The immunotherapy wave has finally hit the shores of the breast cancer landscape
| Dec 12, 2014
Co-authored by Mara Jeffress, Ph.D., Associate Consultant
Immunotherapy is all the rage these days in oncology, and there is particular interest in those agents that target programmed death 1 (PD-1) and its ligand, PD-L1. In several solid tumors (and hematologic tumors as we saw at ASH last week) there is a race to market for this class of compounds by multiple competitors. Data presented in the past two years in melanoma have been impressive and have led to approvals of Keytruda® (pembrolizumab, Merck; U.S. FDA approval September 2014) and Opdivo® (nivolumab, BMS/Ono; Japanese MHLW approval July 2014 ) in advanced/metastatic disease and will likely lead to approvals in other indications in the near future (non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) are nearest term). Robust research in this area continues to push into additional indications, including breast cancer. In general, breast cancer is seen as less responsive to immunotherapy, and there has been some skepticism about the ability of immunotherapy to deliver. In particular, mutant proteins that serve as “neo-antigens” to the immune system are very low in breast cancer compared to other solid tumors.1 However, high levels of tumor-infiltrating lymphocytes (TILs) do seem to predict pathological complete response (pCR) in breast cancer patients,2 suggesting that the immune system is an important factor in the fight against this disease.
The question as to whether or not immunotherapy can be successful in breast cancer began to be answered Wednesday, December 10, 2014, at the San Antonio Breast Cancer Symposium (SABCS) with two presentations demonstrating early signals of activity for PD-1 and PD-L1 inhibitors in triple-negative breast cancer (TNBC) patients. Wednesday’s oral general session was the venue for the first results of Keytruda in 32 advanced TNBC patients treated in the ongoing Phase Ib KEYNOTE-012 study.3 The trial enrolled heavily pretreated patients (47% had three or more prior lines of chemotherapy) with PD-L1+ disease and treated them with pembrolizumab monotherapy at 10 mg/kg every two weeks. In 27 evaluable patients, the objective response rate (ORR) was 18.5% (1 CR, 4 PR) and median duration of response (DoR) was not reached (range, 15-40+ weeks), with three of five responders remaining on therapy for 11+ months. Adverse events (AEs) were mostly Grade 1/2, including fatigue (18.8%), arthralgia (18.8%), myalgia (15.6%) and nausea (15.6%). Grade 3/4 treatment-related AEs occurred in four patients – anemia, headache, meningitis aseptic, decreased blood fibrinogen and pyrexia - with two patients discontinuing drug due to AEs. There was also one death due to disseminated intravascular coagulation (DIC). Based on this encouraging data, the presenter, Dr. Nanda, disclosed Merck’s plans to start a Phase II trial in TNBC in the first half of 2015 and hinted during the Q&A at plans to pursue the other breast cancer subtypes, such as HER2+ patients, who may also be susceptible to immunotherapy. Small trials, such as PANACEA (NCT02129556), which will examine Keytruda in combination with Herceptin® (trastuzumab, Genentech/Roche/Chugai) in advanced Herceptin-resistant HER2+ breast cancer, should start recruiting soon.
Also on Wednesday, there was a poster presentation of data from a small cohort of 12 patients in the ongoing Phase Ia dose-escalation study of MPDL3280A (anti PD-L1, Genentech/Roche/Chugai), which evaluates doses of 0.3-20 mg/kg every three weeks in previously treated patients with advanced, PD-L1+ TNBC. 4 In nine evaluable patients, ORR was 33% (1 CR, 2 PR); however, there were an additional two responders who were initially pseudo-progressors and were not included in the calculated ORR. Grade 3/4 treatment-related AEs occurred in only one patient, and no dose-limiting toxicities occurred. Further evaluation of MPDL3280A is ongoing in both PD-L1-positive and -negative TNBC patients (NCT01375842).
In both studies, response was measured by RECIST criteria, not immune-related-response criteria that take into account that some patients on immunotherapy initially progress before responding. Had these alternative criteria been used, perhaps the ORR would have been higher. Despite this, the ORR reported in these two studies (19% and 33%) are similar to the ORR reported for PD-1 / PD-L1 inhibitors in other solid tumors ( 31%-34% in melanoma,5,6 17%-21% in NSCLC,7,8,9 20% in RCC and head and neck10,11). Perhaps more important than the response rate is the extent to which the PD-1/PD-L1 inhibitors are able to slow the progression of disease and prolong survival. The duration of response data for Keytruda is the only piece of data that is yet available to guide toward an answer to this question in breast cancer, but it is a promising start – metastatic TNBC has a notoriously poor prognosis, and to see duration of response nearing one year in later lines of therapy is very encouraging. What will be more encouraging is to see an OS benefit extending beyond just those patients who achieve an objective response, as we have come to expect from immunotherapies in many tumors.
Despite the small cohort of patients and limited data, discussant Dr. Disis was very positive on the results and called for researchers to move ahead and consider combination trials in breast cancer. This is a bit of a departure from typical breast cancer treatment strategies, which tend to focus on sequential monotherapies rather than combination regimens. The immunotherapy field is beginning to explore combination approaches in other solid tumors, so extending that idea to breast cancer isn’t novel. The approach Keytruda is taking (combining with Herceptin) is somewhat expected in breast cancer, although is limited to HER2+ patients. In TNBC patients, however, no targeted therapy options are yet developed with which to combine; chemotherapy thus becomes the de facto combination partner (Celgene is conducting a Phase I trial that includes study of Opdivo with Abraxane® (nab-paclitaxel) in second-line HER2-negative disease (NCT02309177)), although this approach negates the low-toxicity advantage that immunotherapy is meant to afford.
Breast cancer is the most commonly diagnosed cancer in the U.S. and Europe and is the second most commonly diagnosed cancer globally. Given the large number of patients involved, it is somewhat surprising that the checkpoint inhibitors haven’t been more widely developed in this disease. Perhaps higher unmet need drove early development of PD-1/PD-L1 inhibitors toward other malignancies, but the tides may now be shifting. It seems the immunotherapy wave has finally hit the shores of the breast cancer landscape.
- Disis M., Discussant Oral Session 1, SABCS 2014
- Loi S., Educational Session: Introduction to Immunotherapy, SABCS 2014
- Nanda R., Abstract S1-09, SABCS 2014
- Emens L.A., Abstract PD1-06, SABCS 2014
- Ribas, Abstract LBA9000, ASCO 2014
- Weber, Abstract LBA3, ESMO 2014
- Brahmer, Abstract 8030, ASCO 2013
- Rizvi, Abstract 8007, ASCO 2014
- Spigel, Abstract 8008, ASCO 2013
- Motzer, Abstract 5009, ASCO 2014
- Seiwert, Abstract 6011, ASCO 2014