Devika Das, MD: Hello, everybody. Welcome to another episode of Leading Thoughts - Lung Cancer. I’m Devika Das and I’m a thoracic medical oncologist at the University of Alabama at Birmingham. And I’m excited to welcome my co-panelists, Dr. Jack West and Dr. Charu Aggarwal. I’ll let them introduce themselves, Dr. Aggarwal.
Charu Aggarwal, MD: Hi. It’s great to be here. I’m Dr. Charu Aggarwal. I’m the associate professor for Lung Cancer Excellence at the University of Pennsylvania’s Abramson Cancer Center.
Dr. Das: And Dr. West?
Jack West, MD: I’m Dr. Jack West. I’m a thoracic medical oncologist and associate professor in medical oncology at the City of Hope Comprehensive Cancer Center in the Los Angeles area. Great to be here.
Dr. Das: I’m really excited to be discussing some new drugs and a relatively new mechanism of action in metastatic non-small cell lung cancer and a trial that was presented at the American Society of Clinical Oncology (ASCO) Plenary end of last year. This is really in a population of patients with high PD-L1 and no driver mutations.
And we know these patients do really well with single-agent immunotherapy. But even in those patients, over half of those patients don’t respond. And about 22% or so do progress very early in treatment. The trial that I thought we could discuss was the ARC-7 trial that was discussed by Dr. Johnson, which is a randomized open-label phase 2 study of the drugs, domvanalimab plus zimberelimab and etrumadenant versus zim alone in frontline for metastatic PD-L1-high non-small cell lung cancer, with no EGFR or ALK drivers. So what are these drugs?
Dom is an Fc-silent monoclonal antibody that blocks TIGIT [T-cell immunoglobulin and ITIM domain], thereby reducing immunosuppression of T and NK cells and promoting anti-tumor activity. Etru is also a relatively new drug, which is a dual antagonist for extracellular adenosine receptor and blocks that pathway. And zim is an anti-PD-1 monoclonal antibody that is homegrown and used in a lot of the Asian countries and has an approval for different kinds of lymphomas in that space and is used in patients with high-PD-L1-driven non-small cell lung cancer.
What did this trial show? Essentially, it enrolled patients that were treatment-naive with stage IV squamous or non-squamous non-small cell lung cancer with high PD-L1 expression of TPS [Tumor Proportion Scores] more than 50%, no EGFR or ALK alterations, and a performance status of zero and one. The patients were randomized in a one-is-to-one-is-to-one fashion to the three arms.
The first arm was the zim arm alone, which is the use of the anti-PD-1 monoclonal antibody alone. Arm two consisted of the zim and the dom, which is the anti-TIGIT antibody. And arm three had all three drugs given to the patients together. The patients in arm one who were found to have progression had the option to cross over to arm three in this study. The co-primary endpoints were overall response rate and progression-free survival per resist.
What was presented at the ASCO plenary session was the safety and efficacy results from the interim analysis, which was interesting. All patients, about 133, were randomized at least 13 weeks prior to data cutoff. And they all got more than two post-baseline scans. And with a median follow up of about 11.8 months, the dom-containing arms demonstrated an improved overall response rate in PFS [progression-free survival] compared to zim.
The overall response rates in arm one, arm two, and arm three were 27%, 41%, and 40%, respectively. The median PFS was 5.4, 12, and 10, [respectively]. And something that really stood out for me was the safety data. In the safety population, grade three or more treatment-related adverse events were about 58% in the zim arm, 47% in the dom/zim combination, and 52% in the triplet arm.
There were four deaths in this study. In arm one there was a death from ILD [interstitial lung disease], myocarditis in arm two, and two other deaths were seen, including one from CHF [congestive heart failure] in arm three. At the time of this presentation, it was stated that about 12 patients had crossed over to arm three after progression and continued to show some amount of partial response.
There was a lot of fanfare around this. And we have similar other studies including CITYSCAPE and SKYSCRAPER-01. I’m interested to know what do you think about this study? What do you think about the results? And is this something that you expect is going to be practice-changing? If there’s a phase 3 study in patients with non-small cell lung cancer and a high PD-L1, is it adding anything to that population that pretty much do really well with single-agent or immunotherapy or chemoimmunotherapy? I’m going to start first with Dr. West. What are your thoughts?
Dr. West: I’m pretty skeptical. I’d have to say that I think this was, yes, encouraging, positive. But just as we’ve discussed many times in the series, to me, the question isn’t “compared to some questionable or obsolete comparator arm,” but compared to what we do now. And in this case, yes, there was a PD-1 inhibitor, so fine. But the PD-1 inhibitor that we’ve used since late 2016 has been approved. The first agent that ushered us in this new era of first-line immunotherapy has been pembrolizumab. And the response rate is about 45% with it.
Now, maybe that’s particularly good, but this was a randomized phase 3 trial, and I think we tend to see results that are in that ballpark. And so, seeing that the combinations do almost as well as what we already have, I’d have to say I’m not that impressed with this. And even if there is some incremental benefit to anti-TIGIT or other therapies, they’re going to come with, if not added toxicity, added cost. I mean these are not drugs that come in costing what vinorelbine or gemcitabine does, which is negligible. These are going to be priced at $15,000 a month.
