David R. Spigel, MD, discusses the IMpower110, CYPRESS-1, and CANOPY-A trials, and spoke to the potential future outlook of drug development in NSCLC.
During the 2020 ASCO Virtual Scientific Program, findings from several studies evaluating immunotherapy as monotherapy and in combination strategies were presented, highlighting the evolving treatment landscape for patients with non–small cell lung cancer (NSCLC), explained David R. Spigel, MD.
Recently, on May 18, 2020, the FDA approved atezolizumab (Tecentriq) for use as first-line therapy in patients with metastatic NSCLC whose tumors have high PD-L1 expression with no EGFR or ALK genomic tumor aberrations.1
The regulatory decision was based on findings from the phase 3 IMpower110 trial in which atezolizumab elicited a 20.2-month median overall survival (OS) versus 13.1 months with chemotherapy in this patient population (HR, 0.59; 95% CI, 0.40-0.89; P = .0106).2
At the 2020 ASCO Virtual Scientific Program, an analysis of patient-reported outcomes (PROs) from the IMpower110 trial confirmed that patients who received atezolizumab experienced sustained numerical improvements in physical functioning relative to baseline and did not have worsening lung cancer-related symptoms compared with those who received chemotherapy.3
“IMpower110 is pivotal because we now have another single-agent immune-based strategy that is available beyond pembrolizumab (Keytruda),” said Spigel, lead author of IMpower110. “This is all in the context of recent FDA approvals of other immune strategies like nivolumab (Opdivo)/ipilimumab (Yervoy) with or without chemotherapy. In the first-line setting, the field is getting a bit complicated, so it is good to think of this as another agent [available for] our patients with highly expressed PD-L1–positive NSCLC.”
Prior to the approval of atezolizumab, pembrolizumab served as the standard of care for previously untreated patients with high PD-L1–expressing NSCLC, explained Spigel. Since the introduction of pembrolizumab to the space, investigators have sought to improve outcomes with the PD-1 inhibitor by combining it with novel agents.
However, at the 2020 ASCO Virtual Scientific Program, findings from the randomized phase 2 CYPRESS-1 trial failed to demonstrate a survival advantage with pembrolizumab plus pegilodecakin versus pembrolizumab alone.4
Other novel single agents, such as canakinumab, are also under investigation, explained Spigel. The agent, given as adjuvant therapy, is being evaluated in the ongoing, randomized phase 3 CANOPY-A trial in patients with fully resected NSCLC.5
In an interview with OncLive, Spigel, chief scientific officer, director of the Lung Cancer Research Program, and a principal investigator at Sarah Cannon Research Institute, expanded on the IMpower110, CYPRESS-1, and CANOPY-A trials, and spoke to the potential future outlook of drug development in NSCLC.
OncLive: How did the PROs data reported from the IMpower110 trial at the 2020 ASCO Virtual Scientific Program impact the role of atezolizumab in this patient population?
Spigel: IMpower110 was a trial that was designed some time ago. We are all aware of the KEYNOTE-024 trial that established the role of first-line pembrolizumab monotherapy in patients with high PD-L1–expressing NSCLC. The design of IMpower110 was pretty straightforward as it took patients with newly diagnosed advanced squamous or nonsquamous NSCLC and randomized them to receive either platinum-doublet chemotherapy or atezolizumab. Atezolizumab has already been approved for use in the relapsed/refractory setting in all comers, as well as in the first-line setting in combination with chemotherapy in patients with nonsquamous NSCLC who were unselected for PD-L1 status.
[On May 18, 2020], the FDA approved atezolizumab monotherapy for use in the first-line setting [for patients with metastatic high PD-L1–expressing NSCLC], based on the results of IMpower110. The study was positive for OS in the primary population, which consisted of patients with PD-L1 tumor cell- or infiltrating immune cell-expression of 3+4 or higher.
At the 2020 ASCO Virtual Scientific Program, PROs with atezolizumab were shared. The take-home message is that, like in the refractory or chemotherapy-plus settings, atezolizumab is a well-tolerated agent. No unexpected safety signals were observed with the agent when used as monotherapy in the IMpower110 trial. [The toxicities appear to be] something we can anticipate, [and most of them] are immune related. This analysis [provides us with] more evidence of the safety and tolerability of this strategy in the first-line setting.
The other important thing about the availability of atezolizumab in the first-line setting is now ongoing research [can examine] this agent as the control arm. Certainly, we could do trials with pembrolizumab as the control arm, but this [approval] allows for additional studies to be done with atezolizumab as the control arm. Those trials, comparing atezolizumab with atezolizumab plus a TIGIT antibody, are now in progress. IMpower110 is important for its approval and its use as an additional platform for ongoing and planned research.
Could you provide some background to the CYPRESS-1 trial?
In the randomized phase 2 CYPRESS-1 trial, investigators examined the role of an immunotherapy combination in the first-line NSCLC setting. It is pretty well recognized that in the frontline space, particularly for patients who have high PD-L1 expression, pembrolizumab is the standard of care. At the time of [this interview], that has changed a bit with the approvals of nivolumab plus ipilimumab, and atezolizumab.
