Novel Combos Raise Sequencing Questions in Nonsquamous NSCLC

Rathi N. Pillai, MD

With superior response rates, progression-free survival (PFS), overall survival (OS) and little additive toxicity to chemotherapy alone, chemoimmunotherapy combinations have become a new standard of care in the frontline treatment of patients with advanced nonsquamous non—small cell lung cancer (NSCLC), said Rathi N. Pillai, MD. However, their widespread adoption has also raised an abundance of questions in the second-line setting.

Such chemoimmunotherapy regimens include the combination of pembrolizumab (Keytruda) with platinum-based chemotherapy, as well as the regimen of atezolizumab (Tecentriq), bevacizumab (Avastin), and platinum-based chemotherapy.

“At this point, we don't have clear data to guide us after a patient progresses on chemoimmunotherapy, or data to suggest that [giving chemoimmunotherapy to a patient who progresses on single-agent immunotherapy] would be a viable strategy,” said Pillai. “These are very important areas of investigation that need to be pursued.”

PFS2, defined as the time from randomization to progressive disease after the start of second-line therapy or death, may be one way to evaluate some of these sequencing questions, explained Pillai. For example, in the phase III KEYNOTE-189 trial, patients who were randomized to receive frontline pembrolizumab plus platinum-based chemotherapy had a longer PFS2 than those who received chemotherapy alone (HR, 0.49; 95% CI, 0.40-0.59; P <.00001), suggesting greater amenability to chemotherapy with prior exposure to immunotherapy.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Non—Small Cell Lung Cancer, Pillai, assistant professor in the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, discussed the basis for frontline combinations of chemotherapy and immunotherapy in advanced nonsquamous NSCLC and questions surrounding the optimal sequence of these agents.

OncLive: Could you discuss recent shifts in the frontline treatment of patients with advanced nonsquamous NSCLC?

Pillai: There have been several randomized, controlled phase III studies that have shown improved efficacy with the addition of immunotherapy to platinum-doublet chemotherapy in patients with stage IV nonsquamous NSCLC. On the basis of these data, I prefer to prescribe chemoimmunotherapy to a patient with newly diagnosed nonsquamous NSCLC [versus chemotherapy alone], due to the improvements we’ve seen in response rate, PFS, and OS. Notably, the combinations have not shown a significant increase in toxicity either, which has led to the widespread adoption of these combinations in the clinic.

How have these combinations impacted sequencing strategies?

It's a very relevant question. We currently don't have any data to guide us. We're in a great time in thoracic oncology. We have so many active agents and combinations that are improving patient outcomes, but we also have many questions regarding how to use all of these strategies to the best of our ability. Right now, we don't have any data that suggest giving chemoimmunotherapy to a patient who progresses on single-agent immunotherapy is beneficial. However, that's [an approach] that, when we think about it, might make sense.

Another question we have is about the sequencing of chemotherapy and immunotherapy. Currently, there are no clear data to guide us on what we should do after a patient progresses on chemoimmunotherapy. It is tempting to believe that we could use the KEYNOTE-189 regimen followed by the quadruplet regimen from the IMpower150 study given that they're different chemotherapy drugs with different mechanisms of action. In my practice, when a patient progresses on chemoimmunotherapy, I generally go back to our tried-and-true salvage docetaxel-based regimen. Whether that [regimen is] given in combination with ramucirumab (Cyramza) or alone depends on the patient, their performance status, and their ability to tolerate a more intense regimen.

Could you discuss the updated survival data from the phase III KEYNOTE-189 trial?

The updated analysis of the KEYNOTE-189 trial looked at survival outcomes and time to progression, or PFS2. PFS2 is an endpoint that we're starting to see a little bit more coverage of. Given that many patients in the KEYNOTE-189 trial had the ability to crossover to [pembrolizumab monotherapy], the real relevance of that endpoint was in the sequencing of therapy and how that impacted patients in the long-term. What was really interesting is that the patients who were assigned to receive upfront immunotherapy with a platinum/pemetrexed backbone, still had a more prolonged PFS2 compared with patients in the placebo arm. Similarly to what we've seen in some other studies, and anecdotally, this suggests that prior exposure to immunotherapy helps a patient respond better to subsequent lines of chemotherapy.

The other interesting aspect of the analysis was the fact that several patients were not able to go onto second-line therapy. That was quite remarkable to me because we're looking at a group of patients who started with an excellent performance status. If one-third of those patients couldn’t go onto second-line therapy, it behooves us to really consider that in our practice where the majority of patients wouldn't meet the stringent criteria to go on a clinical trial.

Should PFS2 be included as a clinical endpoint in more trials?

Europeans have been much more interested in looking at that endpoint in analyzing the efficacy of new treatments. We're starting to appreciate PFS2 more in the United States. Given the success we’ve had in lung cancer and with all of the new agents we have to offer our patients, it is a relevant timepoint in helping us understand OS and sequencing, which is a clinically relevant question we would like answers to.

Gadgeel SM, Garassino MC, Esteban E, et al. KEYNOTE-189: updated OS and progression after the next line of therapy (PFS2) with pembrolizumab (pembro) plus chemo with pemetrexed and platinum vs placebo plus chemo for metastatic nonsquamous NSCLC. J Clin Oncol. 2019;37(suppl 15; abstr 9013). doi: 10.1200/JCO.2019.37.15_suppl.9013.