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Nondriver NSCLC Trials: KEYNOTE-189, -407, -024

A discussion on the design, results, and practical implication of KEYNOTE-189, -407, and -024 trials.
 

Roy Herbst, MD, PhD: KEYNOTE-189 is an important study because it took pembrolizumab, which we know can be used as a single agent in people who are PD-L1 [programmed death-ligand 1] high. But even there, the response rates are less than 50%, although the results are quite extraordinary. And the study takes patients, no matter what their PD-L1 status, and treats them with chemotherapy and carboplatin-pemetrexed because they’re all nonsquamous patients or chemotherapy with pemetrexed and pembrolizumab.

So carboplatin-pemetrexed and pembrolizumab. So a triplet versus a doublet. And this trial, of course, was highly positive at its primary end point with hazard ratios in the 0.6 range. But importantly, it was also positive across all lines, at least in the first analysis that was presented at the AACR [American Association for Cancer Research Annual Meeting] in 2018. So the data looked a little bit better for the PD-L1 high than the low and the 0, but the hazard ratios for survival were significant in all 3 groups.

Based on that study for the most common type of lung cancer, non–small cell lung cancer, of which nonsquamous is the most common type of that, most people would use, after discussion with patients, pembrolizumab with carboplatin-pemetrexed. In those patients who are PD-L1 high, more than 50%, there would still be a discussion of trying to use the immunotherapy alone.

Well, you know, the human body can tolerate only so much chemotherapy. Chemotherapy is active and kills dividing cells, but there are dividing cells in the bone marrow, and in the hair, and in the lining of the gut. So usually 4 cycles of chemotherapy, these are data from many years ago and that have continued to be held up; 4 cycles of cytotoxic chemotherapy are enough. There is maintenance therapy, though. The use of pemetrexed as a maintenance has been shown to be quite promising and active. So now you do maintenance therapy and pemetrexed with pembrolizumab. So that’s where that rationale came up. We’re still trying to investigate exactly the biology of what’s happening when you give chemotherapy plus immune therapy. Keep tuned. I think in the next months we’ll start seeing some more of those data emerge. But right now that has become the standard of care for the nonsquamous patient, and we’re using it at Yale Cancer Center, where I work. Both at our main campus and throughout the care centers, that’s being used.

Though still we can do better. At 1 year, 38% of the patients are progression-free, but the rest have progressed, meaning there’s got to be something better. But right now, this is a huge advance. And I can tell you, I’ve been taking care of lung cancer almost exclusively for more than 20 years, and this really is paradigm shifting, especially given that most of these patients do not have driver mutations. So these are the patients who can’t get an EGFR, an ALK, or a ROS1 inhibitor.

Yeah, I think what we’ve seen over 20 years, of course chemotherapy and moving chemotherapy to early disease, then we saw the targeted therapies, starting with EGFR and then everything that’s come behind it accelerated because of the sequencing and the profiling that’s been done. And now immunotherapy—yes, a big wave of new results and data. It’s extraordinary.

Well, different. Immunotherapy has different toxicities from chemotherapy or targeted therapy. You can have pretty severe toxicities in some patients, but it’s fewer than 5% who get the grade 3 or 4 really bad toxicities. The inflammation. Basically, anything that has -itis next to it can happen: pneumonitis, carditis, colitis, inflammation of different organs. But most of the time it’s just mild, maybe some diarrhea, maybe some mild pulmonary infiltrate. We do see thyroiditis. We see loss of thyroid function. So there are toxicities there, but you’re not seeing the cytotoxic toxicities that you see with chemotherapy. And with targeted therapy, you tend to get gut-related and stimulated-type toxicities. So I’d say different. In most cases, I think better tolerated than the other drugs, but in a few cases it can be quite horrific.

Yeah, well, KEYNOTE-407 is a study presented at ASCO [the American Society of Clinical Oncology Annual Meeting] in 2018, which is now looking at chemotherapy plus immunotherapy in patients who have squamous tumors. So in squamous tumors, we don’t use pemetrexed, so we would use carboplatin-Taxol, or now we use the nab-paclitaxel [paclitaxel albumin-stabilized nanoparticle formulation]. In that study, again, positive hazard ratio, not quite as much a benefit as was seen in the nonsquamous. Then, again, we’re not giving maintenance chemotherapy, so that might have a role here. But still, across the board, chemotherapy plus immunotherapy becomes the standard of care based on this trial in squamous patients. In the US, squamous, about 30% of the non–small cell lung cancer, in Europe even more just because of patterns of smoking and so forth, there’s a difference between different countries. So I think now we have another standard of care. So that’s what I would do, in my practice, not having a protocol. We’re very protocol-driven at Yale and other academic centers and many community centers now too. But without a protocol, chemotherapy-immunotherapy should be the standard of care, in my opinion.

Anne Tsao, MD: The KEYNOTE-024 study was a landmark trial. It demonstrated that giving a patient pembrolizumab versus chemotherapy was superior in the patients who had a very high PD-L1 expression, 50% or more. And so this definitely was the first paradigm shift that we saw in frontline metastatic non–small cell lung cancer.

As I mentioned before, when we have high–PD-L1 expression, you have the option of just doing pembrolizumab alone. But if you have to have a rapid debulking, or if the patient is imminently threatened by their disease, there are very high response rates using, for instance, in adenocarcinoma, the KEYNOTE-189 regimen of carboplatin, pemetrexed, pembrolizumab. And so you may want to consider doing that. Or certainly in the squamous cell population, you could consider doing a platinum taxane with pembrolizumab for rapid debulking.
 
 
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