H. Jack West, MD: Howdy. I’m Jack West, medical director of the Thoracic Oncology Program on the Swedish Most cancers Institute, in Seattle. Welcome to Medscape Oncology Insights. Becoming a member of me in the present day is Hossein Borghaei, chief of the Thoracic Medical Oncology Program at Fox Chase Most cancers Middle in Philadelphia. Welcome.
Hossein Borghaei, DO: Thanks.
West: We simply attended the 2018 American Affiliation for Most cancers Analysis (AACR) assembly, and weird for a gathering that’s extra of a showcase for early medical and preclinical work, main medical research have been introduced within the plenary session devoted completely to lung most cancers. I wish to focus initially on the KEYNOTE-189 examine, which I feel goes to have actual medical implications.
On this trial for sufferers with superior nonsquamous, non–small cell lung most cancers with any degree of PD-L1 expression, sufferers couldn’t have EGFR mutations or ALK rearrangements. A little bit over 600 sufferers have been randomized 2:1 to obtain both chemotherapy, cisplatin or carboplatin, with pemetrexed. Two thirds of sufferers acquired pembrolizumab and one third acquired placebo.
Total survival was the first endpoint, and we knew it was constructive from a press launch a few months in the past, however we didn’t know whether or not it was clinically vital. It seems it was vastly vital, with a hazard ratio of zero.49 within the total intent-to-treat inhabitants. That is primarily a doubling of survival throughout the complete time course reported.
Leena Gandhi, lead creator of the examine that was introduced at AACR and revealed on the similar time within the New England Journal of Medication, additionally famous that within the subsets of sufferers (zero or lower than 1% PD-L1 expression, 1%-49%, or PD-L1 50% or better), all benefited considerably when it comes to total survival.
The outcomes have been related for progression-free survival and response charge, specifically large variations within the normal inhabitants favoring the pembrolizumab arm, with actual—however not as spectacular—variations within the lowest PD-L1 subgroup, extra advantages within the 1%-49% group, and essentially the most profit within the 50% or better group.
For toxicity, we noticed just a little extra nephritis than we would have anticipated. We now have had carboplatin and pemetrexed plus pembrolizumab as an FDA-approved choice since Could 2017, based mostly on the trial you have been very a lot concerned in, KEYNOTE-021 cohort G, however approval has not but had a big effect.[2,3,4] Folks have been extra reserved as a result of the general survival profit was not as clear and it was a randomized section 2. What do you see because the affect of this examine, when it comes to adoption of this routine?
Borghaei: I wish to emphasize two issues. First, KEYNOTE-189 didn’t have any sufferers with molecularly pushed tumors; we have to maintain that in thoughts. Second, no one with any proof of mind metastases was allowed within the trial. We now have to watch out with these two subpopulations.
I feel the rationale KEYNOTE-021 cohort G was not accepted straight away, as you counsel, was that it was a randomized section 2, the survival information weren’t fairly as clear, and we actually didn’t understand how the completely different subgroups of sufferers, based mostly on the PD-L1 expression, really did.
We have been all ready for added info, which KEYNOTE-189 has supplied. I feel this examine establishes this routine as the usual of care due to the numerous total survival benefit, virtually in all the subgroups of sufferers, and the truth that responses have been higher in all subgroups. I agree with you that the PD-L1 negatives didn’t have as a lot of a profit, but it surely was nonetheless higher than normal chemotherapy.
For the nonsquamous histology, KEYNOTE-189 turns into a de facto normal of care, such that if I’m designing one other medical trial on this affected person inhabitants, that is going to be my management. The important thing factor to review is tips on how to enhance on these outcomes. There are lingering questions: What’s going to occur to sufferers who’ve EGFR mutations or ALK translocations? Have they got as a lot of a profit from this? Can we do a examine to take a look at that?
