Dr. Roy Herbst:
Welcome to the ASCO Post Roundtable Series, First-Line Immunotherapy for Metastatic Non–Small Cell Lung Cancer: Special Populations and Unmet Needs. I'm Dr. Roy Herbst, Deputy Director of the Yale Cancer Center, and with me today are two of my colleagues. I'll have them each introduce himself. First, Dr. Karen Reckamp.
Dr. Karen Reckamp:
Hello, happy to be here. I'm Karen Reckamp, Professor of Medicine and Division Director for Medical Oncology at Cedars-Sinai Medical Center in Los Angeles, California.
Dr. Herbst:
Thanks, Karen. And Dr. Charu Aggarwal.
Dr. Charu Aggarwal:
Hi, it's a pleasure to be here. I'm Charu Aggarwal. I'm Professor of Medicine and a thoracic oncologist at the Abramson Cancer Center at the University of Pennsylvania in Philadelphia.
Dr. Herbst:
Thank you for being with us. Today, we will be discussing the treatment and management of metastatic non–small cell lung cancer with three patient case studies. Our second installment will focus on the management of a patient with PD-L1–negative metastatic non–small cell lung cancer. Let's look at this case, case two. You can see the X-ray. This is a 57-year-old Asian American female with stage IV lung adenocarcinoma, left lower lobe, bulky hilar and mediastinal metastases, and multiple bone lesions including ribs and pelvis. Patient's a former smoker, 15-pack years, quit 20 years ago. Performance status is 1, with some mild bone pain. An FNA of the left lower primary is positive for lung adenocarcinoma with TTF-1. PD-L1 TPS, however, is completely negative. So, a difficult case. I would've thought that this could be an EGFR-mutated patient, but it's not. The next generation sequencing was performed. So Charu, what would you offer this patient for first-line therapy?
Dr. Aggarwal:
Yeah, and I think this case highlights our dilemma of how to treat patients with PD-L1–negative disease. We have so many robust options now that range from chemoimmunotherapy to quadruplet therapies that may incorporate CTLA-4 inhibition or even bevacizumab in some instances depending on the regimen. But time and again, we've seen that while the data look really good for PD-L1–positive patients, we are consistently lacking a significant improvement for our patients with PD-L1–negative disease. I think this is a subset where potentially there's a role for combination doublet immunotherapy potentially using CTLA-4 inhibition. I think recently there was a pooled analysis done of quadruplet immunotherapy trials evaluating nivolumab and ipilimumab. It seems that the PD-L1–negative population seems to have a median overall survival of about 17 months in this particular patient population of PD-L1–negative disease.
So it leads me to believe that potentially there could be a role. Again, none of this has been prospectively validated for the PD-L1–negative population per se, so it's hard for me to say that there is randomized data to support it, but whatever we are seeing from subset analyses and pooled analyses seems to point towards a combination approach.
Dr. Herbst:
Karen, what do you think?
Dr. Reckamp:
I would agree with everything Dr. Aggarwal has commented on. For these patients, very challenging and many of these patients don't do well with many of our therapies, and so trying to augment that and potentially use the combination of a CTLA-4 and PD-1/PD-L1 inhibitor, and yeah, 5-year outcomes from the CheckMate 9LA study, about 20% 5-year survival in PD-L1–negative patients. And so using this combination may offer more long-term benefits for these patients who are difficult to treat.
Dr. Herbst:
That's interesting. Even though here at Yale we do a lot of these combinations, and they were in many cases developed for melanoma, I probably would use a KEYNOTE-189 type approach, chemotherapy plus pembrolizumab, but I see both of your points. Are there risk factors or performance status factors which would lead you, Karen, to not use the ipilimumab?
Dr. Reckamp:
So obviously somebody with a poor performance status, this person has a performance status of 1, but only with mild bone pain, so I would imagine that the person is relatively functional. For somebody with a closer to 2 performance status, I would avoid a dual checkpoint inhibitor therapy. And then the issue of patients with underlying autoimmune disease, and we see this more commonly, I see this all the time in my clinic where we're trying to make decisions about a patient who may have some mild rheumatoid arthritis or other symptoms that, on their day-to-day basis, it may not be much of an issue for them, but obviously giving immunotherapy can be life-changing and life-saving. And so I think I've been more cautiously giving these agents, not necessarily dual. In a patient with an autoimmune disorder, I would not give a combination therapy as the front-line therapy, but using immunotherapy in these patients, I think we're doing that more and more and doing it cautiously with our rheumatology colleagues and trying to treat these patients and not withhold a drug that may be, again, potentially prolonging their life significantly.
