Devika Das, MD: Everyone, welcome to another episode of Leading Thoughts in Lung Cancer. I’m Devika Das, and I’m a thoracic medical oncologist at UAB, and I’m excited to welcome my friends, Dr. Aggarwal and Dr. West. Dr. Aggarwal.
Charu Aggarwal, MD, MPH: Hi, thank you for having me on the show. It’s really good to be back discussing new science, new clinical trial data. I’m an associate professor for lung cancer excellence at the University of Pennsylvania’s Abramson Cancer Center.
Dr. Das: Dr. West.
Jack West, MD: Yeah. Hi, I’m Jack West and I’m a thoracic medical oncologist at City of Hope Comprehensive Cancer Center in the Los Angeles area. And happy to discuss how to interpret some of these findings. The data itself are interesting. And then, how does this translate into use or not?
Dr. Das: I thought we would discuss a very interesting abstract from this year’s ASCO annual meeting, which a lot of community physicians are interested in knowing if it has real world uptake or is it ready for prime time? And that was the Lung-MAP S1800A report out of overall survival.
Essentially, the clinical relevance is we know a lot of our patients in the second-line landscape, when they get single-line chemotherapy or chemotherapy with anti-VEGF agents, we still know that most of them have progression-free survival in three to five months. And unfortunately, most of our patients progress or pass away at a year mark. So we still don’t have a good second-line therapy in patients with no driver mutations and who get chemoimmunotherapy upfront or sequentially in the second line. So it was a very relevant trial that was done as part of what’s called a Lung-MAP protocol.
Again, this protocol is very interesting because it’s a master protocol for patients with stage IV recurrent or previously treated non-small cell lung cancer that enrolled patients from multiple sites in the country. So it had a very diverse real world, as real as it can get within the constraints of a clinical trial. And patients that were included in this study were those who were not eligible for any other biomarker matched subsets. So certain mutations and STK11 mutation in the NGS. Those patients were at different time points enrolled in other studies, or so not part of this specific substudy.
Essentially, it was a randomized phase 2 study with about 130 patients that were found eligible. And the primary endpoint for the study was overall survival. So the analysis was adjusted to a way that they could better detect delayed effects of, again, knowing that this is a study that involves immunotherapy. The schema was fairly simple. These were patients that previously progressed on PD-1 or PD-L1 inhibitor therapy and platinum-based chemotherapy either in combination or in sequence and have gotten PD-L1 therapy for 84 days and have stayed on it for 84 days after initiation.
All patients were in ECOG 0 or 1, they were stratified by PD-L1 expression histology and the intention to receive ramucirumab in the standard-of-care arm if they were randomized to that arm. So it was a one-to-one randomization. Patients on the study arm got pembrolizumab and ramucirumab, and patients in the investigator choice arm or in the standard-of-care arm got whatever chemotherapy the physician chose in the second line. And as I said, the population was not completely unselected, so certain patients with certain mutations were selectively taken out and put on other sub-studies.
Most patients were male. Most patients were white. Most patients were adenocarcinoma. About 58% of patients in the study arm and about 52 in the other arm were adenocarcinoma, but they had about 40% of patients that had squamous cell and other histologies. Shockingly, most patients were in ECOG 1 and not 0, to the point that they actually had to match for or study for that imbalance to make sure that that didn't make a difference. Most patients were former smokers. They had about 40% of patients on both arms that had no PD-L1 expression and about 25% of patients on both arms that had PD-L1 expression more than 50%.
The study met its primary endpoint of overall survival. And that is what was reported. So the median overall survival for the study arm was 14.5 months versus standard of care was about 11.6 months. And that was statistically significant. And while they touched upon the subgroups in the study, they were very clear to state that you can’t make a lot out of that, because it was just 130 patients overall and the numbers were really small. But in the subgroups, they did not see a big difference based on the PD-L1 expression.
Shockingly, they saw a pronounced response in patients that had squamous cell histology, which in other VEGF trials is not something that we’ve seen. We’ve seen patients with adenocarcinoma have done better, and they saw equal amount of benefit in all performance status and whatever small amount of co-mutations that they saw and studied did not affect the overall survival.
The interesting part of the study, though, was there was a discordance in the overall response rate and progression-free survival from overall survival. So while the overall survival benefit was towards the study arm, there was a progression-free survival benefit in the standard of care arm by a month – 5.2 months for standard of care and 4.5 months for the study arm and the same thing was seen in the best objective response. The overall response rate in the pembro/ramucirumab arm was 22% while standard of care was 28%, and the duration of response in the standard of care arm was 5.6 months and 12.9 months in the pembro/ramucirumab arm.
The way they explained that was there was possibly, in addition to other things that we don't know about, maybe some post-progression prolongation of survival that’s offered by immunotherapy. Again, something that I think is interesting enough for discussion. In terms of AEs, 42% of patients had more than grade 3 treatment-related adverse events on the study arm and 60% on the standard-of-care arm. And about 31% grade 3 to 5 IRAs were seen on the study arm. So clearly it is a toxic regimen and not substantially different from standard of care.
Knowing that, I think a question that a lot of us have, and I’ve heard from a lot of community physicians is, is this regimen something that we’re using in second line for our patients after immunotherapy progression? I’m curious to see how you are using this data in your everyday practice. I’m going to start with Dr. Aggarwal.
