Jia Luo

Hi there, we’re coming in from ASCO Live 2022, and this is with VJOncology.

Julia Rotow

Hi, I’m Dr. Julia Rotow, I’m here with the Dana-Farber Cancer Institute. Happy to be meeting with you here from the in-person ASCO 2022 annual meeting. I’m joined here by my colleague.

Jia Luo

Yup. And I’m Dr. Jia Luo, also from the Dana-Farber. We’re both part of the thoracic medical oncology group, and we’re really excited to present some interesting data that we noticed while attending the sessions here at ASCO.

Julia Rotow

So, Dr. Luo, maybe to lead us off immunotherapy for non-small cell lung cancer, what stood out to you at the conference here today?

Jia Luo

Yeah, so I thought on Friday there was an interesting session, it was called S1800A and it examined pembrolizumab, which is immune checkpoint inhibitor with ramucirumab, which is a VEGFR-2 inhibitor. And the overall results showed an overall survival benefit in this randomized phase two study. So to break down the study a little bit more, it was a large consortium study called Lung-MAP. I don’t know if you’re aware of that, Dr. Rotow.

Julia Rotow

Yeah, I believe it was an academic consortium, is that right?

Jia Luo

Yes. Yeah. So, I think, what was really remarkable where it was they enrolled patients from 600 sites and so, I think, I look forward to more studies coming out of study consortia like this.

Julia Rotow

Absolutely.

Jia Luo

Yeah. And so, what they found, which was interesting, is they took 130 individuals who had non-small cell lung cancer, advanced pretreated, and they randomized these individuals to the pembrolizumab plus the VEGF inhibitor, ramucirumab versus physician’s choice chemotherapy, and that’s also an interesting way to design a study, Dr. Rotow?

Julia Rotow

Yeah. I mean, it gives you a variable control arm, but it also gives you a very real world pick at what people are actually doing when we think about managing patients with standard treatment.

Jia Luo

Yeah. I thought so as well. And so, they randomized the 130 patients and there was an overall survival benefit. What was interesting, though, was that if you looked at the subset analysis, the individuals who had chemotherapy followed by immunotherapy seem to benefit more. And so, this makes me wonder at the time of acquired resistance, if there’s some lesions that still benefit from immunotherapy that maybe adding more in immunotherapy plus ramucirumab, is helpful for those individuals rather than stopping.

Julia Rotow

Absolutely. And you raised an interesting point about chemotherapy, and how that integrates into immunotherapy for advanced lung cancer. I think, we saw some data on that as well in the oral abstract session.

Jia Luo

Yes, we did, and the same session, the FDA actually had pooled 12 different registrational studies of either immunotherapy based treatment or immunotherapy plus chemotherapy based treatment, and I don’t know if you’ve seen projects like this from the FDA.

Julia Rotow

Yeah. So, I think, it’s a novel way to try to answer a clinical question that we all face in clinic, what to do for our PD-L1 high patients when we’re seeing them with a new diagnosis.

Jia Luo

Yeah. So, they specifically looked at the PD-L1 greater than 50% subset and they actually found mixed results and so, there wasn’t a concordance between objective response, PFS and OS, but I thought it was a very interesting way to look at data, especially because the FDA can actually have patient level data to review. And so, I look forward to more interesting analyses like these from the FDA. And so, I know we’ve been talking a little bit about immunotherapy in non-small cell lung cancer, but Dr. Rotow, what did you think about immunotherapy and small cell lung cancer?

Julia Rotow

Yeah. I think, that’s been a challenging issue as well. I know in the clinic, you may have seen response rates to immunotherapy for small cell haven’t been as exciting as we’ve seen in non-small cell. I don’t know if you had experience with our current regimens, I know immunotherapy response rates aren’t so good.

Jia Luo

Yeah, exactly. And so, right now, what I would do upfront is carbo etoposide, so chemotherapy plus immunotherapy based treatment.

Julia Rotow

So, this study that was presented here at the conference called the SKYSCRAPER study, looked at taking the standard regimen of a platinum etoposide atezolizumab and adding the TIGIT inhibitor, which is another inhibitory immune therapy checkpoint tiragolumab in combination with that standard regimen. There’s a lot of excitement around this potential target, hoping to augment immunotherapy responses for small cell. Unfortunately, the study came back negative where there were not advantages in PFS or OS in the small cell lung cancer patient population, but they are looking at biomarkers and maybe we’ll see subgroups who can derive greater benefit.

Julia Rotow

Now, we can put this in context so this target has been looked at in other areas of lung cancer. So, in non-small cell lung cancer in this CITYSCAPE study, which looked at adding the same anti-TIGIT agent to atezolizumab therapy, did demonstrate benefit. So, I think, it doesn’t mean that this target can’t be of use to our patients, particularly in the PD-L1 high patient population, and it continues to be evaluated in prospective studies.

Jia Luo

Yeah, that’s great. And Dr. Rotow, I know you’re an expert on EGFR lung cancers and when I traditionally think about EGFR sensitizing mutations, I think, of exon 19 deletion and L858R, but tell me more about what you learned about these other EGFR sensitizing mutations.

Julia Rotow

Absolutely. We know that genomic targeted therapy has been a real advance for our EGFR mutant patients, but there are some very challenging areas in this space where optimal management isn’t yet clear. And that includes EGFR exon 20 insertions, which are resistant to a lot of our standard EGFR therapies, as well as acquired resistance to standard therapies acquired resistance to osimertinib, and maybe talking about acquired resistance first, Dr. Luo, do you find yourself re profiling when patients do develop TKI resistance?

Jia Luo

I actually do. And, I think, this should be standard practice. We should be looking at what other co-mutations develop besides the original sensitizing EGFR mutation. What have you seen from that, Dr. Rotow?

