DZD9008: A Targeted Therapy for Exon 20 EGFR Mutation

Drs. Vamsi Velcheti and Jack West discuss key abstracts in advanced SCLC and NSCLC, along with highlighting the largest known data set correlating ctDNA levels and efficacy outcomes in the EMPOWER-Lung 1 trial, in advance of the 2023 ASCO Annual Meeting.

TRANSCRIPT

Dr. Vamsidhar Velcheti: Hello, I am Dr. Vamsidhar Velcheti, your guest host of the ASCO Daily News Podcast today. I am a professor of medicine at NYU Grossman School of Medicine and the director of thoracic oncology at Perlmutter Cancer Center at NYU Langone Health. I am delighted to welcome Dr. Jack West, a thoracic oncologist and associate professor in medicine at the City of Hope Comprehensive Cancer Center.

Today, we'll be discussing key posters and oral abstracts in lung cancer that will be featured at the 2023 ASCO Annual Meeting.

Our full disclosures are available in the transcript of this episode and disclosures relating to all episodes of the podcast are available on our transcripts at asco.org/DNpod.

Jack, it's great to have you on the podcast today.

Dr. Jack West: Well, thank you so much, it's my pleasure to be here.

Dr. Vamsidhar Velcheti: Let's begin with Abstract 8512. This is the follow-up of the Gronberg trial, the Danish trial of BID thoracic radiation for limited-stage small cell lung cancer. What are your key takeaways from this trial?

Dr. Jack West: Well, as you noted, this has been presented before a few years ago. It's a trial for limited-stage small cell lung cancer and it directly compared chemotherapy with either 45 Gray or 60 Gray of chest radiation delivered twice daily. It's not an enormous study, it's 170 eligible patients. And years ago, we saw that the efficacy endpoints looked very promising for the patients who received a higher dose of 60 Gray on a BID schedule, which is above our standard. We generally either give 45 Gray BID or probably more commonly in the US and I think globally give maybe 60 Gray on a once-a-day schedule. But the efficacy looked quite promising and without any clear increase in the toxicity of it. And really, despite the impressive results, this hasn't changed practice. It is not a large study and I think that I would say that most of the radiation oncology world has been reserving judgment until potentially seeing a larger study.

But what's being presented at ASCO are the longer-term results that continue to look excellent. You have a progression-free survival median of 18.6 months versus 10.9 months. That's not statistically significant but has a hazard ratio of 0.76 associated with it. And the median overall survival is even more pronounced of 43.5 months favoring the 60 Gray arm compared to 22.6 months in 45 Gray on a BID schedule that has a hazard ratio of 0.69. And this is statistically significant. The authors note that they will be presenting five-year overall survival as well. And there's also just passing mention that, as was seen previously, there was no increase in toxicity, no prohibitive toxicity. So I don't think it's necessarily going to change practice because the numbers of patients, which I think are really the leading concern, hasn't changed. But these very promising results still hold up over time and I think should compel us to carefully assess this as an option to potentially increase outcomes for this challenging setting where progress is slow to come.

Dr. Vamsidhar Velcheti: Yeah, I completely agree, Jack. And I think one of the things that we have seen, at least in the non-small cell setting, like the higher dose of conventional radiation is not superior to the 45 Gray, BID dosing. I think there were some studies with CALGB and the Gronberg trial, but I think at the end of the day, it comes down to patient conveniencer. It's not often feasible for patients to come in twice a day for radiation. That might be something that might limit utilization here.

Dr. Jack West: I think that's a very good point. It's just difficult when you have the potential for higher cure rates, but it is at least challenging, if not completely infeasible. But I really agree with you that that's a big part of why it's underutilized relative to the strength of the data for BID. But we have to be able to actually administer these.

Dr. Vamsidhar Velcheti: So let's move on to another trial. And again, we've seen the data before. This is Abstract 8521, the CheckMate-816 trial. They reported the three-year results of the neoadjuvant nivolumab chemotherapy versus chemotherapy by definitive surgery in patients with resected non-smoker lung cancer. What is the data that's being presented at ASCO this year?

