EVOKE-02 Study Findings, Unmet Needs for mNSCLC, and Challenges Facing Community Oncologists

Bo Wang, MD, of Willamette Valley Cancer Institute in Eugene, Oregon, and Sheena Bhalla, MD, of UT Southwestern in Dallas, Texas, discuss the EVOKE-02 study, which assessed sacituzumab govitecan plus pembrolizumab with or without platinum agents in patients with previously untreated advanced or metastatic non-small cell lung cancer, as well as how these results may impact treatment option decisions in this patient population.

—

Dr.  Wang: We have some exciting data to go over that was recent released at [the 2023 World Conference on Lung Cancer]. Briefly, just to catch us all up, the study that we’re focusing on today is the EVOKE-02 study. The EVOKE-02 study was a multicohort phase 2 study evaluating sacituzumab govitecan with various combinations in frontline therapy settings for non-small cell lung cancer. We’re specifically going over cohort A and B results today. Cohort A and B studied the combination of the PD1 antibody pembrolizumab, which is very well known to many of us, I assume, and sacituzumab govitecan in the frontline setting for metastatic non-small cell lung cancer. That’s including squamous cell cancers and adenocarcinomas and others of the lung.

In terms of cohort A and B data, this was a preliminary analysis that evaluated objective response rates as the primary end point in each cohort. In cohort A, that consisted of patients with TPS, or tumor proportion scores, of 50% or more, and they demonstrated an objective response rate of 69%, with a disease control rate of 82%. Cohort B patients, which differed in the fact that these patients had TPS less than 50%, this cohort demonstrated response rates of 44%, with disease control rates of 78%. Across the total cohorts, these patients had a response rate of 56% and disease control rate of 82%. At this time, from the preliminary analysis, median duration of response had not yet been reached. However, the 6-month duration of response was measured at 88% across the combined cohorts.

I’d like to flip it to you now, Dr. Bhalla. What are the implications of the findings that we are talking about here, and do they impact treatment for metastatic non-small cell lung cancer?

Dr. Bhalla: I think these are relatively small numbers of patients, but I do think the results are intriguing. In the PD-L-high subgroup, as you mentioned, there’s a response rate of about 69%, which is encouraging. However, I think we need to really place these results in the context of our current first-line treatment. Of course, we have to be careful with cross-trial comparisons, but if we compare this response rate to that of pembrolizumab alone in a PD-L1-high population, for example, using KEYNOTE-042, the response rate was lower in that study, at about 39%. But given that we’re adding an ADC [antibody-drug conjugate] here, which has some chemotherapy side effects, I think it’s probably a more fair comparison to think about it in the setting of KEYNOTE-189 with chemotherapy plus pembrolizumab, where there the response rate is pretty similar at 62% for your PD-L1-high population.

In the PD-L1-low group, the response rate with sacituzumab and pembrolizumab is about 44%. Compared to pembrolizumab alone, in KEYNOTE-042, it’s higher; there it was 30%. But then with chemotherapy plus pembrolizumab, it’s pretty similar at 48% using KEYNOTE-189. I think it would be interesting to see a little further breakdown of this PD-L1-low group, for example, because if you’re getting responses in the PD-L negative subgroup, then that I think is actually worthy of further investigation.

I think moving forward, we’re going to need randomized study data, more patients, longer follow-up, to really see how this all compares head to head. Then I also think we really need to look at above just response rate, what’s your survival, how durable are these responses? If adding the ADC with IO [immunotherapy] is promoting immune-mediated responses and there’s some synergy there, then I think that it may be favorable compared to first-line chemotherapy and IO. I think time will tell, but I’m definitely very intrigued.

Dr. Wang: I think it’s worth mentioning that the current standard of care in the frontline patient landscape for non-small cell, those of course without actionable mutations like EGFR and ALK, I think one of the standards of care is the KEYNOTE-189 regimen, which is platinum-based chemotherapy in combination with immunotherapy. That said, this is similarly looking at antibody-drug conjugate, which has some chemotherapy, we’re trying to see here, I think, or hoping for again some synergy or other mechanistic differences that could perhaps bring improvements in various cohorts of patients. I think that’s probably the goal of studying these various combinations, don’t you think?

