Karen Reckamp, MD

Karen L. Reckamp, MD, director, Medical Oncology, associate director, Clinical Research, and Medical Oncology director, Lung Institute at Samuel Oschin Cancer Center, discusses the key findings of the phase 2 Lung-MAP substudy S1800A (NCT03971474) for patients with stage IV, previously-treated non–small cell lung cancer (NSCLC).

evaluated the combination of pembrolizumab (Keytruda) and ramucirumab (Cyramza) in patients with NSCLC

 who had acquired resistance to immune checkpoint inhibitors (ICI). In the study, acquired resistance was defined as previous ICI therapy for at least 84 days with progressive disease on or after therapy.

According to Keckamp, the primary end point was overall survival (OS) and an improvement of OS was seen when compared with the standard of care (SOC) consisting of ramucirumab and docetaxel. The median OS observed with ramucirumab/pembrolizumab was 15.0 (95% CI, 13.2-17) compared with 11.6 months (95% CI, 8.5-13.8) with SOC (HR, 0.61; 95% CI, 0.38-0.97; 1-sided P =0.019).

The primary end point was overall survival. We had 136 patients randomized, and we found an improved overall survival in the ramucirumab and pembrolizumab arm, with a median overall survival of 14.5 months vs 11.6 months in those who receive standard of care. I think importantly, in the standard of care arm, 2/3 of the patients did receive docetaxel/ramucirumab as the most potent combination that we have at this time and as a standard of care for patients who have had tumor growth on both immunotherapy and chemotherapy in the past.

We evaluated the outcomes of overall survival by PD-L1 status, and there was no difference based on PD-L1 status, there was benefit for all patients receiving ramucirumab/pembrolizumab. By performance status, we did see a trend toward increased benefit in those patients who had squamous cell or mixed histology. But again, there was a benefit across all subgroups.

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Karen L. Reckamp, MD, discusses the key findings of the phase 2 Lung-MAP substudy S1800A for patients with stage IV, previously-treated non–small cell lung cancer.


 Lung-MAP Trial of Pembrolizumab Plus Ramucirumab Improves Overall Survival in NSCLC

Karen L. Reckamp, MD, a professor in Medicine, director of the Division of Medical Oncology at Cedars-Sinai Medical Center, and medical oncologist at the Samuel Oschin Cancer Center, discusses the Lung-MAP nonmatched substudy S1800A (NCT03971474) for patients with non–small cell lung cancer (NSCLC) who were previously treated with immune checkpoint inhibitors and develop resistance.

Results of the phase 2 trial were reported at the 2022 American Society of Clinical Oncology (ASCO) annual meeting by lead investigator Reckamp.

This phase 2 clinical trial is investigating the efficacy of the combination of ramucirumab (Cyramza) and pembrolizumab (Keytruda) vs standard of care in this patient population. The primary end point of the study is overall survival with secondary end points including progression-free survival, duration of response rates, and incidence of adverse events.

Overall data indicated that the combination of ramucirumab and pembrolizumab may extend the lives of those diagnosed with NSCLC.

Lung-MAP is a precision medicine platform trial. It allows patients to have genomic testing through FoundationOne, and from that, go on to either a match trial if there's a genomic alteration, or down to the unmatched arm. This was the unmatched arm, S1800A. The combination of ramucirumab and pembrolizumab was for patients who did not meet criteria for the mast arms that we had available at that time.

 This was a randomized phase 2 trial and we wanted to see if there was an indication of efficacy. We knew that overall survival in general has been a better indication of efficacy, especially with immunotherapy in the second line setting. We chose to use overall survival as our primary endpoint. Knowing that we often do see discordance of overall survival with things like progression-free survival, we do often see discordance with overall survival and other outcomes such as progression-free survival and objective response.

Karen L. Reckamp, MD, discusses the Lung-MAP nonmatched substudy S1800A for patients with non–small cell lung cancer who were previously treated with immune checkpoint inhibitors and develop resistance.


Ramucirumab/Pembrolizumab Combo as Potential Treatment for NSCLC

Karen L. Reckamp, MD, a professor in Medicine, and director of the Division of Medical Oncology at Cedars-Sinai Medical Center, as well as a medical oncologist at the Samuel Oschin Cancer Center, explains the need for more treatment options for patients with non–small cell lung cancer (NSCLC) who have been previously treated with immune checkpoint inhibitors (ICIs) and develop resistance.

As upfront treatment for NSCLC, the majority of patients are administered immunotherapy with chemotherapy or immunotherapy alone. Although these strategies are very beneficial to patients, disease progression is inevitable, and some patients become resistant to their frontline regimen.

