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 at the Yale Cancer Center. Joining me today are two of my colleagues. Dr. Karen Reckamp, would you please introduce yourself?
Dr. Karen Reckamp:
I am Karen Reckamp, Division Director of Medical Oncology and professor of Medicine at Cedars-Sinai Medical Center in Los Angeles.
Dr. Herbst:
And Dr. Charu Aggarwal.
Dr. Charu Aggarwal:
Hi, it's such an honor to be here with both of you. I am Charu Aggarwal. I'm a Professor of Medicine at the Abramson Cancer Center at the University of Pennsylvania.
Dr. Herbst:
It's really great to have both of you here today, thanks. Today, we'll be discussing the treatment and management of metastatic non–small cell lung cancer with three patient case studies.
Our first installment will focus on the management of a patient with metastatic non-small cell lung cancer and squamous histology. I will now present to you the first case. This is a 63-year-old man with a prior 30-pack year smoking history presenting with a cough and shortness of breath. The CT scan, which you can see on the right, reveals a left upper lobe primary mediastinal and hilar adenopathy plus bilateral lung and bone metastases. Fine-needle biopsy reveals non–small cell lung cancer, TTF-1 negative, squamous cell histology. Brain MRI shows no metastatic disease. The PD-L1 is read as 10%. So, unfortunately, an all-too-common presentation.
Karen, how would you treat this patient? We have a few choices shown here. Would you use a KEYNOTE-407 type regimen, CheckMate 227, POSEIDON, CheckMate 9LA, any of the above or something different?
Dr. Reckamp:
Generally for this type of patient, I am thinking about the KEYNOTE-407 study and utilizing either carboplatin/paclitaxel or carboplatin/nab-paclitaxel with pembrolizumab. I do think that the other options are reasonable and the CheckMate 9LA may be something that we start to think about. But at this moment in time, I'm still using KEYNOTE-407.
Dr. Herbst
What about you, Dr. Aggarwal?
Dr. Aggarwal:
Yeah, I think amongst all the options, one of the options that isn't listed here that has an approval is single-agent pembrolizumab, although I think many of us don't really reach out for it in somebody with a PD-L1 expression of greater than 1%. But I think it's important to just point out that there are some options for patients who may be a little bit more frail, perhaps, or don't have a lot of disease burden or elderly. Could we consider them for pembrolizumab? Sure, there's an FDA approval, but I agree with Karen that I think for the most part, PD-L1 10%, squamous histology. I think we have long-term data to say that triplet chemoimmunotherapy may be the way to go. I tend to use nab-paclitaxel a little bit more frequently than paclitaxel. I find that it's much better tolerable. I've certainly seen less neuropathy. I do omit day 15 dosing for the taxane for many of my patients and we'll do day 1, day 8 on an every-21-day basis.
Dr. Herbst:
Okay, I have a few questions and then we'll discuss the chemotherapy regimens again. First of all, tumor profiling. It is a squamous tumor. We're pretty sure of that. But Charu, would you tumor profile? Would you do next-generation sequencing?
Dr. Aggarwal:
We are certainly beginning to think about this more broadly. We are testing the capacity of our molecular pathology lab because as you know now, we are testing almost all of our early-stage non–small cell lung cancers as well. So I think if there is a likelihood that I'm going to be able to capture a genomic alteration, I'm more likely to order it. For example, definitely ordering it in patients with mixed histology, so squamous and adenocarcinoma together, or somebody presents with a squamous histology and has no smoking history or very remote smoking history. I actually discovered an EGFR L858R mutation in a squamous histology just 2 weeks ago. But if somebody has a 30-plus pack-year of smoking history, has a central tumor radiographically, looks and behaves like a squamous histology, I think I'm feeling okay with at least beginning treatment. But you can't overlook the possibility of them having BRAF and KRAS and we know that these can be actionable.
Dr. Herbst:
Karen, is there anything you would look for in next-generation sequencing, co-mutations that would tell you it's more aggressive and perhaps cause you to use a CTLA-4 inhibitor?
Dr. Reckamp:
So I think it's squamous cell in all lung cancers where we don't have an actionable mutation we're looking for, KEAP1, STK11, and those are probably less common in squamous cell, but still can be found. And if we see those mutations, we may be thinking a little bit more about utilizing a CTLA-4 and PD-1, PD-L1 inhibitor, something like the CheckMate 9LA, CheckMate 227, or even the POSEIDON regimen.
Dr. Herbst:
Tell us a little bit, Charu, about CTLA-4 and some of the different regimens here. When would you use ipilimumab or tremelimumab, one of those drugs?
