Roy S. Herbst, MD, PhD, discusses the rationale for exploring immunotherapy/TKI combinations like pembrolizumab plus lenvatinib in patients with non–small cell lung cancer, and outlined the different efforts that comprise the LEAP clinical trial program.
Although the addition of lenvatinib (Lenvima) to pembrolizumab (Keytruda) did not improve overall survival vs pembrolizumab alone in the first-line treatment of patients with metastatic, PD-L1–positive non–small cell lung cancer (NSCLC) in the phase 3 LEAP-007 trial (NCT03829332),1 combining this immunotherapy/TKI regimen with chemotherapy could serve to improve outcomes for these patients, according to Roy S. Herbst, MD, PhD.
Pembrolizumab plus platinum-based chemotherapy serves as a standard frontline therapy for patients with metastatic NSCLC. In the first portion of the phase 3 LEAP-006 trial (NCT03829319), the combination of pembrolizumab, lenvatinib, and platinum-based chemotherapy demonstrated early evidence of antitumor activity, with an acceptable safety profile.2,3 As such, part 2 of the trial is evaluating the combination of pembrolizumab, platinum-based chemotherapy, and pemetrexed with either lenvatinib or placebo.
“There is some skepticism about pembrolizumab and lenvatinib alone; [the LEAP-007] trial did not hit its end point,” Herbst, an ensign professor of medicine (medical oncology) and professor of pharmacology at Yale School of Medicine, said. “My sense is that [the quadruplet being examined in LEAP-006] is a powerful regimen. You add a little bit of toxicity when you add the lenvatinib, but it is not unreasonable…This is an exciting trial, and I am interested [to see] the results when they [are available]. We have several patients here, at Yale, who have been on that trial.”
The safety and efficacy of the combination of pembrolizumab and lenvatinib is also being compared with that of docetaxel in patients with metastatic NSCLC who progressed following treatment with platinum-doublet chemotherapy, as part of the phase 3 LEAP-008 trial (NCT03976375).
In an interview with OncLive®, Herbst, who is also the director of the Center for Thoracic Cancers, chief of Medical Oncology, associate cancer center director of Translational Science at Yale Cancer Center, Smilow Cancer Hospital, discussed the rationale for exploring immunotherapy/TKI combinations like pembrolizumab plus lenvatinib in patients with NSCLC, and outlined the different efforts that comprise the LEAP clinical trial program.
Herbst: It certainly makes sense that we combine therapies. Immunotherapy has so much promise in lung cancer. The issue is that TKIs tend to work in patients who are never smokers and who have driver mutations. Immunotherapy works best in patients who are smokers and who have many mutations; as such, there are more chances for a mutation to drive the immune response.
We have not been that successful in combining immunotherapy with TKIs, to date. [This is] because, theoretically, it does not make sense to use immunotherapy in [a patient] who you would give a TKI, or vice versa. I believe that there could probably be some benefit, especially if the TKI killed some tumor cells, because we know that there are often other associated mutations, even in patients who have not smoked or who have smoked very little.
The problem of that has been the associated toxicities, [such as] rash and the interstitial lung disease that develops with third-generation TKIs such as osimertinib [Tagrisso] and alectinib [Alecensa] with PD-1 and PD-L1 antagonists. We do not understand [the adverse effects (AEs) that come with this approach too] well, but they have been a problem.
Hopefully soon, [we will see whether] RAS-[targeted] agents can be combined with immunotherapy; that [combination] would be more for a smoking population. To date, we are looking for other immunotherapy mechanisms that could [allow for potential combination]. Someday, there might be an immunotherapy that does not toxicity and that can be used [in combination]. For right now, people are cautious, to the point where we pretty much avoid this in the clinic.
I have been working with TKIs since 1997 in some of the earliest trials with gefitinib [Iressa] and erlotinib [Tarceva]. I have seen great benefit [with these agents]; there are patients who have lived a good quality life for a long period of time [because of them], but I have never seen anyone cured. With immunotherapy, which I have used [for just] 10 or 12 years, I do have people who have maybe [been] cured; they are certainly still alive.
It would make sense if we can add an immunotherapy into a driver-addicted patient. However, the problem with TKIs is that resistance will always develop, and there are so many different resistance mechanisms. Will we be able to have a drug for every patient? I am not sure. Some people think maybe tumor-infiltrating lymphocytes might be a way to use immunotherapy in that setting. Perhaps blocking other immune pathways could help; for example, CD73 has been discussed. Time will tell.