Dr. Jack West: So yes, as you mentioned, we've seen data on CheckMate-816 for a few years now. It's been published in the New England Journal of Medicine and it's FDA-approved and has become a standard of care, if not the standard of care, but there are many dimensions to this. And one of the questions has been what happens to the patients who did not undergo surgery, which was about 17% of patients on the chemoimmunotherapy arm, a full quarter of patients on the chemo arm. What happened to these folks? And that's what is being presented by Dr. Jonathan Spicer, a thoracic surgeon in Montreal who's been heavily involved with this trial. And I think that's going to be the overwhelming focus of this.

And what is reported in the abstract, and I'm sure we'll see more interesting results, is that the outcomes are superior in the patients who received chemoimmunotherapy with nivolumab, in the patients who did not undergo surgery as well as those who did. Specifically, they report on the median time before death or distant metastases, and that was 24.8 months as a median for the chemoimmunotherapy arm versus 15.6 months for the patients who receive neoadjuvant chemo alone. The hazard ratio for that's 0.63. There was also a striking difference in the three-year survival rates, 36% versus 13% also favoring chemo and nivolumab.

They also talked about the actual treatments that patients received when they didn't have surgery, and about 60% in both of those arms received radiation instead of surgery, and about half the patients also received additional systemic therapy. So we will see more. But I think it helps to address one lingering question of what happens to the patients who did not end up pursuing surgery and showing that the results were more favorable for the recipients of chemo nivolumab, even in that subset.

Dr. Vamsidhar Velcheti: It's simply fascinating how the field is evolving in the perioperative space, Jack. And there are more unanswered questions here and up for debate for years with the recent agent trials we had seen at AACR. We've seen the same kind of trend even with the agent, I think it was 20%, who did not make it to surgery. A lot of them are like stage 3 patients. So it begs the question, are we kind of just being more aggressive with induction therapy? Maybe some of these patients are biologically or anatomically not bound to have surgery. I mean, it's hard to really tell.

Dr. Jack West: It really is important for us to still select appropriate patients for this, rather than become overly ambitious and try to shoehorn patients who are really not ideal or appropriate candidates for surgery and anticipate or have kind of aspirational resectability if they aren't de novo great candidates for surgery. We, of course, need to remember that chemoradiation followed by consolidation durvalumab on the PACIFIC trial is not some terrible consolation prize. We've done remarkably better with this over the years, and it's a very strong option.

Dr. Vamsidhar Velcheti: Exactly. The other open question, but of course this abstract doesn't really address is, what do you do with all the patients who perhaps have major pathologic responses and what do you do after surgery? That's kind of an open question, and we probably need a better way to determine who might need adjuvant therapy or surgery. I don't know if you have any thoughts on that.

Dr. Jack West: As you say, I think that's a big question, a gaping hole in our knowledge base, but it's not addressed here. I think we are going to be struggling with that in the coming years.

Dr. Vamsidhar Velcheti: Right. So let's move on to Abstract 9002. This is a report of the first pivotal study results of DZD9008 sunvozertinib in patients with exon 20 EGFR mutation. What are your key takeaways from the study?

Dr. Jack West: So I would say obviously we have a couple of agents that target EGFR exon 20 mutations, but unfortunately, neither of the agents that are commercially available is especially active. And they certainly have toxicity challenges, whether it's amivantinab or mobocertinib, they both share some challenges and they're not as efficacious as some of the other targeted therapies we use in different molecular settings. So I would say there's still some unmet need here. And these results with sunvozertinib DZD9008 selective irreversible EGFRexon20 insertion inhibitor really got my attention as very impressive. These are patients who were heavily pretreated. The median was two prior lines of therapy. This is not de novo first line, and that's a setting where it's pretty hard to see response rates that are over 30 or 40%, but what they actually report is about 60.8% response rate and nearly 100 patients assessed. They also looked at patients who had brain metastases and 31 patients in their sample had de novo metastases and the intracranial response rate was 48.5%, so nearly half.