Once a tumor grows too large or patients are ICI refractory, no effective therapies are available. The Lung-MAP nonmatched substudy S1800A was designed to address the need for treatment option after frontline ICI therapy in patients with NSCLC. The phase 2 clinical trial (NCT03971474) investigates the combination of ramucirumab (Cyramza) and pembrolizumab (Keytruda) vs standard of care.

 All patients now receive either a combination of immunotherapy and chemotherapy or immunotherapy alone as part of their frontline treatment for advanced non–small cell lung cancer. We're also starting to use immunotherapy in the treatment of earlier stage non–small cell lung cancer. So, most patients do get exposed to immune checkpoint inhibitors at some point during their therapy. And we know though there are great benefits that patients experience most will have tumor progression and develop some tumor resistance to immune checkpoint inhibitors.

At this moment in time, we don't have the best therapies. We don't know the best therapies to provide patients once a tumor has grown on immune checkpoint inhibition and chemotherapy. So, this study is to evaluate what might be better therapies than our standard of care which generally include

Karen L. Reckamp, MD, explains the need for more treatment options for patients with non–small cell lung cancer who have been previously treated with immune checkpoint inhibitors and develop resistance.



Challenging the Standards of Care for ICI-Pretreated Patients With NSCLC

Thoughts about what happens next? Again, in real life, you see a patient who has been on lorlatinib for 6 or 7 months, has progressive disease. You rebiopsy, there’s nothing targetable. They have a high PD-L1 and have been through three TKIs [tyrosine kinase inhibitors]. What do you do?

: The challenge with high PD-L1, most of the trials have included very few patients with 

, where there’s very limited benefit, I’ve extrapolated to the light or never-smoking category, where there are some data that response to at least monotherapy with immunotherapy is 5% or less. I’m not certain what the immunotherapy is adding. As you mentioned, chemotherapy, especially pemetrexed-based chemotherapy, is very effective in this population, and potentially adding a VEGF receptor inhibitor may be more beneficial than adding immunotherapy. I have moved away from using immunotherapy in these patients, but I’m at equipoise for the patients who are 

positive. In part, the immunotherapy has shown to increase interstitial lung disease for osimertinib, and when you combine it with some of these drugs, potentially increased toxicity, liver toxicity. But if you’re not combining it, it may not harm a patient to receive it, and some patients are really bent on receiving immunotherapy. I have a little more equipoise than thinking that I might be doing harm in this case, but I’m not certain that we’re adding anything, especially with the response rates to chemotherapy. I agree with you.

New therapies are needed. Information about when we might use immunotherapy would be helpful. But the other piece of this is we’re still not curing people. Five years is great, but these are young people, we want more than 5 years. How do we move this into the early stage setting?

Certainly our hope is that we diagnose more people at early stage disease, right? These are not patients we would routinely imagine would undergo CT screening. But as we develop biomarkers and there’s more awareness, we may see it at an earlier stage. But certainly, we cure patients with early stage disease. There has certainly been a large effort to include targeted therapies in the treatment paradigm for patients with lung cancer. Recently, osimertinib was approved for patients with

[mutations] who underwent resection. You receive osimertinib for 3 years, and we know that’s a significant improvement in disease-free survival. We have yet to see what that looks like for OS [overall survival]. These studies take a long time. But it is certainly a standard of care to offer osimertinib for our patients.

Before that, there was a study called ALCHEMIST, and that’s our federal effort looking at marker-driven trials. Again, for resected patients, patients who underwent sequencing when it was still pretty novel, and had an 

mutation, those patients could receive erlotinib versus placebo. That trial is powered for OS, and we await the data. There’s also an 

 arm with crizotinib. Again, sort of historic. That has admittedly barely accrued. These patients are rare in the resection setting, and many of us have ambivalence about putting a patient on a less effective TKI. But certainly, that’s an answer that we’ll await.

It may be that you can extrapolate from other studies and provide a TKI. In a very real-world scenario, I recently had a discussion with a patient with really bulky stage III disease, who had undergone induction chemotherapy and resection, and had cleared N2 nodes, but still had N1 nodes and persistent tumor in the resection specimen, and the patient was 

 positive. We had a very long discussion about whether it would be reasonable to give the TKI out back, and there is no evidence to suggest it. But when we look at what we think a hazard ratio would be for the ADAURA [trial regimen], and how to extrapolate that for alectinib, certainly that was something that we talked about and talked about all our gaps in knowledge. But it was something that we went in with eyes open and did offer the patient a TKI.