And I think for that, we should be blown away by their efficacy. And I think that it’s hard to envision these combinations coming anywhere close to that. We’ll see if bigger randomized phase 3 studies are more positive than this, but taken on its own, taken what we have right now, I’m underwhelmed, and I think this is a pretty weak positive.
I think that while it was an ASCO monthly plenary, I think that some months there’s more to choose from than others. And I don’t think this was one that would have been anything close to a plenary in the regular annual meeting. That’s my take on it. I think this is, if anything, maybe a question of, if this is a positive trial for TIGIT, I mean is that damning it with faint praise?
Dr. Das: What do you think, Charu?
Dr. Aggarwal: Yeah, absolutely. I think a couple of things to highlight here, dom as we are going to call it, is anti-TIGIT, but it has a slightly different mechanism of action. You alluded to this, it’s Fc-silent. The other TIGIT antibodies in development are Fc-enabled. Slight differences. Fc-enabled can also activate antibody-dependent cellular cytotoxicity, can potentially increase immune infiltration.
This antibody doesn’t carry that. How this will differentiate it in clinical activity at this point is unclear, but it could be that it causes less immune-related reactions. Certainly, we’ve seen a better tolerability profile with this compound compared to the other molecules that are out there that are Fc-enabled. And those are tiragolumab. We have ociperlimab as well as vibostolimab. And these are all three anti-TIGIT compounds that are being tested both in the front-line setting in combination with PD-1 or PD-L1s or in the second-, third-line settings in our PD-L1–refractory patients.
I think overall, the signal is pretty weak in patients who’ve been previously treated with PD-1, PD-L1. Our romanticism of “Oh, we’ll come in with these subsequent lines of drugs that will just continue to iterate upon what immunotherapy they receive” has faded pretty quickly because there isn’t really an immunotherapy drug that we’ve come up with that can overcome “immunotherapy resistance.” Maybe it’s acquired or it’s primary immunotherapy resistance.
I think it may have a role in the first-line setting. ARC-7 is preliminary data, but they’re launching a phase 3 trial for PD-L1-high combining dom plus zim, actually comparing with pembro, if I’m not mistaken. We’ll have somewhat of a sense of what that eventual improvement is in greater than 50%. And if we are going to base it on anything, we have it as the flavor of the month, we can base it on a press release from SKYSCRAPER-01, where the press release said that there is numerical improvement in both overall survival as well as progression-free survival for patients that received atezolizumab plus tiragolumab compared to atezolizumab alone for the PD-L1 greater than 50%.
We had seen this in CITYSCAPE, which was a smaller phase 2 version of it where we saw an improvement in response rate for the PD-L1 greater than 50%. And potentially, even on that trial, if I’m remembering correctly, we actually saw an improvement in progression-free survival for PD-L1 greater than or equal to 50%.
It’s a little surprising that in SKYSCRAPER-01, we are not seeing PFS improvements, but we are potentially going to see an overall survival improvement. And then the question will be if we are seeing a hazard ratio improvement of survival of 0.7, even if it’s 0.7 or 0.75, I think, Jack, I disagree with you that if we see a hazard ratio of improvement in overall survival for that group and the toxicity is not that significant, that may represent a paradigm change.
Dr. West: Well, I think if we see that, I would have a somewhat revised view. I’d just say I’ll believe it when I see it. Otherwise, I think that what we’ve gotten are just slight intimations of maybe positivity or “it’s not negative now.” I think that I’m going to put my money down today that we will not see a hazard ratio below 0.8 for overall survival here.
And for me, I think that you will need to have an overall survival benefit that is quite convincing to justify what I anticipate the cost will be for something like this. If it’s 0.7, okay, let’s talk. But if it comes back as 0.87 and p-value of 0.05, I’m not necessarily going to say that this is staggeringly positive and a mandate for a new standard of care.
Dr. Aggarwal: And that’s exactly what I think. And it’s going to be one of those things where again, I think we’ll have an FDA approval because, quote, unquote, the trial met its primary endpoint. Or co-primary endpoint of PFS and OS [overall survival] if PFS wasn’t met they at least met the co-primary endpoint of OS. And then we are going to be debating what is the actual value in clinic. I completely agree with you. I think meeting a clinical trial endpoint is not similar or the same as meeting our clinical bar of the risk-efficacy ratio and calculation.
Dr. Das: Charu, you summarized it really well for anybody who’s listening to this. As a physician in the community, if I have a patient with high PD-L1 TPS score, should I be treating them with standard of care or just being very quick to add a second and third drug upfront?
I think that is something that makes me take a pause if that’s absolutely necessary because those are patients we see in clinic every day. And I’m not necessarily jumping to get on that bandwagon. I’m not sure if I want to put them on a triplet regimen, that’s for sure. I might still be open to looking more at the anti-TIGIT antibody. And for now, I think for a practical setting, I would be open to enrolling them in a clinical trial but really not making a practice change even if there’s an FDA approval tomorrow.
That was a great discussion, and I’m hoping to have some hopefully more positive and practice-changing discussions come up in the next few episodes. But thank you so much for chatting with me today.