This is, of course, something that we hope to see as a pattern when we have a targeted therapy that's very effective for the right target, not just overall extracranial, but intracranial efficacy. And we're going to need to see the details on the tolerability because, as I mentioned, the available agents now have the dual challenge of just modest efficacy and really quite challenging, particularly GI toxicities and amivantamab has issues also with infusion reactions. So some work there and I think there's room to improve on that. This looks to me very promising and I would welcome having the opportunity to use it in my patients who have an exon20 mutation.

Dr. Vamsidhar Velcheti: Yeah, I think certainly the brain intracranial activity is perhaps going to be the differentiator here. Given that mobocertinib has limited intracranial activity, I think that's very encouraging to see. So let's move on to the next abstract, the SCARLET trial, Abstract 9006. So this is a clinical trial of sotorasib plus chemotherapy in KRAS G12C-positive patients. Can you tell us a little bit more about this study, Dr. West?

Dr. Jack West: Sure. So this was a single-arm phase II trial. It's not large, it's 30 patients, but we really have yet to see results that would compel me to move sotorasib into the first-line setting. I was a little underwhelmed with the CodeBreaK 200 results that didn't beat docetaxel for survival in the second-line setting. But here it's a combination of carboplatin pemetrexed with sodorasib in the first-line setting in patients, of course, with a KRAS G12C mutation and nonsquamous histology. And the reported response rate by independent review is 88.9%, which is quite impressive. The median PFS is not reached yet. The PFS at six months is 61.2%. So I think we'll need to see the full data set, but that really impresses me as a very relevant finding. So I would love to learn more about this. And I think that if it is anything close to holding up with these response rates, close to 90%, I mean, even if it's 70 or 80%, I think that is compelling enough to really want to study this further in the first line setting and maybe a path to getting KRAS inhibitors used in the front line.

Dr. Vamsidhar Velcheti: Yeah, I completely agree. And I think with all the issues around the combination with checkpoint inhibitors, especially with sotorasib high liver toxicity, so I think the only way this could move into the frontline is with combination with chemotherapy, especially in certain subsets like KEAP1 CUL drug patients, STK11/KEAP1 patients where immunotherapy historically underperforms. So it'll be interesting to see how this can evolve.

So, moving on to Abstract 9012, this is a clinical trial evaluating a often very neglected patient population. This is a retrospective study of chemo without immunotherapy in the elderly population of patients with PD-L1-positive tumors. So what is your takeaway from this study?

Dr. Jack West: I would say that it really complements in my mind the presentation by Dr. Akinboro and colleagues from the FDA last year at ASCO, which was looking at the data for the trials of immunotherapy or chemoimmunotherapy in patients with high PD-L1 50% or higher. And what they found was that there was an improvement in response rate and progression-free survival and a trend, but not a significant difference in overall survival favoring chemoimmunotherapy in those patients. But they also noted that patients who were 75 or older did not seem to benefit from chemoimmunotherapy relative to immunotherapy alone. Now, that is in patients with high tumor PD-L1. This is looking specifically at patients who are 75 and older in Japan, 58 centers, and we're talking about over 1,200 patients, 1,245. And they looked at patients with any PD-L1. So the full spectrum, about 22% had PD-L1 less than 1%,31%, one to 49%, and just over a third, 34% with PD-L1 over 50%. I would presume the balance, that missing 13%, was not tested. But these are real-world data and they have strengths and limitations relative to controlled clinical trials.

But I think that there is some power in numbers and real-world data. And what they saw was that the patients who received chemoimmunotherapy had a median overall survival of 20 months. It was 19.8 months with a checkpoint inhibitor alone. And those data for both of those conditions are far better than a platinum doublet alone with a median overall survival of 12.8 months. Single-agent chemo just median overall survival of 9.5 months. And then when they looked at toxicities, saw that the grade three or higher immune-related adverse events was clearly higher in the patients who had chemoimmunotherapy, they had a greater need for steroids and a greater probability of pneumonitis than the patients over 75 who received a checkpoint inhibitor alone.

