Levy Lends Insight on Pivotal NSCLC Trials

Benjamin P. Levy, MD

Researchers are looking to further improve outcomes in non—small cell lung cancer (NSCLC) through a novel regimen of immunotherapy, angiogenesis inhibition, and chemotherapy—a synergistic combination that Benjamin P. Levy, MD, says would be exciting to have in the landscape.

The IMpower150 trial has investigated the combinatory use of antiangiogenic drugs and immunotherapy, regardless of PD-L1 expression, to improve progression-free survival (PFS), response rates, and overall survival (OS). The addition of atezolizumab (Tecentriq) to bevacizumab (Avastin), carboplatin, and paclitaxel was found to delay disease progression or death by 38% compared with bevacizumab and chemotherapy alone for patients with advanced nonsquamous NSCLC.¹

“There is a lot of biological rationale why adding immunotherapy to an antiangiogenic drug such as bevacizumab may have synergy,” said Levy. “Antiangiogenic therapies can help T-cell trafficking and T-cell mobilization into the tumor microenvironment.”

Additionally, the phase III KEYNOTE-189 trial has suggested pembrolizumab’s (Keytruda) PFS and OS benefit in combination with chemotherapy. KEYNOTE-189 served as the confirmatory trial for the accelerated approval of pembrolizumab plus carboplatin/pemetrexed in the frontline setting for patients with NSCLC, regardless of PD-L1 expression. The approval was based on phase II data from cohort G of the KEYNOTE-021 trial.²

OncLive: Can you discuss the data we have with frontline pembrolizumab and chemotherapy from the KEYNOTE-189 trial?

In an interview with OncLive, Levy, assistant professor of oncology, clinical director, Medical Oncology, Johns Hopkins Sidney Kimmel Cancer Center, Sibley Memorial Hospital, expanded on these strategies and highlighted other trials that continue to shape the treatment landscape for patients with lung cancer.Levy: What we know right now is that single-agent pembrolizumab is the standard of care for patients with a PD-L1 score greater than 50% in advanced-staged patients. However, there are new data emerging from KEYNOTE-189, which is a randomized phase III trial comparing carboplatin/pemetrexed versus carboplatin/pemetrexed with the addition of pembrolizumab.

What we have heard from a news report is that there are early signals of an OS advantage for adding pembrolizumab in combination with chemotherapy. This builds on a smaller, randomized phase II trial: cohort G of the KEYNOTE-021 trial. Similarly designed, this trial tested carboplatin/pemetrexed versus carboplatin/pemetrexed with pembrolizumab. In that trial of 120 patients, we saw an improvement in response rate, an improvement in PFS, and early signals of an improvement in OS. It will be interesting to see the results from the phase III trial.

What other combination regimens are showing promise?

They are likely to be presented at either the 2018 AACR Annual Meeting or the 2018 ASCO Annual Meeting. In that trial, I’m interested to see the outcomes for the patients who had a PD-L1 score greater than 50% and the outcomes for the patients who had a PD-L1 score less than 50%. For the right patients, having these drugs available as single agents in the chemotherapy-refractory and upfront settings is going to be beneficial. We're all very interested and excited to see the data as they unfold. The IMpower150 trial is a 3-arm trial that has been recently presented but not yet published, looking at the standard regimen of carboplatin/paclitaxel and bevacizumab (Avastin) as the control arm. This was compared to 2 other arms: carboplatin/paclitaxel and bevacizumab with atezolizumab, and carboplatin/paclitaxel and atezolizumab alone. The first analysis compared the ECOG-4599 standard of carboplatin/paclitaxel and bevacizumab to carboplatin/paclitaxel, and bevacizumab with atezolizumab.

What we saw in the data that were presented at the 2017 ESMO Immuno-Oncology Congress, was an improvement in PFS, response rates, and early signals for OS in the intention-to-treat analysis. That benefit was also seen in the patients who were PD-L1 negative. It’s a 4-drug combination, and the jury is still out on how we'll use this. However, it is exciting to see that adding another drug to an existing 3-drug regimen, specifically atezolizumab, may benefit patients.

What about the PACIFIC trial, which looked at durvalumab (Imfinzi)?

There's a lot of biological rationale why adding immunotherapy to an antiangiogenic drug such as bevacizumab may have synergy. Antiangiogenic therapies can help T-cell trafficking and T-cell mobilization into the tumor microenvironment. By adding these 2 drugs together, we are witnessing biological synergy that’s translating into the data. It will be very interesting to compare the outcomes of the IMpower150 trial to the outcomes of the KEYNOTE-189 trial. These will be 2 competing strategies, specifically for nonsquamous patients.Stage III NSCLC comprises about one-third of the patients that we see. For the past 10 to 20 years, we haven't had much movement advancing care. Patients are generally given concurrent chemoradiation but after that, it’s a vacuum. We have had no real strategies to improve outcomes, though there are different strategies we have looked at.

The PACIFIC trial is one of those seminal works that are altering the treatment paradigms for these patients. This was a trial looking at unresectable stage III adenocarcinoma and squamous cell carcinoma patients who received concurrent chemoradiation. They were randomized to immunotherapy every 2 weeks, specifically durvalumab for 1 year versus placebo. In this trial, we saw a marked difference in PFS, and we saw early signals of an improvement in time to metastatic disease and OS, a composite endpoint that favored the durvalumab arm.

What is being done to address patient resistance to immunotherapy?

These data are practice changing because we have nothing in this area for our patients right now. We all need to think about using durvalumab after concurrent chemoradiation for eligible patients. Interestingly, if you look at the subset analysis from this trial, all patients benefited whether they were PD-L1 negative or positive and whether they were a neversmoker or not. It will be interesting to see the OS data mature, but because of this, we have a new standard after concurrent chemoradiation for our patients for stage III disease. In stage III and stage IV disease, it is such a moving target. If immunotherapy moves upfront in stage IV disease, where patients’ tumors progress, we’ll have to focus the science on what to do afterwards. There is a ton of effort going on looking at different agents, such as OX40 agonists and LAG-3 inhibitors. There are a ton of different agents that we're trying to wrap our head around to understand how to overcome resistance.

We have a better understanding of how to overcome resistance in the targeted therapy realm than we do in the immunotherapy realm. Right now, chemotherapy after immunotherapy works and that should be the standard. Clinical trials certainly need to look into different combination strategies that may work for patients whose tumors progress on immunotherapy.

References

1. Reck M, Socinski MA, Cappuzzo F, et al. Primary PFS and safety analyses of a randomized phase III study of carboplatin + paclitaxel +/− bevacizumab, with or without atezolizumab in 1L non-squamous metastatic nsclc. Ann Oncol. 2017;28(11). doi.org/10.1093/annonc/mdx760.002.
2. Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016;17(11):1497-1508.