Immunotherapy Combinations Emerging in NSCLC

Chad Pecot, MD

Immunotherapy has already carved out a place for itself in the treatment landscape of non—small cell lung cancer (NSCLC), but a wave of new combination therapies is imminent, says Chad Pecot, MD.

When compared with chemotherapy, the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) was found to improve progression-free survival (PFS) in treatment-naïve patients with high mutation burden NSCLC, according to preliminary findings from part 1a of the phase III CheckMate-227 trial. Bristol-Myers Squibb (BMS), the manufacturer of both immunotherapy agents, has not released any further data.

Additionally, findings from the phase III IMpower150 trial showed that the addition of atezolizumab (Tecentriq) to bevacizumab (Avastin), carboplatin, and paclitaxel delayed progression or death compared with bevacizumab and chemotherapy alone in patients with advanced nonsquamous NSCLC. The addition of the PD-L1 inhibitor delayed progression or death by 38%, and demonstrated a median PFS of 8.3 months compared with 6.8 months with bevacizumab and chemotherapy alone (HR, 0.62; 95% CI, 0.52-0.74; P <.0001).

OncLive: Can you please provide an overview of you talk?

What combinations are there currently data for?

Can you highlight some of the success with these combinations?

Pecot, an assistant professor in the School of Medicine at University of North Carolina (UNC)-Chapel Hill, discussed the rapidly growing area of combination immunotherapy in NSCLC in a presentation during the 2018 OncLive^® State of the Science Summit™ on Non—Small Cell Lung Cancer. In an interview during the meeting, he shared his insight on current clinical trials of immunotherapy combinations in NSCLC.Pecot: I spoke about immunotherapy combinations in lung cancer. There are quite a few different combinations being tested, and there are some emerging data with these combinations. I discussed the combinations that we have data for, and the few caveats and warnings. Then I discussed some clinical trials that are about to launch that are exciting.We have several different types of combinations. Ones that I discussed were chemotherapy plus immunotherapy, and some of those trials looked good and did work. Some are showing early signs of promise, but it is a little too early. There is a very recent trial, IMpower150, which was presented in Europe a few months ago and looks promising. There are also immunotherapy combinations with various immune agents together, such as nivolumab plus ipilimumab, as well as IDO inhibitors plus immunotherapy. The IDO inhibitors plus nivolumab or IDO inhibitors plus pembrolizumab (Keytruda)—both of those combinations were presented at the 2017 ASCO Annual Meeting. There are a couple successes there. One is that the response rates were higher than historical rates. We are now looking at 40% to 50% response rates with those combinations. What is exciting is that there did not seem to be any added toxicities. That implies that we can combine even more agents together to perhaps move that response rate even higher.

What other checkpoint inhibitors are under investigation?

Can you share your insight on the combination of talimogene laherparepvec (T-VEC; Imlygic) and PD-1 inhibitors?

It is still early days for the combination of ipilimumab plus nivolumab; it is a very large phase I trial that has expanded. BMS has publicly announced that this trial was a success; however, we have yet to see the most recent data. What is nice is that it looks like lowering the dosage of ipilimumab and spreading out how often it is given—from every 3 weeks to every 6 weeks, sometimes every 12 weeks—actually improves responses compared with single-agent therapy. It is also quite tolerable.Innumerable; I don't even know the number. There are so many, and that is part of what makes it so exciting. There are about 2000 to 3000 clinical trials of immunotherapy combinations around the globe, and there is likely to be a huge wave of new immunotherapy combinations coming out. Some will fail, and they are largely being driven by an empiric combination, so it is too soon to know.T-VEC is, more or less, herpes. It is genetically engineered so that it cannot give you the pathogenic disease of herpes, but it will replicate preferentially inside cancer cells. The idea is that it will lyce cancer cells once it replicates inside of them. It also produces a protein called GM-CSF, and what that will do is recruit a lot of immune cells to the tumor.

What progress has been made with vaccines?

Is there anything else that you would like to touch on?

It is lycing the tumor. It is presenting a lot of the antigens from the tumor to the immune system, and it is also secreting the protein GM-CSF in combination with immunotherapy. The idea is that you are presenting a lot of antigens inside the cancer to the immune system, and then adding in immunotherapy. That trial is already being put together in lung cancer at UNC before there is actual evidence of this working in a different tumor type. There is a Cell paper that just came out in melanoma at the end of 2017, which showed very impressive response rates with this combination. This makes us even more enthusiastic about using this in lung cancer.Most of the interest currently with vaccines is in discovering neoantigens, which essentially gets at the idea that you can make a personalized vaccine based on the abnormal peptides that a tumor is making. There are various genomic approaches to do that with a patient’s blood and tumors. People are looking at different ways to create vaccines based on a specialized neoantigen. We are in the early days, but we are seeing that you can make a personalized vaccine for a patient, which can lead to a reduction in tumor size. That is about the extent that I know, but a lot of groups have a lot of enthusiasm about this. There is a lot of reason for all of the enthusiasm. Sometimes things seem a bit hyped up with all of the commercials and hysteria. Everyone feels it, even outside the cancer community. There is a reason for it. It is very early days, but immunotherapy is very exciting.

One of the nice things about immunotherapy is that it is extremely well tolerated in general. That is usually what limits the amount of chemotherapies we can combine, so immunotherapy will allow us to leverage the immune system more powerfully, without creating substantial toxicity. That is the hope, and it would allow us to created combinations that lead to cure. Now, we are seeing more oncologists using that word. We usually use words such as remission and partial response, but a lot more of us would like to use the word cure. You are going to start hearing us use that term more often.

References

1. First-line nivolumab monotherapy and nivolumab plus ipilimumab in patients with advanced NSCLC: long-term outcomes from CheckMate-012. In: Proceedings from the 17th World Conference on Lung Cancer; December 4-7, 2016; Vienna, Austria.
2. Reck M. 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 (IMpower150). Ann of Oncol. 2017;28(11). Abstract LBA1_PR.

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