Julia Rotow

Yeah. So, here today, there was a really interesting poster that was presented looking at the MET ADC Teliso-V. And this is a Met MMAE conjugated antibody drug conjugate, which was evaluated for use for patients with MET over expression at acquired resistance to osimertinib. And this makes up a subset of patients and it is a very interesting biomarker because it requires IHC rather than genomic testing alone. And they showed an impressive response rate of 58% to this antibody derived therapy. So, I think, it raises a broader question. We’ve derived great advances in lung cancer using genomic testing in treatment of our advanced disease patients, but maybe IHC-based testing is now also going to be valuable as we think about how to allocate next line therapies.

Jia Luo

I absolutely agree with that. I mean, just even looking at our Plenary with the DESTINY-Breast04 data, I think there’s going to be a lot of interest in profiling cancers using IHC, and then also in the antibody drug conjugate space. I’m pretty excited about that.

Julia Rotow

Exactly. Now, there was a different challenging setting, EGFR exon 20 lung cancer had some interesting data too. And this is an area we have a lot of different, small molecule inhibitors in development. We have mobocertinib which is FDA approved, but number of other drugs that are being looked at, and, I think, some parameters we’re looking at for those drugs are things like drug potency, drug tolerability select, so selectivity against wild type EGFR and potential for CNS activity, which is a big unmet need for our EGFR patient population. I think, we see a lot of CNS disease in these patients.

Jia Luo

We absolutely do, and what did you find about that, Dr. Rotow, when you looked?

Julia Rotow

Yeah, absolutely. So, I’m going to highlight one abstract that was presented actually in the oral abstract setting, looking at CLN-081, which is a novel, small molecule EGFR exon 20 inhibitor. And this drug described in the presentation, both the efficacy and tolerability data currently available, and it showed the maximum tolerated dose, an impressive response rate of 41%, I think, at least comparable to some of our other approved agents in this space like amivantamab, but also a reasonable toxicity profile. We saw a lot of the classic EGFR wild type toxicities, like rash and diarrhea, but at a lower grade than we’ve seen before. And notably, there were no great three rash or diarrhea.

So, this remains interesting to me and, I think, we’ll see more on this drug as we get more updated data. There was a little hint as well, they presented one patient at a free described who had potential CNS activity. And again, this is an unmet need. And, I think, for many of the drugs we’re evaluating these days, looking at CNS activity is critical. Even this turns my attention to another agent we saw and are going to see a bit of CNS data on adagrasib. I think, about KRAS lung cancer. I think, you were going to talk about that.

Jia Luo

Yeah, exactly. And I guess Dr. Rotow, maybe to first have you start off, how do you approach individuals who have KRAS lung cancer in your clinic?

Julia Rotow

It’s a great question. This is a real change in practice. We now have KRAS-G12C targeted therapies. So, when patients are found to have a KRAS-G12C mutation, which you’ll find on standard NGS, the use of a KRAS-G12C inhibitor is now standard of care in the second line setting, but we have a number of different drugs approved. And Dr. Luo, I know right now we have sotorasib approved, but there are many other drugs in development, including adagrasib.

Jia Luo

Yes, exactly. And so, this was a very exciting study as well, presented on Friday in the non-small cell lung cancer session. So, it was a study looking at adagrasib, which has been submitted to the FDA for NDA, looking at a different G12C inhibitor and what is its objective response rate and early look at PFS data. And so, I found that this drug is comparable to the FDA approved sotorasib in terms of objective response and then, also the PFS data that we’ve seen so far. I think, the study that they had presented showed what would happen to individuals who’ve had CNS radiation, but as you discussed, it is an active issue. And I believe this afternoon, we’ll have some additional data on untreated brain metastasis and how individuals would do with adagrasib.

Julia Rotow

Dr. Luo, do you have any sense of how toxicity might compare between these two drugs, are they similar?

Jia Luo

Yeah, no, it’s a good question. And once again, it was a small data set. It was over a slightly over a 100 patients and there was actually the New England Journal paper that was published simultaneously, which I encourage individuals to check out as well. GI toxicity, I think, is something we always think about in individuals with non-small cell lung cancer, especially when we think about it in combination with immune checkpoint blockade and other drugs that are used in the KRAS space. And so, we’ll have to see if we can see more additional or there is some hint of GI side effects compared to sotorasib, we’ll have to take a look at that data more carefully.

Julia Rotow

And, I think, you’re actually giving a talk tomorrow a bit more about KRAS and even talking about non-G12C KRAS-positive lung cancer. I didn’t know if you wanted to make any comments on that.

Jia Luo

Yeah. Exactly. So tomorrow, which is Tuesday at ASCO, 2022, there’s going to be an entire hour and 15 minutes devoted to talking about KRAS lung cancers. This was considered to be an undruggable protein. We discovered it was one of the original oncogenes, and for 30 plus years, we haven’t been able to target it wasn’t until last year with the approval of sotorasib, we are able to. So, we’re going to highlight the history, talk about the G12C inhibitors and give some foresight to the non-G12C, and then other ways to overcome resistance to these treatments.

Julia Rotow

Really exciting time for KRAS lung cancer. I know so many of our patients have these mutations. I think, it’s almost as common as EGFR or more common in some populations.

Jia Luo

Right. Precisely. Yeah. We think it represents about a quarter of individuals with non-small cell lung cancer. So, I think, this is a very exciting time, both for non classical EGFR mutations and also KRAS lung cancers and so, yup.

Julia Rotow

Okay. So, I think, looking forward to what’s to come in the last day here of the conference and Dr. Lou, if you want to close things out.

Jia Luo

Yeah. No, thank you all so much for listening. And we look forward to hearing from you again.