Immunotherapy and especially immune checkpoint inhibition continued to occupy the centre stage at this year’s meeting of the American Association for Cancer Research (AACR) in Philadelphia. Among many cancer immunotherapy presentations, key data from three clinical studies were presented involving the already approved pembrolizumab (Keytruda), ipilimumab (Yervoy) and nivolumab (Opdivo) and which were also published, back to back, in the 23rd of April 2015 issue of the New England Journal of Medicine. Other notable results were also presented of immune checkpoint modulation using novel approaches and in tumour types besides melanoma.
Pembrolizumab, recently approved by the US Food and Drug Administration (FDA) as second-line therapy for patients with metastatic melanoma no longer responding to BRAF inhibitors or ipilimumab, is now moving closer to first line therapy while also trying to enter the Non Small Cell Lung Cancer (NSCLC) space. In a Phase III trial in advance melanoma and head-to-head comparison with ipilimumab, pembrolizumab produced superior results in all outcomes studied (Ribas at al., Abstract no. CT101). In this trial patients were randomized to receive four doses of ipilimumab (at the approved dose of 3 mg per kilogram) every 3 weeks or pembrolizumab (at a dose of 10 mg per kilogram of body weight – higher than the approved dose) every 2 weeks or every 3 weeks.
The six month analysis revealed that both progression-free survival (PFS) and overall survival (OS) were higher for the pembrolizumab than ipilimumab (45% versus 26% for PFS and 87% versus 75% for OS). At 12 months OS was 74% and 68% for the two pembrolizumab arms whereas it was 58% for ipilimumab. In terms of adverse reactions, events were lower in the pembrolizumab arms (12%) compared to ipilimumab (20%).
In NSCLC and following last year’s initial presentation of the KEYNOTE-001 Phase I trial, it was now reported that pembrolizumab generated durable responses in patients with advanced NSCLC and that PD-L1 expression in at least half of the patient’s tumour cells correlated with improved efficacy (Garon at al., Abstract no. CT104). More specifically, the Overall Response Rate (ORR) in the 495 patients included in the study was 19%. The median duration of response exceeded a year among responders regardless of the degree of PD-L1 expression. The ORR was closer to 50% in the quarter of the patients who had PD-L1 expression in at least half of their tumour cells. For patients with less than 49% and 1% of tumour cells showing PD-L1 expression, the ORRs were 16.5% and 10.7%, respectively.
After a median of 10.9 months of follow-up, in patients with PD-L1 expression in at least half of their cancer cells, the median overall survival had not been reached irrespective of whether they were treatment-naïve or had received therapy previously. Approximately one fifth of all patients that were recruited to this trial were treatment-naïve.
Clinical data indicated that inhibition of the PD-1/ PD-L1 immune axis may be a promising therapeutic target in other tumour types as well. Pembrolizumab was found to be well tolerated and safe, and showed signs of clinical benefit, for patients with malignant pleural mesothelioma (Alley at al., Abstract no. CT103). Preliminary data in a subset of the KEYNOTE-028 Phase I trial showed that among the 25 patients with malignant pleural mesothelioma, 7 patients experienced a partial response (PR) and 12 had stable disease. Only patients whose tumours were positive for PD-L1 were eligible for enrolment in this study.
In patients with triple negative breast cancer, the novel monoclonal antibody MPDL3280A targeting PD-L1 was found to be safe, tolerable, and showed early signs of durable clinical activity in patients with the disease in a first-in-human phase I clinical trial (Emens et al., Abstract no. 2859)
The simultaneous targeting of multiple immune effectors generated a lot of interest triggered by promising data. One such high profile combination clinical study examined the inhibition of two checkpoint modulators, CTLA-4 and PD-1, using ipilimumab and nivolumab, respectively (Hodi at al., Abstract no. 2860). The safety and tolerability of this combination were confirmed in a Phase II trial that included 142 patients with advanced cancer but who had not received prior therapy. Approximately a third of these had BRAF V600 mutations. All patients were randomised to receive ipilimumab together with nivolumab followed by nivolumab alone or ipilimumab plus placebo followed by placebo alone. Patients with no BRAF mutations who received ipilimumab plus nivolumab had an objective response (OR) of 61%; those who received ipilimumab plus placebo had an OR of 11% with no complete responses (CRs) reported in this group.
The combination treatment was also superior in patients with BRAF V600 mutations, where a 44% ORR was observed (17% CR and 26% PR). However adverse events in the combination arm were higher compared with patients treated with ipilimumab alone.
An alternative combination approach presented was that of an immunostimulatory molecule, the anti-CD40 monoclonal antibody CP- 870,893 with a checkpoint inhibitor, the anti-CTLA4 antibody tremelimumab (Bajor et al., Abstract no.CT137). In a Phase I study enrolling 24 patients, there was clear clinical evidence of response to this combination, including patients with highly morbid visceral disease. After a median follow-up of 22 months, the ORR was 27%, with median PFS and median OS of 2.5 and26.1 months, respectively.
The findings of these clinical trials raise several points about the future of cancer immunotherapy. The ability and usefulness of biomarkers and especially PD-L1 to predict response to therapy is a key area of investigation. The adverse events observed with such therapies and especially the high grade immune-related events warrant caution. In addition, the current data based on ORR will have to translate into meaningful OS data.
What is encouraging from these trials is that the multiple immune pathways may remain relevant in the tumours irrespective of previous treatment(s) and could be targeted in order to achieve synergistic and maximum clinical benefit. Similar to other targeted therapies, combination therapy is the way forward. Overall, the clinical picture so far indicates that cancer immunotherapy will continue to remain in the limelight for a while.
- Postow MA, et al. Nivolumab and Ipilimumab versus Ipilimumab in Untreated Melanoma. N Engl J Med. 2015, Apr 20
- Garon EB, et al.Pembrolizumab for the Treatment of Non-Small-Cell Lung Cancer. N Engl J Med. 2015. Apr 19.
- Robert C, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015. Apr 19.