Now, we are talking about a different type of TKI, a VEGF TKI. Those [agents] have been shown to be tolerable. Lenvatinib is a multi-TKI that targets VEGF, among others. It makes sense that blocking VEGF could increase T-cell infiltration into the tumor. VEGF inhibition can increase dendritic cell performance and enhance immune response. As such, that combination make some sense.
Lenvatinib does have toxicity; when you have a [multikinase inhibitor], you are going to see rash, diarrhea, and dry mouth, [among others]. However, some [ongoing] trials [are investigating] pembrolizumab plus lenvatinib, as well as pembrolizumab plus lenvatinib and chemotherapy.
The LEAP-006 trial [is now examining] chemotherapy plus pembrolizumab/lenvatinib. We are all excited to see how that [regimen] works. [This will answer the question of whether we can] add lenvatinib to chemotherapy and pembrolizumab. Again, there will be some toxicity. Is it specific enough? Will it work? Only the results will tell.
This has been an iterative process. We have big leaps, and then we have gradual improvement. The big leap was pembrolizumab, nivolumab [Opdivo], the PD-1/PD-L1 inhibitors. Then, what is the next step? Refining that benefit.
Chemotherapy with pembrolizumab—carboplatin, pemetrexed, and pembrolizumab, [for example]—looks good, regardless of PD-L1 status. [This regimen is] used quite commonly in the United States and around the world. However, still, at a couple of years, 70% or 80% of patients will progress, and so [this regimen] is not a home run. For patients who benefit [from this combination], that is great, but what about those who do not?
Someday we will learn about [which patients will benefit] in advance. Right now, we want to add to [the regimen] and try to make it even better. If that quadruplet [of pembrolizumab, lenvatinib, carboplatin, and pemetrexed] proves to be better than the triplet, that will give us [another combination for our] armamentarium.
The idea would be that lenvatinib increases pembrolizumab delivery to the tumor and possibly overcomes resistance because high VEGF might decrease the activity of T cells, and it might stimulate inhibitory macrophages and the like. [The rationale is] theoretically strong. Will that [regimen] beat docetaxel? [We know that] docetaxel will have a response rate of 5% [to] 10%. We certainly know [docetaxel] will be quite toxic and produce a lot of that neutropenia, edema, and other [AEs].
Will the [combination prove to be more efficacious than docetaxel]? It is hard to say. Lenvatinib has toxicity of its own. [Regardless,] it is a reasonable trial question. I personally worry a little bit that we do not know why our patients are resistant. What are the mechanisms of resistance? That will limit us to some extent. However, again, science can only do so much. You must take your best hypotheses and test them in clinical study, and that is what is being done here.
There is a drug called sitravatinib [Sitra], which is a [spectrum-selective TKI targeting TAM receptors], but it also [targets] VEGF. [The agent] is being looked at [in combination] with nivolumab. [The phase 3 SAPPHIRE trial (NCT03906071) is examining] sitravatinib plus nivolumab vs docetaxel [in patients with advanced nonsquamous NSCLC]. That trial has been going on for a while, so hopefully that phase 3 [study] will report at some point.
Also, ramucirumab [Cyramza], a VEGFR-2 antibody, has been combined with pembrolizumab. We [evaluated] that in our phase 2 Lung-MAP trial [NCT03971474]. Those data should [read out] at [the 2022] ASCO Annual Meeting.
Several other [combinations are also under exploration]. Bevacizumab [Avastin] is being explored [in combination with atezolizumab [Tecentriq] and chemotherapy] in the phase 3 IMpower150 trial [NCT02366143], so we are adding VEGF-[targeted therapy] in that way. Some other [anti]–VEGFR-2 [agents are also being explored]. This is a common pathway; it has been done renal cancer because those tumors are driven by von Hippel-Lindau syndrome.
I would look closely at [efforts focused on] moving drugs to earlier stages of disease. During [the 2022 AACR Annual Meeting,] we saw [results from the phase 3 CheckMate-816 trial (NCT02998528) examining neoadjuvant] nivolumab plus chemotherapy in stage I to III [early-stage NSCLC], which showed a remarkable improvement in event-free survival, improved response rate, and improved molecular response rate [over chemotherapy alone]. Although survival [data are] not quite mature yet, it certainly was trending in the right direction.
We have adjuvant atezolizumab now. Adjuvant pembrolizumab is not yet approved, but [we saw] a positive trial. We have adjuvant osimertinib [based on data from] a trial that I was closely involved with, the phase 3 ADAURA trial [NCT02511106]. All the best drugs, the targeted therapies, are moving to earlier-stage disease. That is the future.