Immunotherapy Combinations Provide Long-Term Benefit in Stage IV NSCLC

Suresh Ramalingam, MD, FASCO

The FDA granted approval in May 2020 to the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) as treatment of patients with metastatic or recurrent non–small cell lung cancer (NSCLC), based on findings from the phase 3 CheckMate 227 clinical trial. Updated long-term data for part 1 of this trial were recently shared during the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Meeting, which depicted further benefit with the immunotherapy combination in patients with newly diagnosed advanced NSCLC.

Frontline treatment with this combination induced durable and long-term efficacy regardless of PD-L1 expression. After a median follow-up of 43.1 months, the median overall survival (OS) was 17.1 months with the combination versus 15.7 months with nivolumab alone and 14.9 months with chemotherapy. The 3-year OS rate was 33% for the combination, 29% with nivolumab monotherapy, and 22% with chemotherapy.

Additionally, 18% of patients with PD-L1 expression ≥ 1% remained progression-free at 3 years with the combination compared with 12% receiving nivolumab alone and 4% who received chemotherapy. For patients with PD-L1 expression < 1%, 13% remained progression-free at 3 years with the combination compared with 8% for those receiving nivolumab and 2% for chemotherapy. The 3-year progression-free survival (PFS) was 18% with the combination, 12% with nivolumab monotherapy, and 4% with chemotherapy in those expressing PD-L1 ≥ 1%, and 13% versus 8% and 2% in those expressing PD-L1 < 1%, respectively.

In an interview with Targeted Oncology, Suresh Ramalingam, MD, FASCO, deputy director, Winship Cancer Institute of Emory University, discussed the findings from the CheckMate 227 study that support the FDA’s approval of the combination of nivolumab and ipilimumab in patients with advanced NSCLC.

TARGETED ONCOLOGY: What was the rationale for this research?

Ramalingam: The main purpose of this trial was to look at the combination of ipilimumab and nivolumab as an IO/IO combination. There is preclinical rationale on why this combination is particularly helpful to promote anti-cancer immunity, and this combination has also been shown in other cancers like melanoma to be an effective approach.

This trial was designed to look at this combination. It is a very large trial, and we had 2 groups of patients. One group was those with PD-L1 expression greater than 1%, and the other group was those with PD-L1 expression less than 1%. We randomized patients in the PD-L1–high group to either the combination or nivolumab or chemotherapy in the frontline setting. For the PD-L1–low group, they received either chemotherapy, ipilimumab plus nivolumab, or chemotherapy plus nivolumab. These were newly diagnosed NSCLC patients with stage IV disease that had not received any prior treatment. The overall results of this trial were reported late last year in the New England Journal of Medicine. What we reported at ASCO 2020 is a longer follow-up and 3-year OS data.

TARGETED ONCOLOGY: Could you describe the previously published research before getting into the updated data?

Ramalingam: We found that for patients treated with ipilimumab plus nivolumab, the median PFS was improved compared with chemotherapy in the PD-L1–high group and the PD-L1–low group. The survival was also improved, and the OS hazard ratio was 0.79 for the PD-L1–high group and 0.62 in the PD-L1–low group. The trial met its primary end point of showing superiority in the PD-L1 high group and a secondary end point of OS in the PD-L1–low group.

TARGETED ONCOLOGY: What are the results that were presented this year?

Ramalingam: The exciting news we have is that with longer follow-up, the benefits we see with ipilimumab and nivolumab continue to hold up. There was no change in the hazard ratio. The other finding is we are reporting the 3-year OS data, and this shows that [among] patients who get ipilimumab plus nivolumab in the PD-L1–high group, 33% were still alive. In the PD-L1–low group, there was a similar percentage of patients who were alive, so almost 1 out of 3 patients with stage IV NSCLC are alive at 3 years. I think this shows how far we have come and the power of the combination immunotherapy approach.

The second point I want to make is we looked at the duration of response (DOR). If the patient has a response to ipilimumab and nivolumab, chemotherapy, or nivolumab and chemotherapy, what is the likelihood that they maintain that response? This is where the IO/IO combination makes a big difference. For the PD-L1–high group, the median DOR was almost 2 years, whereas with chemotherapy alone in this group of patients, the median DOR was only about 6.5 months. You see a big difference there, and we see similar trends in the PD-L1–low group. The ability to maintain response for a longer period of time is made possible by using ipilimumab and nivolumab.

The third point I want to make is we conducted a landmark analysis that looked at if a patient received ipilimumab and nivolumab or chemotherapy or nivolumab, by looking at their best response from the time of starting treatment to the 6-month time point, what does it mean for OS? If a patient had a complete or partial response to ipilimumab and nivolumab, their likelihood of being alive at 3 years is over 70%. In the PD-L1–low group, it was over 80%, whereas with chemotherapy alone, those numbers were substantially lower. Again, this notes the point that if you have a response with ipilimumab and nivolumab, the likelihood of long-term benefit is substantial.

These are the 3 take- home points. First, the 3-year OS rate is approximately 34% with ipilimumab and nivolumab. Second, the median DOR is substantially higher, almost 3-fold higher, with ipilimumab plus nivolumab compared with chemotherapy. Thirdly, the likelihood of achieving long-term survival with an objective response of 6 months is over 70% with ipilimumab and nivolumab.

TARGETED ONCOLOGY: Are there any next steps for this trial or any questions you hope to answer with further research?

Ramalingam: We just heard that the FDA approved ipilimumab and nivolumab for the frontline treatment of NSCLC in the PD-L1–high group. This is a big step forward for our patients to have a chemotherapy-free option that has the ability to prolong results. The next steps, in my view, are to look at this regimen in other settings of NSCLC, for instance stage III disease, and if this can be the basis for other novel combinations to build on. That is exciting to think about as we move forward.

TARGETED ONCOLOGY: What are your final thoughts on these findings?

Ramalingam: One question that often comes up when we talk about multiple immunotherapies put together is whether there is a high incidence of autoimmune toxicity, what is the impact of that on patients? We have the long-term data analyzed, so what we can say is that most of these salient toxicities occur in the first 6 months of therapy and are manageable in the vast majority of patients. When we get beyond the 6-month period, the likelihood of developing any of these toxicities is relatively low, which tells us that with appropriate supportive care, even if patients developed these toxicities, we were able to get them through the planned 2 years of therapy; that is reassuring to the patients and our physicians.