Trial 'Desperately Needed' to Sequence Immunotherapy and Chemo in Lung Cancer

H. Jack West, MD; Hossein Borghaei, DO


May 18, 2018

H. Jack West, MD: Hello. I am Jack West, medical director of the thoracic oncology program at the Swedish Cancer Institute in Seattle. Welcome to Medscape Oncology Insights. Joining me today is Hossein Borghaei, chief of thoracic medical oncology at Fox Chase Cancer Center in Philadelphia. Welcome, Hoss.

We've been talking about the KEYNOTE-189 trial, since it was presented at the American Association for Cancer Research (AACR) plenary session,[1] and its implications for clinical practice. The study was concurrently published in the New England Journal of Medicine. To briefly summarize, this was a randomized, phase 3 trial in nonsquamous, non–small cell lung cancer, regardless of level of PD-L1 expression, in patients with wild-type EGFR and ALK and no brain metastases. Two thirds of patients were randomized to chemotherapy with pembrolizumab and one third were randomized to chemotherapy with placebo. The chemotherapy was cisplatin or carboplatin and pemetrexed.

The study was reported as positive in a press release a few months ago, but many of us were surprised at how positive it ultimately was, which was screamingly positive. The study had a hazard ratio for overall survival of 0.49, a 20% difference in 1-year survival favoring chemotherapy with pembrolizumab over chemotherapy-placebo. The 1-year survival was about 70% versus almost 50%—a big difference. Lead author Dr Leena Ghandi, who presented the study at the AACR meeting, showed the results by PD-L1 subgroup, essentially one third of patients each in buckets of less than 1% [PD-L1 expression], 1%-49%, and 50% or greater. Patients with the lowest PD-L1 had a benefit, but it was less than that seen with the PD-L1 positives, particularly the highest PD-L1. The benefit in the lowest range was not as dramatic. There was still a hazard ratio of 0.59 in overall survival favoring the combination, and the progression-free survival hazard ratio is still 0.75. There was also a higher response rate with the combination, even in the low- or no-PD-L1 subgroup. So, that's an option, but so is sequential [lines of therapy].

The crossover from chemotherapy alone was 50% to pembrolizumab, not 100%. Skeptics might argue that the study was not necessarily concurrent versus sequential, but rather 100% of people getting chemotherapy and immunotherapy versus 50% of patients getting chemotherapy and immunotherapy. We have this option available, and in the immediate future we are not likely to have a lot more information about the low- or negative-PD-L1 group. The KEYNOTE-042 trial that will be featured at the American Society of Clinical Oncology (ASCO) meeting is only for the 1% or higher group and is comparing pembrolizumab monotherapy to chemotherapy.[2]

This overall improvement looks pretty good for the combination, but the competing option is sequential, with a better separation of the toxicity issues. What's your approach going to be, going forward, for this not uncommon group of patients?

Hossein Borghaei, DO: That's a really interesting question and an area where we need a little more data to guide us. Given the fact that in the overall patient population the triple combination is so effective, I think that discussion needs to be had with the patient, saying, "You are in a subgroup that is a little bit different." But overall, patient benefit is so huge in this study that it is kind of difficult to not give this option, the triple combination, to a patient who you think can tolerate it. Even though the trial didn't really show significantly more toxicity, there still was more toxicity as expected with a triple combination versus the platin-doublet chemotherapy.

For the PD-L1 less-than-1% population, sequencing chemotherapy followed by immunotherapy is a proven and established standard of care, and I think it is still a really good option. For those patients who come to the clinic with significant burden of disease, where there might not be a possibility or opportunity for subsequent therapy, giving your best shot in a front-line setting might make sense. However, as far as I'm concerned, for the less-than-1% group, I still consider platinum-doublet by itself a very viable option for patients. I don't feel that everybody who comes to the clinic should get the triple combination.

West: I think it is fair to individualize treatment. It is not obvious that everybody should get treated the same way. We will be getting information from other studies that I hope will give us more information about this and potentially identify other biomarkers to consider, like tumor mutational burden (TMB).[3,4]

Borghaei: I think that is important, because with this patient population, we might have a potential option down the road in terms of immune-oncology (IO) combination, maybe using a different biomarker, like TMB, to select patients who should not get either chemotherapy, or chemo-IO, but a different approach altogether. The data are still percolating; they're making their way through all of the presentations, and it is something to keep an eye on.[4,5,6]

West: Then there is the question of whether or how to sequence. We have seen various bits of data but just hints, such as better response rates to salvage chemotherapy administered after immunotherapy.[7] Scott Gettinger and colleagues from Yale just published a study that looks at the trends in patients who received immunotherapy in various settings, and he reported that those who received immunotherapy seemed to have had better results after chemotherapy.[8] Do you think we know enough now to sequence or are we just babes in the woods?

Borghaei: I don't think the sequencing question has been addressed at all. I think that's one area where a clinical trial is desperately needed. And if I might say, the two cooperative groups, ECOG and SWOG, have come together, and we have proposed this study where we are going to be looking at the exact question of sequencing: immunotherapy followed by chemotherapy, or immunotherapy and then at progression adding chemotherapy. The study is under review right now.

This is the ECOG Study 5163, but it's called the INSIGNIA trial. It has a significant biomarker evaluation component through our colleagues at the Yale Cancer Center. I encourage everybody to look for the study when it's up and running. It's going to be over 800 patients enrolled in three different arms. In at least two of the arms, we are asking the exact questions that you are raising: Should we do chemotherapy after immunotherapy? We will have an answer to that once the study is completed. I think most of the sequencing information we have is mostly, at this point, anecdotal. One institution says, "We did that and this is the result," and the other institution says, "We e did the reverse." We need a randomized study to examine this.

West: Yes, we need to move beyond just single-institution, retrospective work. I'm glad you brought up the INSIGNIA trial. I think that it's ironic that it's been in development for a while, but with all of the developments over the past couple of years, it has only recently become more pressing. This is now an incredibly timely study, and I look forward to enrolling my patients. It's also going to help address the question of what is the least maintenance we need to give. Should we give chemotherapy-immunotherapy maintenance or can we do just as well with one or the other? I think that's going to be a really valuable question, both for minimizing toxicity for our patients and also for reducing financial toxicity.

Borghaei: Besides the clinical question, this study provides a tremendous opportunity to answer a few really important biomarker questions.

West: Great. Hoss, thank you for joining me today. It has been a great discussion. And thank you for joining us. This is Jack West for Medscape.


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