: With the right discussion, it seems worthwhile. We’re not going to get these answers for another decade, especially with 

: If that. Are we going to wait 20 years to do something that we know we can do with the more common

 alteration? That extrapolation in some of these rare diseases is necessary.

I would add that there are several efforts with the Lung Cancer Mutation Consortium that are looking at sort of proof of principal. These are single-arm studies in which patients get an induction TKI and then have surgery, then get appropriate chemotherapy and get the TKI out back, so we’ll have some phase 2 data to compare to historical norms. Again, remember atezolizumab was approved for patients who were high-PD-L1 positive, and likely I would know that a patient was 

 positive and would not offer atezolizumab to a resected patient who was 

: Right, I would agree with that, though there are very little data to support either way. It would be wrong to give it. With a person with 50% or more PD-L1, it would be a discussion. But from the metastatic setting, there’s very limited benefit in these patients from the immunotherapy.

Any other combinations you’re interested in? I know there is a drug that is looking at overcoming resistance to the solvent-front mutations from Turning Point [Therapeutics, Inc]. Outside of that, because these patients are so rare and there are many drugs available, it’s hard to develop in this area. The patients do so well, with progression-free survival of nearly 3 years. These are larger trials and prolonged trials that need to be done, unless you’re doing it in the refractory setting. As we spoke about, ensartinib is also in that frontline setting, but we have short follow-up, and it will take time to see if it measures up to the data we have from alectinib or even brigatinib. But obviously it seems incredibly efficacious, well tolerated, and has CNS [central nervous system] penetration that is excellent, similar to what we’ve seen with the other next-generation TKIs. What are your thoughts about next steps or final comments?

Drug development is ripe for patients with 

 translocations, for combinations, a couple of trials with SHP inhibitors, with newer targeted therapies that are

 specific. Certainly, we’ll watch that. Other therapies that you can enroll your patients on now are consolidation trials. If you have limited disease or are induced oligometastatic, you’d be eligible for the NRG [Oncology] study in which you can have radiation to persistent sites of disease. In patients with 

 mutations, an interesting strategy of looking at minimal residual disease is one that is being tested. If you don’t have such a deep response, can you intensify therapy with upfront chemotherapy to treat those persistent cells and then have a longer progression-free survival? There are a number of tools that we can integrate into our treatment with radiation and chemotherapy, and then still the effort to get better drugs.

: That’s great. This has been extremely informative. Thank you, Dr Patel, for your insightful discussion, and thank you to our audience for watching this 

 Gene Rearrangement as a Therapeutic Target in Non–Small Cell Lung Cancer.” We hope you’ve found this discussion to be useful and informative. Thank you.

Karen Reckamp, MD, and Jyoti Patel, MD, discuss unmet needs, novel treatment strategies, and future perspectives for patients with ALK+ advanced NSCLC.

Unmet Needs and Future Directions

: Moving forward with CNS [central nervous system] activity, we’ve talked a lot about how we want to avoid radiation in these patients, and we want to talk about the data of why we can avoid radiation. As far as CNS metastases, you had mentioned that somewhere around one-third to a quarter of patients will have frontline metastases. Can you speak about the efficacy of the TKIs [tyrosine kinase inhibitors], listing them somewhat specifically, but more general categories? I know you did mention earlier that we can’t compare the efficacy, no cross-trial comparisons can be done, but talk about the efficacy of the TKIs in the brain.

Sure. We generally avoid crizotinib in patients who have CNS metastases, but if you look at the earliest trials, even crizotinib can have efficacy in the brain of about 40%. When we look at particular TKIs, brigatinib has had the most robust story with about a 79% CNS response rate, and alectinib is just under that in the mid-70% range. Again, these are drugs that are effective.

 The response rate for lorlatinib was 82% versus 23% for crizotinib.

Right, and 79% for brigatinib. Again, the volume and number of lesions would matter as you’re making these decisions.

Certainly, there are a number of early trials or investigator-initiated trials that have tried to couple these TKIs with VEGF inhibitors—ramucirumab and bevacizumab—to try to increase CNS efficacy, though when it’s that high, it’s hard to do. So it is more looking at CNS relapse rather than true response rate up front, and lorlatinib, with that deep hazard ratio, sort of wins there.

 With these drugs and the high response rates in the brain, what do we do for patients who do develop progression in the brain?