In CYPRESS-1, investigators evaluated the combination of pembrolizumab and the novel agent pegilodecakin versus pembrolizumab alone. [Pegilodecakin] is a pegylated form of human interleukin-10 (IL-10) that activates CD8+ T cells. This drug was studied earlier in a phase 1 trial in patients with several refractory malignancies. Pegilodecakin showed signals of activity when it was combined with a checkpoint inhibitor, as well as some single-agent activity.
The trial did not have OS as its primary end point. Rather, the primary end point was response rate. The trial was conducted at multiple centers across the country.
What were the results of the study?
Unfortunately, no advantage was seen with the combination of pegilodecakin and pembrolizumab versus pembrolizumab alone. No signal was observed in terms of response rate or progression-free survival (PFS) in the secondary analysis. Even in exploratory work, we didn’t see a signal of extra activity [with the combination]. [Overall], this would be regarded as a negative study.
There is not much more we can take from this trial given its size; this was a study of about 100 patients, and it was not designed to show anything more than increased activity.
Something that we should always consider when we have a group of patients whom we expect to see great results in—such as a high PD-L1–expressing group receiving pembrolizumab—is that raising that bar to improve outcomes can be difficult. We would have had to show a substantive benefit [to improve outcomes]. This study demonstrates that despite the early activity seen in phase 1 studies, in a randomized phase 2 setting there was no advantage to this strategy.
It is a very disappointing outcome for this drug’s development. However, there is ongoing work being done. Other studies are examining [pegilodecakin] in lung cancer and other tumor types.
Could you shed light on the CANOPY trial?
One of the other posters that was presented at the 2020 ASCO Virtual Scientific Program is from a suite of studies called the CANOPY trials; these trials examined the role of canakinumab. We are beginning to see some early results, but at ASCO, we presented our strategies [that are being used] to develop this [agent] in the adjuvant setting.
Canakinumab is an interesting drug that we first heard about a few years ago in a study that was not designed for patients with cancer. The agent is a monoclonal antibody that targets interleukin-1 beta. This is a proinflammatory mediator and specifically, a mediator of what appears to be chronic inflammation.
In the pivotal CANTOS study, when we gave this agent subcutaneously every 3 months to individuals with heart disease who were at risk for secondary cardiovascular events, not only were outcomes improved, but a subset analysis showed improvement in the risk of developing and dying from lung cancer. This was an interesting finding from a study that had been [originally] designed for cardiovascular research.
As such, this drug was moved into 4 large trials that are evaluating its role in lung cancer. The one that we have been most involved with is CANOPY, which is evaluating canakinumab in the adjuvant setting. The trial is examining the agent in patients with early-stage lung cancer. Patients are allowed to have surgery and then receive standard cisplatin-based doublet chemotherapy. Then, patients are randomized to receive either canakinumab or placebo.
The trial is ongoing and actively enrolling patients globally. Hopefully, any pause in that enrollment [due to] with the coronavirus disease 2019 will pick back up. This could be a very important study that will help us understand whether a drug like this, that appears to have a profound effect in preventing chronic inflammation, could impact how patients with early-stage disease might do in terms of disease-free recurrence and OS.
Could you elaborate on TIGIT therapy and how it is being evaluated in combination with immunotherapy? What is your outlook for the future of drug development in NSCLC?
Several strategies are in development to improve upon single-agent checkpoint inhibition. Combinations of LAG3 and CTLA-4 inhibitors with PD-1/PD-L1 inhibitors [are being examined]. Another concept is combining a PD-L1 inhibitor like atezolizumab with a TIGIT antibody. TIGIT is an immune receptor that is present on natural killer T cells. Could this be a strategy of releasing a checkpoint, in the case of atezolizumab, and allowing the immune system to wake up? In addition, could this address or inhibit proinflammatory cytokines and other mediators that a checkpoint inhibitor wouldn’t address? This could be a dual approach in lung cancer, although this combination is being developed in several other disease areas, as well.
In lung cancer, we saw some preliminary results at the 2020 ASCO Virtual Scientific Program where the combination of atezolizumab and a TIGIT antibody resulted in improved outcomes, specifically for our patients with high PD-L1 expression. Response rates and PFS look encouraging, but we await phase 3 trials which randomized patients with newly diagnosed NSCLC who have high PD-L1 expression to the combination versus atezolizumab monotherapy. Those studies [are going to be] important, [as they will allow us] to see whether we can go beyond where we are currently.
However, again, the first-line space is very complicated. We could think of pembrolizumab with or without chemotherapy, atezolizumab with or without chemotherapy, and nivolumab/ipilimumab with or without chemotherapy. We have several immune strategies, some based on PD-L1 expression, with different toxicity profiles.
The ultimate question is, “Which is the best?” We don’t have a way right now to say that 1 [regimen] is better than another, as none have been compared head to head. We have to take each individual study on its own merit, think about efficacy in that patient population, and how it applies to the patient in front of us. Is [that regimen] the right choice for them? Also, we have to consider toxicity because I don’t want to minimize the potential differences in these safety profiles. The toxicity profile of each regimen is different. In particular, the [toxicity profiles of] CTLA-4 or PD-1/CTLA-4 combinations are going to be different than monotherapy profiles or chemoimmunotherapy profiles. It is a lot to consider, but it is all good news because we are starting to see the fruits of a lot of research efforts that were initiated many years ago.