Dr. Bhalla: Yeah, exactly. I think if we can improve our outcomes in the first-line setting, that’s the goal.

Dr. Wang: In terms of unmet needs in the frontline lung cancer space, again, those without actionable mutations, what are some of the things that come to mind where we really need some improvement?

Dr. Bhalla: We’ve come a long way, but a couple things come to mind. First, I think we really need to improve first-line options for those patients who carry non-targetable genomic alterations that are associated with poor response and poor prognosis, so KRAS with concurrent STK11 or KEAP1. We know these patients are usually resistant to immunotherapy and there’s a number of approaches under study right now to help mediate the immune response in these patients. That’s one area. I think another area in the second-line setting for those patients without targetable alterations, the standard of care continues to be docetaxel plus/minus ramucirumab, which I’m hoping we can beat that someday soon. Of course, as you know, there’s plenty of ADCs in that second-line setting, and I think we’re going to have to start thinking about how are we going to sequence these drugs as these first- and second-line treatment options continue to evolve.

Dr. Wang: I think especially looking beyond just first-line treatment, one thing that we say about our patients who are on docetaxel is we’re basically beating them up. I see them aging in front of my eyes sometimes. Most second-/third-line trials right now that we have are, if they’re randomized, they’re randomized against a docetaxel, usually docetaxel monotherapy or a docetaxel based combination. I think we’re all hoping that at some point we’ll see better alternatives for future patients to use in the second- and third-line and also eventually be randomized to better alternatives than docetaxel.

Dr. Bhalla: Absolutely.

Dr. Wang: In terms of some challenges for treating lung cancer in community settings, being a community oncologist myself, I see this firsthand, there are a number, and we are recently faced with a more unprecedented type of challenge, which is platinum therapy shortages in this country, in the United States. This is something that I never imagined would happen in our lifetime, in today’s day and age, and I have seen myself and colleagues be affected by this. Our patients ultimately are the ones who are really affected by this.

Have you seen some of your colleagues affected by this? If they have been, both in academic settings or community settings, what are some ways that you’ve seen people try to get around some of these supply shortages?

Dr. Bhalla: We’ve also been affected by the platinum shortage. I practice at our cancer center as well as our safety net hospital, so there’s been different strategies used at both. We’ve had to round down carboplatin, for example, by 10% at our safety net hospital for metastatic patients. Instead of Q3-week, we’ve had to sometimes do Q4-week. I think that issue unfortunately has really affected all of us.

Dr. Wang: We hope that these types of good response data will ultimately translate to PFS [progression-free survival] data and survival advantage data. We see this happening with pembrolizumab and enfortumab vedotin in the urothelial cancer space. They’ve had some very exciting data actually that is arguably practice-shifting in terms of platinum-free frontline therapy for metastatic patients. Perhaps we might see that type of paradigm shift into lung cancer too. As you said a little early right now, but I think we can all hope that we’ll see some improvements and really exciting developments in the future.

We want to just cap off by having a few take-home points. What should community oncologists know about this EVOKE-02 data with sacituzumab and pembrolizumab combination? What can we learn? What can we also just generally look forward to?

Dr. Bhalla: I think based on this preliminary analysis that was presented at World Lung this year, we do see that sacituzumab plus pembrolizumab demonstrated antitumor activity in patients with metastatic non-small cell lung cancer across all PD-L1 levels. It looks like there was a manageable safety profile with toxicities matching what we would expect with each agent. I think moving forward, we’re going to really need to see randomized trials to understand where exactly this is going to fall in our first-line treatment algorithm.

Dr. Wang: Even from the standpoint of sacituzumab, I believe there are some other sacituzumab-based combination trials, like the VELOCITY study, which we actually have at our site, and then Sarah Cannon, which looks at various combinations of TIGIT plus PD1 antibodies plus sacituzumab and other immune-sensitizing agents. There’s just so many out there, and we just hope to be able to offer these really exciting studies to all of our patients, at both in the community and also at large academic prestigious centers like yours, Dr. Bhalla. Let’s just keep going back and forth and getting the patients the best that we can, right?

Dr. Bhalla: Absolutely. I agree. I think getting patients on these trials is most important, and I think both academic and community sites are essential for that.