For new brain metastasis on lorlatinib, I would likely try, if I didn’t have an available trial, to add bevacizumab, if SRS [stereotactic radiosurgery] or limited resection were not feasible. Importantly, pemetrexed also has CNS penetration and chemotherapy does. If that’s the main site of progression and I didn’t have other local therapies available, then I’d switch to carboplatin and pemetrexed with or without bevacizumab.

Jyoti Patel, MD, and Karen Reckamp, MD, evaluate the treatment of patients with ALK+ advanced NSCLC with brain metastases.

Brain Metastasis in ALK+ NSCLC

: What about patients who progress on frontline treatments? Fortunately, they have very long progression-free time, but most of the patients will have tumors that develop resistance and have progression. What do you think about when you’re thinking about sequencing?

A lot has changed here. Certainly, we have approvals that are just based on line of therapy. There is benefit to doing molecular testing for our patients. Generally, the patient is progressing, I’ll end up doing a blood test as well as tissue if it’s safe. Sometimes if it’s progression in the brain alone, it’s a little bit more difficult, but I hope that can inform my treatment. Usually, it doesn’t because it’s usually progression after alectinib and I am usually going to move to lorlatinib.

In the Goto study in Japan, looking at claims data, most patients were treated with alectinib from J-ALEX, and then about half of patients at progression ended up getting lorlatinib.

The duration of response for these patients was about 5 months, again shorter than one would have expected from the clinical trials. But remember, there’s a myriad of reasons why patients come off of study. Probably their PS [performance status] and comorbidities weren’t as good as enrolling in a trial in the second-line setting.

And then interestingly, there’s also a study from France called the BrigALK2 study, and this was the study of brigatinib in the second line, and then also looked at a subset of patients who received lorlatinib after brigatinib, and it was essentially looking at patients who were on the EAP [expanded access program] for brigatinib. The duration of treatment for brigatinib was 7.3 months, and then it broke up in how many

 before brigatinib. It was about 13 months if you had only received one TKI, [tyrosine kinase inhibitors] presumably crizotinib, it was down to 4.9 months if you had 3 

TKIs before, again presumably ceritinib and alectinib and then brigatinib. The likelihood of response was lower. On that study on brigatinib, 74% of patients had disease control, certainly nice to see.

Of those patients that received brigatinib and progressed, about two-thirds of them went on to receive lorlatinib. Impressively, even with these early drugs, even if we’re looking at patients that were diagnosed in 2015, for example, the time from their diagnosis of non-small cell lung cancer [NSCLC] to lorlatinib start was 52.8 months. That, to me, is the real-world evidence that even off trials, that patients were doing this well.

: Sometimes the real-world evidence does help to show us the advances that have been made, and even when clinical trial populations are very specific in this setting, this is something that is translated into patients. So that’s great. And there were also, unfortunately, all of the trials in the second-line setting were after crizotinib. We know these drugs work exceptionally well after crizotinib, but we have little data about how well they do after each other, other than the lorlatinib which has some of the best data and has approval in the post second/third generation TKI setting. We’re really extrapolating from small numbers of patients and this real-world data.

The J-ALTA study was a second-line study of patients getting brigatinib after alectinib, and this is a subset of this study. Forty-seven patients in that trial had prior alectinib, and in those patients the response rate was about 34%, with a progression-free survival of about 7 months. Disease control rate was very good at 79%. This is hinting at what we saw with lorlatinib post alectinib. In that study, only 1 of 72 patients had experienced pneumonitis, and then when they looked at the anti-tumor effects, they did see activity to the G1202R, the I1171N, the V1180L, and the L1196M mutations that we see, and the G1202R which can be incredibly difficult to treat. Brigatinib seems like a reasonable choice post alectinib, and we know that lorlatinib and brigatinib do have some of the most coverage of the resistance mutations that you do get post crizotinib and alectinib.

As you had mentioned, Dr Patel, from the BrigALK study, as we see the number of prior therapies you receive, the PFS goes down. We’re getting less and less a benefit. There have been multiple studies looking at liquid biopsies in tissue, and the complexity of alterations that occur in these patients who have received multiple therapies. That being said, many of them started with crizotinib. Most of the data we have is still a crizotinib starting point and then these other drugs, but we should be getting more information as obviously the alectinib trials have longer follow-up.

But at least we know they work, they can work after each other. To me, this tells me that after 2, that’s when I tend to bring in chemotherapy or other therapies. We can talk more about that and when you stop the TKIs. But you can always go back to these TKIs. Cycling through and understanding sequencing can be helpful, and doing liquid biopsy or tissue biopsy if you’re able to, to try and understand which mutations are there, may help us to decide how to sequence these. What are your thoughts about sequencing?