And so I would say it's not randomized data. You can only take this so far, but the fact is that it, I think, complements what we saw from the FDA. And that would help me in a situation where we need to make a nuanced decision, there's competing potential standards of care. I think this is informative along with the IPSOS trial that has been presented in some other settings and shows a benefit for in that setting was atezolizumab, I believe, first as the immunotherapy for older patients and PS2. So I think that we're seeing converging evidence to support this concept.

Dr. Vamsidhar Velcheti: Yeah, and I completely agree. And I think sometimes the clinical nuances at the individual patient level, I think there are so many other factors that we can actually look at the real-world data, like, for example, tumor burden and medical tomographies. There's so many things that we need to factor into while making those decisions.

Let's move on to the next abstract. This is Abstract 9022. This is an abstract looking at correlations of ctDNA levels and efficacy outcomes in the EMPOWER-Lung 1 trial. What are your key takeaways from this study?

Dr. Jack West: I would love to use ctDNA for clinical decision-making in a few years. I think it could be as pivotal as PET scans, but we don't have the data yet to show that you can use the results to improve outcomes. But this is looking at ctDNA in a different setting, as you mentioned, it's looking at the EMPOWER-Lung 1 trial, which was cemiplimab versus chemotherapy in patients with PD-L1 over 50% and did not have a driver mutation. They had ctDNA samples available from 175 patients who were pretty evenly split between chemo and checkpoint inhibitor cemiplimab. What they found was that molecular response, or particularly complete molecular response, if it was seen as in complete eradication of ctDNA at week nine, so after three cycles, was highly correlated with imaging-based response for patients who got cemiplimab. It was not correlated for the patients who got chemotherapy and, perhaps not surprisingly, the patients who had a complete molecular response that was associated with the best overall survival, an immediate overall survival of 29 months compared to the rather dismal results for patients who had no drop in their ctDNA, where the median overall survival was just eight months.

So, I think that it would be wonderful to be able to use this as a help. We know that sometimes patients have ambiguous imaging. There is the possibility of pseudoprogression and just potentially pneumonitis, making it difficult to interpret. I think that ctDNA could be helpful in that situation, but also for early feedback on who might benefit from intensification and adding chemotherapy, who we should cut our losses and switch to something else other than cemiplimab. And in the best-case scenarios, we do have a subset of patients who are doing extraordinarily well, potentially one or a couple of years later, and we just don't know if or whether to stop it and whether patients can do just as well after stopping after a prolonged period on treatment compared to staying on it. And we don't want to give this for years longer at the expense of cumulative toxicities and requiring a patient to come in for ongoing treatments month after month, year after year, for any longer than they would need.

I think that there's great potential utility for this as a concept. But again, at some point, what we'll really need is not to just apply this retrospectively, but prospectively to guide therapeutic decisions, to see if we can have patients do better by intensifying for those patients who need it or de-intensifying for patients who don't.

Dr. Vamsidhar Velcheti: It's great, Jack. And I completely agree. I think those kinds of de-escalation trials are very much needed. I'm hoping that we'll get there very soon.

Thank you so much, Dr. West, for sharing your valuable insights with us today on the ASCO Daily News Podcast. We really appreciate your time. Thank you so much. Look forward to seeing you in Chicago.

Dr. Jack West: Awesome. Great.

Dr. Vamsidhar Velcheti: And I'd like to thank all the listeners for joining us today. If you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Thank you so much.

Disclaimer:

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

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Disclosures:

Dr. Vamsidhar Velcheti:

Honoraria: ITeos Therapeutics

Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen, Elevation Oncology, Taiho Oncology, Merus

Research Funding (Inst.): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline

Dr. Jack West:

Honoraria: AstraZeneca, Genentech/Roche, Merck, Takeda, Mirati, Regneron, Amgen, Abbvie

Consulting or Advisory Role: AstraZeneca, Genentech/Roche, Merck, Takeda, Mirati Therapeutics, Regneron, Amgen, Abbvie, Summit Therapeutics

Speakers' Bureau: Takeda, Merck, AstraZeneca