Expert Anticipates Avalanche of Data to Impact Treatment Landscape in NSCLC

Corey J. Langer, MD

Treatment in lung cancer continues to evolve at a rapid pace with the arrival of a set of efficacious new agents and promising evidence-based data. According to Corey J. Langer, MD, a veritable avalanche of additional data is on the way.

“There’s certainly a lot of exploration expanding immunotherapy to the first-line setting, both as single agents for those who are enriched for PD-L1, but also in combination in all-comers with other immunotherapy approaches, as well as with standard platinum-based chemotherapy,” said Langer, a professor of Medicine at the Perelman School of Medicine and director of Thoracic Oncology at the University of Pennsylvania.

OncLive: What did you discuss at the CFS?

In an interview with OncLive at the 34th Annual Chemotherapy Foundation Symposium™ (CFS), Langer discussed some of this groundbreaking data, novel combinations potentially on the horizon, and much more in the field of lung cancer.Langer: I focused on squamous cell advanced non—small cell lung cancer (NSCLC). I summarized the therapeutic landscape, which really begins first with cytotoxic, so gemcitabine and taxanes combined with platinum. We’ve now seen the emergence of nanoparticle-bound paclitaxel, which seems to have advantages over conventional taxanes in this setting.

And more recently, the addition of EGFR monoclonal antibodies—necitumumab (Portrazza) in combination with gemcitabine/platinum—is clearly looking better than chemotherapy alone. And ramucirumab (Cyramza) in the second-line setting offers a survival advantage in combination with docetaxel (Taxotere) versus docetaxel alone.

But probably the most striking data are really for immunotherapy, certainly in the second-line setting, where nivolumab bested docetaxel. The response rates were more than double—20% or 21% versus 8% or 9%. Progression-free survival (PFS) was 50% higher for nivolumab (Opdivo) versus docetaxel, and median survival was at least 3 to 4 months better, and about 10% to 15% better at 1 year for nivolumab compared to docetaxel.

Could you discuss CheckMate-017 in detail?

We also have extraordinarily striking P-values and hazard ratios in the CheckMate-017 trial, which focused exclusively on squamous cell, and had an immediate effect on standard practice, and overnight, we shifted from docetaxel to immunotherapy second-line in squamous cell.CheckMate-017 was based on phase I and phase II data that showed promise, both in response in selected patients, and in prolonged PFS in individuals who received nivolumab—not just second-line, but third-, fourth-, even fifth-line. This was specifically in the second-line setting—individuals who had been exposed to a platinum-based combination who had had disease progression. CheckMate-017 randomized 1:1 between nivolumab and docetaxel and had striking results, major improvement in response rate, progression-free, and overall survival. And this really secured the place of immunotherapy in the second-line setting.

How robust is exploration of immunotherapies like this in the first-line setting?

What sort of impact do you think that avalanche of data is going to have?

Could you compare the current treatment landscapes for squamous cell and non-squamous cell lung cancer?

Just as important, the toxicity was considerably less. The incidence of grade 3 or higher toxicity was maybe 10% or 15% for nivolumab, compared with 50% or 60% for docetaxel. The effects of this trial were almost overnight. We saw a major paradigm shift in how we manage second-line squamous cell based on that study.There’s certainly a lot of exploration expanding immunotherapy to the first-line setting, both as single agents and for those who are enriched for PDL-L1, but also in combination in all-comers with other immunotherapy approaches, as well as with standard platinum-based chemotherapy. Just about all the biotech and pharmaceutical companies that are investigating the role of immunotherapy are conducting trials in the frontline setting. So, stay tuned, there’s going to be an avalanche of clinical data looking at frontline immunotherapy.That impact probably already exists, though I don’t think we’ve quite seen it in clinic yet, but the frontline pembrolizumab (Keytruda) data—which showed an advantage in those with 50% or higher PD-L1 expression for PFS and survival compared to standard chemotherapy—is likely to change how we manage frontline advanced NSCLC. About 20% to 30% of individuals have higher levels of PD-L1 expression, and I dare say in the next 1 to 2 years, those individuals will most likely be treated preferentially with a single-agent immune therapy head of chemotherapy, with chemotherapy not out of the picture, but reserved for second-line treatment.The vast majority of patients with advanced NSCLC, unfortunately, do not have oncogenic drivers. Those are confined, really, to maybe 20% to 30% of the group, and certainly we’ve seen lots of promise for new agents based on the molecular target. But the majority doesn’t have it. We’re still really in the era of systemic cytotoxics, and we have made some headway here, too. In the last 10 or 12 years, we’ve seen distinctions histologically with the role of pemetrexed (Alimta) and bevacizumab (Avastin) clearly secured for nonsquamous cell phase III trials that have shown a survival advantage for those agents in combination with platinum, or platinum and other cytotoxics that have proven superior. And that really is our platform for nonsquamous.

For squamous, it’s been a far greater challenge. There are phase III histology-based data that show, for instance, that gemcitabine and platinum is superior to pemetrexed and platinum. And so gemcitabine is certainly one of our go-to agents for those with squamous histology.