Dr. Aggarwal:
It's a very good question. I think all that we've seen so far is subset analyses of trials. Subset analyses have shown, for example, from the POSEIDON trial that subset of patients with STK11 and KEAP1 tend to be the ones with the highest median PFS that led to the launch of the TRITON trial that is actually randomizing such patients in the first-line setting to the POSEIDON regimen vs KEYNOTE-189. I think this would be very meaningful for us as we think about treatment stratification in the future.
Currently, I tend to think of it more in my PD-L1–negative patients, perhaps more in squamous histology. I do sometimes think about in patients with STK111 and KEAP1. But I think one of the things I really want to highlight with our audience here today is that not all panels include KEAP1. So just because it's not reported on the report, it may be that it's just not even included on the panel. So I encourage everyone to really look at what all genes are covered on the panels that they're using.
Dr. Herbst:
Great. And Karen, how do you follow response? Still using mostly CT scans, or are you using blood-based assays these days?
Dr. Reckamp:
So at this point in time, I am using CT scans for the most part, interspersed with PET-CT to look for active disease as you see in this patient's case with the consolidation there. It may be helpful to look at PET-CT to see where the disease is actually active. As far as following with ctDNA, I think this is an emerging area and something we'd all like to use. We have seen in, again, more retrospective studies that responses may correlate with a dropping of ctDNA levels and I think this is something that we may be able to use in the future.
At this point in time, if the ctDNA starts rising, we don't have a lot of indication that that's the time that we should change therapies. And so I'm cautiously optimistic that this is something that we may be able to use to treat patients in the future, but at this moment in time, we don't have a lot of great options following first-line therapy with chemoimmunotherapy. And so to change that just based on a blood test at this moment in time that hasn't been validated, I think it's just not quite ready for the clinic.
Dr. Herbst:
Yeah, I agree with that. And how often do you check the brain?
Dr. Reckamp:
Generally in a patient who doesn't have brain metastases, I check on an annual basis in this type of case. And obviously, if they have brain metastases, I do it with all the other imaging.
Dr. Herbst:
Okay. Charu, immune toxicities, what do you look for? What would you be most concerned about? Most people are familiar with it these days, but anything special in this type of patient?
Dr. Aggarwal:
I think our patients with lung cancer tend to have a compromised pulmonary reserve and I almost honestly worry about pneumonitis the most because it can compromise them and tank their performance status very quickly.
Dr. Herbst:
I would agree. Prognosis. So I can tell you I've had several patients in the early days with phase I who have had squamous cancer like this and they've gone single-agent IO and some of are alive 10 years, 11 years later. What's your sense, Charu? How many patients would have the amazing result here and some with some response and then progression? What's your sense of how this group does compared to other patients?
Dr. Aggarwal:
Yeah, I think we all have a subgroup of patients who've lived such a long time. They were some of them were on the initial phase I trials of these agents and I know, Roy, you've shared that patient information with us over several years and we all are accumulating these. There is no good way for us to predict who's going to be a long-term survivor vs who's not. And I think one of the biggest questions also is how do you predict for which patient may benefit from prolonged therapy vs really stopping at 2 years.
Dr. Herbst:
Karen, any final thoughts on this case? So we'll treat with the regimen as described and we'll hope for the best. But if and when the patient becomes refractory, any suggestions for what to use in the refractory setting?
Dr. Reckamp:
So I think in the refractory setting, we are still challenged and there are limited options. The approved option is still docetaxol or docetaxol/ramucirumab and we are working on finding better options for patients. And our ongoing Pragmatica-Lung trial with pembrolizumab and ramucirumab in a phase II trial did show an improvement in survival and we're hoping to see that maybe we can have nonchemotherapy options for our patients in the future.
Dr. Herbst:
Absolutely. We have to keep plugging away, but we have multiple options in a case like this. So to summarize, we have a patient with widely metastatic squamous cancer but with reasonable performance status. It sounds like our consensus was to use KEYNOTE-407. That can be a couple of different chemotherapy regimens and it sounds like both of you would use a taxane. Is that correct? Do I read that correctly? And then with pembrolizumab and then we'll monitor and watch the patient and we have some options if the patient doesn't have a complete response and very durable response. And then we're continuing to think about clinical trials and other things in the future, such as the Pragmatica-Lung trial, which Karen, that's accruing quite rapidly. It's quite adaptable to the community setting.
Dr. Reckamp:
It's been very good. We may finish accrual by the end of the year.
Dr. Herbst:
So great. Patient can come to any of our centers for treatment. Thanks a lot.
This brings us to the end of the case. Please see the other segments for future... this brings us to the end of the case. Please see the other segments for further discussion about the latest research in lung cancer or visit ascopost.com.
