Rizvi Recounts Recent Immunotherapy Advances in Lung Cancer

Naiyer Rizvi, MD

With frontline pembrolizumab (Keytruda) recently receiving a priority review, immune checkpoint therapy has moved 1 step closer to regulatory approval as a first-line treatment for non—small cell lung cancer (NSCLC).

The review is based on data from from the phase III KEYNOTE-024 trial, in which frontline pembrolizumab improved overall survival (OS) and progression-free survival (PFS) versus chemotherapy in patients with NSCLC and PD-L1 expression levels ≥50%.

The PD-1 inhibitor nivolumab (Opdivo) was also examined in the frontline NSCLC setting in the CheckMate-026 trial, but the agent did not improve PFS versus chemotherapy; however, experts have highlighted issues with the trial design, including the primary endpoint and the lower PD-1/PD-L1 expression cutoff of 5%.

Nivolumab did show promising clinical activity when combined with the anti—CTLA-4 agent ipilimumab (Yervoy) in patients with recurrent small cell lung cancer (SCLC) enrolled in the CheckMate-032 trial. In the study, treatment with the combination of nivolumab and ipilimumab demonstrated a median OS of 7.7 months and a 1-year OS rate of 43%.

OncLive: What was your reaction to the results of the CheckMate-026 trial of frontline nivolumab in NSCLC?

What do the CheckMate-026 and KEYNOTE-024 trials tell about tumor PD-L1 expression levels and the success of anti—PD-1 agents in lung cancer?

In an interview with OncLive, Naiyer Rizvi, MD, director of Thoracic Oncology and Immunotherapy at Columbia University Medical Center, discussed these trials and expressed his optimism about immunotherapy in the field.Rizvi: I think that the results reflect that for first-line therapy, where the comparator is the more effective therapy, you probably need to have a more stringent cutoff for having durable response to these treatments. We also know that timed progression isn't always the best endpoint for immunotherapy trials. I don't know if it's been publicly disclosed what cutoff they used, but the likelihood is that they chose a lower cutoff than the pembrolizumab trial and it wasn't statistically geared, presumably, to the the higher cutoff. That's my interpretation for the positive pembrolizumab trial but the negative nivolumab trial.I think it generally tells us that these therapies only help a small segment of the lung cancer population, whether it's 15% or 20%. And although we know that patients who have low levels of expression have some responses—some durable responses—that can be observed, I think that would tell us that it's a reasonable biomarker, but it's not a great biomarker.

Beyond PD-1/PD-L1 expression, what other biomarkers are being explored as alternative options with immunotherapy in lung cancer?

Focusing on small cell lung cancer, can you discuss the CheckMate-032 study, which examined the combination of nivolumab and ipilimumab in SCLC?

To me, I think the results really helps us, probably more, in deciding who should get first-line PD-1 use versus second-line use. So if you're highly positive and it's better than first-line chemotherapy, you would get it first-line. If it’s low level expression or negative, then it’s probably still better than second-line chemotherapy you would give to the rest of the population when chemotherapy fails first line.There are lots of them. I think that mutation load is being looked at and gene expression profiles are being looked at. Those are the 2 leading ones, but I don’t think that any of the data has been reported in a validated way in terms of being able to be used. I don't think they're going to necessarily be used instead of PD-L1 expression, but they will probably be complementary results to use together to enhance the sensitivity.Those data are very important. We haven't had any advances in small cell since forever, and there's nothing other than standard chemotherapy, which has been around for a long time. Small cell does seem biologically different than NSCLC in that the response to single-agent PD-1 therapy is lower than that of NSCLC. I think that may be from other mechanisms of immunosuppression within the tumor.

Also in SCLC, what are your thoughts on the recently announced study exploring the antibody-drug conjugate rovalpituzumab tesirine (Rova-T) in combination with nivolumab alone or with nivolumab and ipilimumab?

How do you see the treatment landscape of lung cancer changing in the next 5 to 10 years or so?

The combination data looked very encouraging, albeit there were other toxicities which were an issue from the data. But there are definitely people who are getting durable benefit in small cell, so I think that these data are promising.It makes sense to do that trial. Rova-T, again, demonstrated high levels of activity in tumors expressing DLL3. It seems that this will be an exciting study to look at, in terms of potential combination synergy with the 2 treatments.Completely. There's a lot of data that will be coming out in the next couple of years, so it's hard to have a crystal ball and say how we're going to treat lung cancer in the future, but I think we could be using immunotherapy completely in [PD-1/PD-L1] positives, as well as negatives. The potential for combination immunotherapy in the first-line space could be for both positives as well as negatives. We'll have to see how the Roche trials read out in terms of chemotherapy combinations with immunotherapy. I think it's really just the beginning.