Taxanes have also proven superior to pemetrexed in the second-line setting in squamous, and so taxanes are generally used upfront there, too. We do have very interesting data looking at nanoparticle albumen-bound paclitaxel in combination with carboplatin which, compared to conventional solvent-based paclitaxel, has led to a significant improvement in response rate, although that hasn’t really translated into either progression-free or overall survival advantage in squamous cell. It should be noted that in individuals over 70, there was an advantage. Again, it’s a retrospective analysis. It’s only 150 patients or so, but about an 8- or 9-month difference favoring the nanoparticle bound taxane over the conventional standard solvent Cremophor-based molecule.

Could you talk about some of the toxicities of some of those agents you mentioned, either in combination or as monotherapies?

A big remaining question is, are there other agents that may have benefit in squamous? There are data in the second-line setting combining ramucirumab, which is an angiogenesis inhibitor that targets the receptor on endothelial cells, in combination with docetaxel. Clearly, we see a survival advantage compared to standard chemotherapy alone. This was observed not just in adenocarcinoma, but also in squamous cell. It’s certainly an option in the second-line setting, and we have compelling data for EGFR monoclonal antibody, necitumumab, in combination with the gemcitabine regimen, which has led to a survival advantage in the frontline setting. So the options are expanding, but not as quickly as nonsquamous.Pemetrexed compared to taxane is generally less toxic. We don’t see the hair loss that’s typically associated with taxanes, much less neuropathy, virtually no neuropathy with pemetrexed. We do see some rash, sometimes gastrointestinal toxicity or myelosuppression. But the routine use of vitamins like B12 and folic acid has really mitigated the toxicity of pemetrexed.

What are some of the ongoing studies in this space that you’re particularly excited about?

Will there be anything in the works for pembrolizumab as a combination therapy?

There was a recent FDA submission for brigatinib in ALK-positive NSCLC. Could you discuss the findings that that was based upon, and what this drug might offer for patients if it is approved?

When it comes to necitumumab, it’s an EGFR monoclonal antibody, so rash is seen. You do see some hypomagnesaemia. There is some concern about the increasing incidence of thromboembolic phenomena, although the incidence overall is quite low. And for any drug like ramucirumab, or for that matter, bevacizumab, you have to worry about bleeding. Endothelial cells are the target, and we’ve seen both bleeding and blood clots with this class of agents, and patients need to be closely monitored for those effects.In the second-line setting, really across the board for driver-negative NSCLC, for individuals without targeted agents—Immunotherapy has really shown a major impact. CheckMate-017 showed superiority for nivolumab over docetaxel in squamous cell. CheckMate-057 showed major advantage, the same advantage for nivolumab over docetaxel in nonsquamous, although the P-values and hazard ratios weren’t quite as robust as seen in the squamous cell group. We’ve seen similar data now for pembrolizumab in the same setting in those with PD-L1 expression, and now it’s just a press release. We’ve not seen the data, at least as of mid-September 2016, but in those with 50% or greater expression by IHC, pembrolizumab, single-agent immunotherapy, appears to be superior to standard platinum-based combinations in the frontline setting, both with respect to progression-free and overall survival.There are ongoing studies pairing pembrolizumab with other immunotherapy agents, including ipilimumab (Yervoy). The data are still very preliminary, but it does seem to combine fairly well with these other agents. Of course, you’re always worried about heightened immune-mediated toxicity. And there are frontline studies now, combining pembrolizumab with standard chemotherapy combinations. Dr. Shirish Gadgeel and others presented early phase I/phase II data for pembrolizumab combined with pembrolizumab/carboplatin, paclitaxel/ carboplatin, and paclitaxel/carboplatin/bevacizumab. And there are very likely going to be, in the near future, randomized data comparing chemotherapy plus various immunotherapies, not just pembrolizumab, in the frontline setting. So, again, stay tuned. We’ve seen a survival advantage for single agent, and we may further expand that survival advantage using combinations.Brigatinib is a highly active ALK inhibitor, really amongst the second-generation agents. It seems to be as effective as ceritinib (Zykadia) and alectinib (Alecensa) in this setting in individuals who have already been exposed to, have responded, and then had disease progression on crizotinib (Xalkori) which, by the way, is actually a very poor ALK inhibitor. Crizotinib really started out as a MET inhibitor. So we see a new generation of agents, each of which seems to have, at least in the frontline setting, better progression-free survival outcomes. We’ve recently seen data—the J-ALEX trial—that compared alectinib to crizotinib in the frontline setting and showed major improvement in progression-free survival. The hazard ratio was under 0.4, and really around 0.1 in individuals who had CNS involvement. This whole new generation of agents—brigatinib as well as alectinib—seem to have more CNS penetrance than frontline treatment.

So brigatinib is on the fast track, we think, for drug approval based on phase I, and now randomized phase II data, response rates in the 50% to 60% range, progression-free survival of 12 to 16 months, depending on which study we look at, and major CNS penetrance. The biggest issue for brigatinib, I think, is the relatively low incidence of pulmonary toxicity, but it can still occur, and often occurs almost immediately within 24 to 48 hours in about 3% to 6% of patients. So learning how to manage that toxicity, perhaps learning how to prevent it, I think, is one of the challenges. But, beyond that, from personal experience, brigatinib is extremely well tolerated. And I have at least 2 patients now with ALK-positive disease that had progressed on crizotinib who have been on brigatinib now for over 4 years.