That’s great. Certainly, you want the biology to dictate the drug that you use, and these multiple biopsies over time can help you understand if there’s tumor heterogeneity, particularly in the blood biopsies. I tend to start with alectinib or brigatinib. If a patient has been on alectinib and progressing, then I want to see where the resistance mechanism is. Generally, lorlatinib will have good coverage. At the time of progression with lorlatinib, I will usually biopsy, but I have not found a drug I can go back to after lorlatinib. It really is what is happening in the second-line space. Am I trying brigatinib or moving to lorlatinib is practically speaking what my decision is?

But after lorlatinib, then I’d agree with you, generally we’re looking at doing some chemotherapy at that juncture. For most patients, I’ll start chemotherapy with carboplatin and pemetrexed. We know that pemetrexed is a preferred platinum doublet from early trials with crizotinib, knowing that pemetrexed had longer PFS than docetaxel. For fusion-positive cancers, that’s across the board. I’ll usually do carboplatin and pemetrexed and often keep the lorlatinib going if I can, particularly if there’s CNS [central nervous system] disease. Usually, I’ll do a short course depending on response, I might just do 4 cycles of carboplatin and then do a lorlatinib maintenance, or do PEM/lorlatinib [pemetrexed] afterwards.

One of the biggest issues for our patients is CNS metastasis and what that looks like over multiple years. We know that 20, a fifth to a third of patients have CNS metastasis at the time of diagnosis. That’s the piece in which holding tight and waiting until you get an answer can be a little bit tough. For an asymptomatic patient, when you’re waiting for NGS [next generation sequencing] to come back, certainly I would say hold tight because these drugs are so CNS active. For a symptomatic patient or someone with large volume of disease, often you’re forced to move forward. But the paradigm for these patients has switched to try to do systemic therapy first. If you must, do limited radiation like SRS [stereotactic radiosurgery] or resection, and then sort of that last piece is in extreme circumstances, and I can’t think of any patients in the past few years that I’ve had to do whole-brain radiation early on. But the implications are that we’re seeing some patients that were treated with whole-brain radiation 6, 7 years ago, it has impacted their quality of life, now with good systemic control. It’s balancing that piece of being patient and letting the systemic therapy work for you. Thoughts about that?

: I would agree. Interestingly, as we see that patients are living for years, and we’re seeing this for many types of advanced non-small cell lung cancer, that survival is increasing, the way you think about whole-brain radiation and the potential toxicities. In the past, patients lived 6 months, the toxicities were about the immediate toxicities and not so much about the longer-term sequelae. These tend to be younger patients, they tend to be working and productive in society, and so avoiding those long-term effects of whole-brain radiation I think are important. We are moving toward more aggressive SRS in these patients and rarely, rarely do whole-brain radiation in most of these patients. Again, fortunately we have drugs that work very well and are very CNS penetrant.

The other piece is that, yes, we use SRS a lot, that a lot of these patients over time, particularly if you add a new drug on, will end up with things like radiation necrosis. It’s very multidisciplinary in how to handle what could be progression that truly is treatment response. We’ll use systemic therapies like bevacizumab for a couple of cycles, or now LITT, which is essentially laser ablation, at which time you can get a biopsy to make sure that it’s not progressive disease versus radiation necrosis. It’s become much more of a team-based sport in many ways. There are a lot of touch points with multiple providers, everyone from endocrinology to your neurosurgeon to radiation oncology, and then your entire care team as you’re managing these patients.

: Many patients who ended up going to surgery in some of these trials did have necrosis rather than growth of their tumor. But the necrosis can be just as difficult symptomatically for a patient as growth of a tumor. I agree with you that this multidisciplinary care and continued follow-up care is incredibly important.

That’s great. This has been extremely informative. Thank you, Dr Patel, for your insightful discussion, and thank you to our audience for watching this 

Karen Reckamp, MD, and Jyoti Patel, MD, outline their treatment approaches for patients with ALK+ NSCLC who progress on frontline TKIs.

Karen Reckamp, MD | Authors

Articles

Lung-MAP Trial of Pembrolizumab Plus Ramucirumab Improves Overall Survival in NSCLC

Ramucirumab/Pembrolizumab Combo as Potential Treatment for NSCLC

Challenging the Standards of Care for ICI-Pretreated Patients With NSCLC

Unmet Needs and Future Directions

Brain Metastasis in ALK+ NSCLC

Treatment Options for Patients with ALK+ NSCLC who Progress on First-line TKIs