Dr. Aggarwal: Yeah. I would say that I’ve started to hear a lot of commotion around this idea of using ramucirumab and continuing the immunotherapy backbone. There are several physicians who have commented on how they think this would be an ideal regimen for patients and they would start to use it, citing the overall survival advantage.
I hesitate to use it right away because I feel that at the end of the day, this is still a phase 2 trial. This is not a phase 3 study. It’s still a relatively small study and the patient population has been defined. As you clearly pointed out, patients had to have at least 12 weeks of immunotherapy. So they’re selecting the patients who had some benefit from their initial immunotherapy.
I sort of agree that rapid progressors or patients that have primary immunotherapy resistance should not be included in such a study, but it begs the question, is 12 weeks the appropriate cutoff? Should it be longer? Or should it be a different cutoff altogether? And then what’s curious is, as you pointed out again, that there’s no PFS benefit, there’s no response rate benefit. So is the overall survival benefit really being driven by the subsequent therapy that’s being received?
Docetaxel after having received immunotherapy is a very different drug. We all know this from our clinical practice. We see very different outcomes than we would’ve seen if somebody received docetaxel in the era of the REVEL trial, where many patients had not received immunotherapy. So I think it behooves us to ask for a phase 3 trial. I would refrain from using it in my clinical practice, but curious to see what Jack has to say as well.
Dr. West: I would say I totally agree that it is important to consider this as a positive phase two trial. And I wouldn’t take away from that, but I think that is as far as we should take it. I think it is a mistake, and unequivocally, I would say it should not be applied broadly in clinical practice today. We have seen over the last decade or two, many examples of phase 2 trials that looked very promising but failed completely in larger phase 3 studies. And I think we should not have any great confidence that a trial with 65 or so patients per arm is going to be replicated in a much larger phase 3 setting.
I would just say that with the small numbers, it’s pretty easy for it just to have a good day and stick the landing with the overall survival that, again, as you both stated, is discordant with PFS and response rate. So I think that just may have been how the numbers broke, and I wouldn’t have a ton of faith that this is absolutely the way it is going to pan out.
I think it is absolutely worthy of further study. I’m very anxious to see the phase 3 trial, but I think it’s a mistake to interpret or even intimate that while we’re waiting for that, that this should be widely used based on the rather limited data that we’re provided. It’s very good phase two data, but there’s a reason why we go on to phase 3 trials based on that.
Dr. Das: I completely agree. Do you think it made a difference that... So 45% or so of patients in the standard-of-care arm also got docetaxel and ramucirumab. So the question is really, does the ramucirumab... What is it that made the difference? I think there’s a lot of... Is it because they continued pembro post-progression? So people are just making different interpretations. Again, I feel like it’s too small of a study to make decisions out of that. I’m getting questions asked about, just because of that, should I just keep continuing the pembro or should I switch to another immunotherapy? Would that work? And so far I've been cautioning against that and I don’t think that is the way to interpret the data that we have seen from the study. Thoughts?
Dr. Aggarwal: I think it’s really hard to say what’s contributing here. Is it pembro? There is data to support use of IO in the post-progression setting. We know that we can see responses in a small percentage of patients. There can be this idea that, yes, you could prolong immunotherapy and potentiate immunotherapy response by VEGF inhibition. So that’s the concept of the hypothesis for this trial. So is it really the pembro or is it the ramucirumab that’s driving the survival? It is, again, I think, unclear.
I think also there’s different regimens that were received in the standard-of-care arm, which made it very hard to interpret what’s going on. I think as we’ve said, having a randomized phase 3 trial that looks at a very exact standard of care regimen would perhaps help to clarify the question.
Dr. West: I really agree. I think that it is a credit that the study did include the majority of patients getting docetaxel/ramucirumab, which I would say is the most evidence based best regimen. And to the extent that the phase 3 trial might directly test, ramucirumab is a variable that’s not changing. And the only variable is pembro versus docetaxel with the ramucirumab. I think that’s great.
The problem is I think that it’s valuable to have some dealer's choice, and replicates the way the world works, but essentially a quarter of the patients on the control arm got totally ineffective therapy. Six people got no therapy at all and 12 got gemcitabine, which has been studied as second-line therapy. It’s not more effective than a hug.
And so I think that may also have a real role here, that a quarter of the patients on the control arm got therapy that has no value. And when you’re talking about a small study that can really skew the results. So yeah, I think we should see what happens in a larger study, but I think it’s not maligning it to say it’s positive. It should move forward. It is just not so unfathomably positive that we should skip the phase 3 and adopt this as a standard of care while waiting.
Dr. Das: I think that’s a great summary. I think the take-home points from this is it was a great study, it was a positive study, but until we see phase 3 data, at least the three of us on this call will not be using this doublet regimen as one of our second-line standard of care. But clearly a space that needs more trials. And if we have patients that could be enrolled in a phase 3 trial, I think this would be a trial to get our patients into. Great discussion. Thank you so much. And I hope to join the two of you again in another episode soon.
Dr. West: Excellent. Thanks.
Dr. Aggarwal: Thank you.
