 8.5 months versus 5.5 months).

The combination of Tecentriq and Abraxane was considered tolerable with most of the adverse advents observed attributed to the inclusion of Abraxane. Low grade nausea (46% versus 38%), cough (25% versus 19%) neutropenia (21% versus 15%) and hypothyroidism (17% versus 4%) were elevated n the experimental arm compared to control.  Peripheral neuropathy was the only Grade 3-4 adverse event that was increased in the experimental arm versus the control arm (6% versus 3%). According to the authors, this increase in peripheral neuropathy can most likely be attributed to the increased exposure to Abraxane in the experimental arm.

Given the improvement of PFS observed with minimal increase in toxicity, Tecentriq plus Abraxane has the potential to become the new standard of care in first-line TNBC, but questions remain. At this point in the trial, Tecentriq plus Abraxane struggles to improve response rate and while this issue has often plagued PD-1/PD-L1 monotherapy, it has been less of an issue when these agents are combined with chemotherapy like Abraxane. A numerical OS improvement in the ITT population was seen during this interim analysis, but that leads one to ask how much the inclusion of PD-L1+ patients in the ITT population drives this given the larger numerical improvement in OS observed in PD-L1+ patients.  This leads to the question, what percent of the PD-L1+ population would be considered PD-L1 high versus PD-L1 low and how much did the level of PD-L1 positivity within the trial population contribute to the PFS benefit in both the ITT and PD-L1+ populations? Further follow-up of both PFS and OS including analyses by level of PD-L1 expression will be highly anticipated. Additionally, no data was presented on the impact of patients’ BRCA status to benefit achieved with Tecentriq plus Abraxane. This will be a question of interest given the approvals of PARP inhibitors Lynparza (olaparib, AstraZeneca) and Talzenna (talazoparib, Pfizer) for breast cancer patients who harbor BRCA mutations. These approvals as well as the benefit observed with Tecentriq plus Abraxane in PD-L1+ patients have the potential to subdivide the already small population of patients in TNBC. Even with these questions remaining, the improvements achieved in IMpassion130 warrant rapid adoption in a patient population with high unmet need.

Roche is also conducting two additional Phase III trials in first-line metastatic TNBC, IMpasssion131 (NCT03125902) and IMpassion132 (NCT03371017).  IMpassion131 started in August 2017 and is investigating Tecentriq combined with paclitaxel versus paclitaxel alone while IMpassion132, initiated in January 2018, is investigating Tecentriq combined with either gemcitabine plus carboplatin or capecitabine. If this strategy proves successful, Roche has the potential to capture a large share of the first-line TNBC market regardless of physician’s preferred chemotherapy approach. However, Tecentriq is not the only PD-1/PD-L1 inhibitor being developed in metastatic TNBC.  Merck is evaluating Keytruda in both the first-line (KEYNOTE-355, NCT02819518) and relapsed settings (KEYNOTE-119, NCT02555657). Additionally, both agents are being evaluated in the early stage setting. Thus, IMpassion130 is only the tip of the iceberg for PD-1/PD-L1 inhibitors in TNBC.

 

References:

  1. Kantar Health, CancerMPact, Patient Metrics, accessed September 2018. Available at www.cancermpact.com
  2. Budczies J, Bockmayr M, Denkert C, et al. Classical pathology and mutational load of breast cancer - integration of two worlds. J Pathol Clin Res. 2015;1(4):225-238.
  3. Banerji S, Cibulskis K, Rangel-Escareno C, et al. Sequence analysis of mutations and translocations across breast cancer subtypes. Nature. 2012;486(7403):405-409.
  4. Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015; 348 (6230): 69-74
  5. Mittendorf EA, Philips AV, Meric-Bernstam F, et al. PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res. 2014;2(4):361-370. doi: 10.1158/2326-6066.CIR-13-0127.
  6. Tung N, Garber JE, Hacker MR, et al. Prevalence and predictors of androgen receptor and programmed death-ligand 1 in BRCA1-associated and sporadic triple-negative breast cancer. NPJ Breast Cancer. 2016;2:16002
  7. Yi M, Jiao D, Xu H, et al.; “Biomarkers for predicting efficacy of PD-1/PD-L1 inhibitors;” Molecular Cancer. 2018;17(1):129-143. doi: 10.1186/s12943-018-0864-3.
  8. Pohlmann PR, Diamond JR, Hamilton E, et al.; “Abstract CT028: Atezelizumab (atezo) + nab-paclitaxel (nab-pac) in metastatic triple-negative breast cancer (mTNBC): 2-year update from a Ph Ib trial;” Cancer Research, 78(13): Abstract CT028, 2018.
  9. Kantar Health, CancerMPact, Treatment Architecture, accessed September 2018. Available at www.cancermpact.com
  10. Schmid P, Adams S, Rugo HS, et al.; “Abstract LBA1_PR “IMpassion130: Results from a global, randomized, double-blind, phase 3 study of atezolizumab (atezo) + nab-paclitaxel (nab-P) vs placebo + nab-P in treatment naïve, locally advanced or metastatic triple-negative breast cancer (mTNBC);” Annals of Oncology, 29, Abstract LBA1_PR, 2018.

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