What’s the actual long-term profit from all of this? By that, I imply that we’ve information now from earlier immuno-oncology medication that there’s a 5-year survival profit for a really small subpopulation. Are we prone to see that 5-year survival enhancing considerably, or to any extent, with the addition of chemo-IO? For me, this actually turns into one of many requirements of care that I focus on with my sufferers within the clinic.
West: There was a really vital absolute distinction in 1-year survival: practically 70% within the chemotherapy-pembrolizumab arm versus just below 50% within the chemotherapy-alone arm. The response charge with chemotherapy alone and placebo was 19%. Some folks have grumbled that that’s disappointing for a management arm nowadays, particularly when it’s nonsquamous and in a world the place we’ve second-line immunotherapy.
On this trial, 50% of sufferers who have been eligible crossed over to pembrolizumab. To me, that could be a little disappointing when we’ve immunotherapy accessible and of confirmed profit after chemotherapy. What would you say in regards to the management arm? Is that an actual concern or are these variations so substantial that it actually washes out?
Borghaei: I’m not actually involved about it. On occasion, you get trials like this the place the management arm doesn’t appear to do fairly as nicely. We now have to take into account that this can be a randomized examine; all people had the identical eligibility and acquired the identical chemotherapy spine. It’s laborious to argue that one thing occurred with the chemotherapy within the management arm. Might the hazard ratio be barely much less? Perhaps, however the magnitude of profit is so nice that it’s actually laborious to argue that this isn’t an efficient routine.
West: Once more, even when the hazard ratio have been zero.57, we’d nonetheless have the identical normal conclusions.
Borghaei: So far as 50% not getting an efficient drug, I do marvel about that, however a number of completely different questions come into play. Bear in mind from a trial many, a few years in the past within the period of platinum-doublet, we discovered that as much as 35%-40% of sufferers by no means make it to second-line remedy. Is that taking part in a job right here? I have no idea.
West: Definitely, there are information from not that way back that we simply don’t ship second-line therapy in additional than 55% or 60% at most. The issue with that’s that was within the docetaxel-based chemotherapy, with modest efficacy and difficult tolerability. Now, we’ve a number of trials of checkpoint inhibitors which have all persistently proven main survival advantages and good tolerability.
Only a few of those sufferers who have been initially eligible for first-line chemoimmunotherapy needs to be ineligible for subsequent immunotherapy. In my clinic, I’d say that over 85%-90%, and as near 100% as doable, are going to get immunotherapy if eligible.
Borghaei: I agree with that, and I’ve made that argument at varied conferences, however once more, if you see information like these, it’s important to marvel what share of the sufferers who have been within the management arm actually couldn’t go on. We now have by no means captured that sort of info.
The opposite half is that we now have some information from KEYNOTE-024 suggesting that for some sufferers, sufferers with actually excessive PD-L1, possibly immunotherapy after chemo isn’t fairly pretty much as good. Perhaps sufferers ought to get immunotherapy proper off the bat. That’s an space that I feel requires extra investigation and extra evaluation.
It’s doable that one thing like that’s in play in the case of the crossover in some sufferers not likely getting the lively drug. Additionally, the place you do the research typically issues. I imply, was the examine carried out in locations the place maybe an lively IO agent was not accessible after chemotherapy? We have no idea.
West: Have been there any actual points with tolerability or was that just about as anticipated?
Borghaei: Toxicity was what you’ll count on, apart from nephritis, which was just a little little bit of a shock as a result of we didn’t see that within the section 2 examine. Once more, clinically, I’ve not essentially observed any elevated charge of nephritis, however it’s what the examine suggests, and I feel it’s one thing for investigators and for docs to remember when they’re treating their sufferers. I don’t see any main security considerations.
West: Nice. We’re going to do just a few subsequent movies on the implications for the precise subgroups, as a result of I feel that these completely different teams, whether or not they’re destructive for PD-L1, low, or excessive, have completely different choices, each now and within the near-term future. I stay up for folks following that.