Dr. Herbst:
Right, we're treating a very difficult disease, so we want to be aggressive but prudent. You agree with that, Charu? Any other thoughts?
Dr. Aggarwal:
No, I agree with it, and I think as we are becoming more comfortable with these regimens, especially with the modified dosing in some of the newer regimens as well as I think, for example, POSEIDON doesn't continue dual checkpoint inhibition after the initial induction, I do think that these options are becoming a little bit more feasible. Definitely much better than how the introduction was rolled out. I remember using ipilimumab and pembrolizumab, ipilimumab and nivolumab on the initial phase I studies and the grade 3 and 4 adverse events at that time used to be over 70%. I think all three of us remember that, and it was very, very hard. But I think with the new regimens and the new dosing schedules, it's easier. Certainly not a walk in the park, but something that we can manage.
Dr. Herbst:
Right. Let's talk a little bit about the PD-L1 being zero and the smoking status. So here we have an Asian patient who is EGFR mutation–negative, hadn't smoked in 20 years. Does that worry you a little bit? Many people worry about using immune checkpoint inhibitors in never-smokers. Or if there's no actual mutation, it doesn't mean there isn't something we haven't found yet. But what do you think, Karen?
Dr. Reckamp:
The first piece of this information is that the patient had an FNA. And with an FNA, I am always cautious, especially in somebody, this is a younger patient who's got Asian race and has limited smoking history, and so I would actually really want to re-biopsy this patient and would be a little more cautious about giving this patient immunotherapy. It would be in the back of my mind that we may actually find an actionable alteration, and EGFR would be very high on the list of what we might find. In that case, I would generally avoid immunotherapy in that patient. So this patient, I think, still could have an actionable alteration.
I think that's important to note, is that just because there's an NGS that says no actionable alterations doesn't always mean it's negative. Sometimes we get the blood test back and it's negative, and that is not necessarily something you can just jump and treat with. And so these patients, especially with small samples to begin with, I think we need to keep an open mind and be curious and continue to evaluate that. And if the patient needs treatment, I would consider treating the patient, actually, with chemotherapy without immunotherapy as we try to get another biopsy or another sample.
Dr. Aggarwal:
I would just add that an NGS is done doesn't mean that an NGS is done. I think finding out what exactly was done, so it could be that only the DNA testing was done and nobody did RNA fusion panel testing. And especially for these never-smokers, I think fusion panel testing can be so important to look for ROS, RET, ALK and not to forget that it may also pick up MET exon 14- kipping mutations that may have been missed by DNA sequencing alone. So I think not just knowing what NGS was done, I completely agree with Karen that I would probably go and look a little bit deeper, but I would definitely check what kind of testing was done. And actually, some companies will just do IHC for NTRK or they will do IHC for RET, so I think it's really important for us to know what panel is being used.
Dr. Herbst:
I couldn't agree more. I was going to say it myself, but you said it better. The one thing that I also worry about is the PD-L1. Are we really getting an accurate measure on that with an FNA? And if immunotherapy is going to work, there has to be some PD-L1, right? So it's just probably a matter that we're not measuring it, but if the patient's truly 0 and truly has no actionable mutations, it sounds like there's pretty good consensus here to go with the CTLA-4 combo, and then, of course, manage the toxicities as best possible. Any final thoughts on this case before I do a quick wrap up, Karen?
Dr. Reckamp:
Again, I think this PD-L1–negative cohort of patients is still a challenge for us to treat and seeing some prospective trials looking at this patient population, I think will help us make better decisions for the future.
Dr. Herbst:
Charu?
Dr. Aggarwal:
No, I think important points were raised about testing in a patient without a smoking history, which I think should really form the key pearls for this patient. We must, must, must absolutely make sure that we're not missing an actionable mutation.
Dr. Herbst:
Yeah, you look at the X-ray here, you think an EBUS would be very easily done and you could get some good tissue or core, so I would agree. To summarize this case, make sure that you have accurate histology and accurate molecular profiling. But if, in fact, we have a PD-L1-negative patient and no actionable mutations, our panel feels that performance status, notwithstanding, if that remains strong, to use a combo of PD-1/PD-L1, or CTLA-4 agent in combination. So very good.
Thank you both for joining today. This brings us to the end of this case. Please see the other segments for further discussion about the latest research in lung cancer or visit ascopost.com.
