Raffaele Califano, MD, discusses the KEYNOTE-028 and CheckMate-032 trials, the role of PD-L1 as a biomarker in small cell lung cancer, and what is on the horizon for immunotherapies in the landscape of SCLC.
Raffaele Califano, MD
Immunotherapy has the potential to change the natural history of small cell lung cancer (SCLC), according to Raffaele Califano, MD, a consultant in Medical Oncology at the Christie NHS Foundation Trust and University Hospital of South Manchester.
“In SCLC, unfortunately, from a systemic anticancer treatment point of view, we have really had no new drugs over the last 20 years,” says Califano. “We really need something that can help our patients to achieve better outcomes, and I do believe that immunotherapy has that potential.”
Currently, the most promising immunotherapy agents in SCLC are the PD-1 inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda), says Califano.
Single-agent nivolumab, and the combination of nivolumab plus the CTLA-4 inhibitor ipilimumab (Yervoy), was investigated in the phase I/II CheckMate-032 trial in pretreated patients with SCLC.1
Patients who received the combination had a median progression-free survival (PFS) of 3.35 months with the combination and 1.38 months with nivolumab alone. Median overall survival (OS) was 7.75 months with the combination and 3.55 months with single-agent therapy. The objective response rate (ORR) with the combination was 31.1%.
Pembrolizumab was investigated in the phase Ib KEYNOTE-028 trial, where the PD-1 inhibitor demonstrated an ORR of 29.2% (95% CI, 12.6-51.1) in patients with SCLC who had prior chemotherapy.2
These findings are preliminary, says Califano, but extremely promising.
OncLive: What role do you see immunotherapy playing in SCLC?
In an interview with OncLive, Califano further discusses the KEYNOTE-028 and CheckMate-032 trials, the role of PD-L1 as a biomarker in SCLC, and what is on the horizon for immunotherapies in the landscape of SCLC.Califano: SCLC is a very aggressive disease. Despite being highly responsive to chemotherapy, the vast majority of patients who have received first-line platinum chemotherapy will progress, and, unfortunately, outcomes from second-line chemotherapy are very poor. We have a desperate need for new treatments that will change patient outcomes.
Can you discuss some of the data we currently have with immune checkpoint blockade in SCLC?
The data on immune checkpoint blockades, mostly nivolumab and pembrolizumab, are very exciting. These are early-phase data that show that these drugs can be effective, in terms of higher response rates and potentially improving PFS from the historical data that we have of second-line treatment with chemotherapy. This data needs to be confirmed in ongoing randomized phase II and III studies. However, by certainly looking at the results, there is a lot of enthusiasm in the medical community.Immune checkpoint blockade has been investigated in a number of clinical trials in non—small cell lung cancer (NSCLC). It is only recently that there has been a lot of research starting in the SCLC setting. This is very exciting because the immune checkpoints play a critical role in balancing the activity of the immune system in the fight against cancer cells.
Two of the main inhibitor checkpoints are currently targeted by 2 monoclonal antibodies, which have been trialed for patients with SCLC. The first one to be studied was ipilimumab, which is currently approved for melanoma.
It was examined in a phase II randomized trial with 3 arms. Ipilimumab was given together with chemotherapy in the concurrent setting. This trial demonstrated an immune-related PFS, but not an improvement in PFS or OS, despite having a trend toward an improvement in OS. A phase III randomized trial has launched and did close, but the results have not yet been presented.
Certainly, what is more exciting, are the anti—PD-1 agents such as nivolumab and pembrolizumab. These have been studied in an early-stage trial.
CheckMate-032 has investigated patients in a number of cohorts receiving nivolumab either with or without ipilimumab at different doses. This was followed by continuous maintenance nivolumab after 4 cycles. To summarize the results, these patients have achieved quite an impressive response rate. In the single-agent nivolumab arm, it was about 18%; in the combination, it was in the region of 30% with a disease-control rate that reaches about 60% in the combination arm.
The drug seems to be well tolerated, and the adverse events profile mirrors the adverse events that we have seen in NSCLC. On the basis of these promising data, there are now trials ongoing looking at nivolumab as second-line treatment and as maintenance therapy.
Do you see a continued role for PD-L1 as a biomarker for these treatments in SCLC?
Pembrolizumab was investigated in SCLC in the KEYNOTE-028 study. That was given as a single agent until progressive disease or up to 2 years of treatment. In this study, the patients were only selected on the basis of positive PD-L1 expression. The response rate was pretty high—in the region of 30%—and the drug was well tolerated. Also, on the basis of this preliminary result, a number of studies have been launched looking at pembrolizumab in association with standard chemotherapy as a first-line or as a maintenance treatment.It is very difficult to give an answer regarding that now, because the data are very preliminary. The nivolumab study did not select for PD-L1 positivity, but they only looked at it retrospectively; therefore, it was not an inclusion criteria. When they looked at the correlation between the PD-L1 expression and response rate, there was really no difference.
In KEYNOTE-028, it was required for patients to be PD-L1—positive. Again, when they looked at the gradient of positivity and response rate, there was really no difference. It is really difficult at this time to say, “We should only select patients who are PD-L1–positive.” The vast majority of trials that are ongoing are not selecting for PD-L1 positivity.