Roundtable Discussion: Forde Reviews Chemoimmunotherapy as Treatment for Squamous NSCLC

Patrick Forde, MBBCh (Moderator)

Codirector, Division of Upper Aerodigestive Malignancies

Director, Thoracic Oncology Clinical Research Program

Associate Professor of Oncology

Johns Hopkins Sidney Kimmel Comprehensive Cancer Center

Baltimore, MD

CHISM: [Regarding] the number of cycles of chemotherapy, I have rarely been able to get my patients to [have] more than 4 cycles, due to the age of the population and some of the comorbidities. I think that it is rare to get more than 4 cycles. Certainly, it points toward chemotherapy plus dual immunotherapy, given the central nervous system data.

FORDE: I think we see the same [in my experience]. Around the third or fourth cycle, we definitely see patients starting to tire and, not infrequently, asking to stop chemotherapy at that point. I think that’s 1 possible positive for the 9LA regimen.

KUZUR: I find it harder to get patients to stop immunotherapy as they’re responding past 2 years. I have a patient who’s on the fourth year. Eventually, he developed diarrhea, in addition to diabetes and hypothyroidism, but he still looks like the picture of health. He had stage IV [disease]. In August, it will be 4 years since his diagnosis. I had the hardest time convincing him to get off pembrolizumab [Keytruda].

I think the study shows that when you stop the immunotherapy, you still have the benefit.¹ These patients should be told that even though we stop, they’re still going to be benefiting from the effects of immunotherapy. For my patient who [stopped immunotherapy], if he should develop a relapse, [could] the same regimen [be used], assuming it’s been more than 6 months?

FORDE: At Johns Hopkins [Sidney Kimmel Comprehensive Cancer Center] we have a patient who was on immunotherapy for over 9 years. I think patients are often reluctant to change what’s working. We stopped quite a few patients at the start of the [COVID-19] pandemic in 2020. Patients were more open to taking a break at that time. We held therapy for 4 or 5 patients who were in response. Only 1 of them has relapsed.

He was on maintenance pembrolizumab, and we restarted after about a year off therapy and he’s responded again. If you were a patient and you’re told you have a fatal cancer—it’s hard for them to make the decision to take that break, especially with a relatively nontoxic therapy.

KUZUR: We don’t [know] the optimum duration.

FORDE: There are some data on reinduction. There was a study in the Journal of Clinical Oncology maybe a year and a half ago that looked at re-treating patients who either have stable disease or responsive disease.² At least in that mixed population, there did appear to be some suggestion about continuing on therapy. But criticism of the study [included] that it was a mixture of stable and responsive disease, and it didn’t focus on patients who had a good response.

LOBINS: When ipilimumab/nivolumab first came out, the ipilimumab was front-loaded, then you carried a maintenance nivolumab or PD-1 drug. With the new trials that are coming out, they now space out the ipilimumab, but you never stop it. So instead of giving it 4 cycles up front and being done with it, now you’re giving it every 6 weeks. Did they do a study for that rationale, or was that simply because they wanted to give more ipilimumab?

FORDE: They found that patients with lung cancer couldn’t tolerate the melanoma dose—hepatocellular cancer has a different dose as well, with higher ipilimumab and lower nivolumab. But what they found was that for NSCLC in particular, patients had quite a lot of toxicity with either more frequent ipilimumab dosing or higher ipilimumab dosing.³ They eventually landed on this ipilimumab [dosage of every 6 weeks].¹

Do patients actually need maintenance ipilimumab? I tend to stop the ipilimumab if there’s a suggestion of toxicity emerging—particularly if it’s something that seems a bit more ipilimumab-related, such as colitis.

ZOGHBI: I have a couple patients who have renal metastases and they did very poorly. I feel the renal metastases tend to be more aggressive. A patient progressed after concurrent chemoradiation, followed by durvalumab [Imfinzi]. I did also give him ipilimumab/nivolumab, and he didn’t qualify for a clinical trial. But despite that, those patients of mine did poorly. We have some patients who don’t do well up front. I haven’t used ipilimumab/nivolumab and chemotherapy with them, but I have used chemotherapy and pembrolizumab, and they progressed relatively fast on that chemoimmunotherapy.

How do we select these patients to offer them ipilimumab/nivolumab? [Is it] those [with] low PD-L1 expression, or maybe young patients?

FORDE: I’ve used it…in patients who have progression after the PACIFIC [NCT02125461] regimen [of durvalumab following chemoradiotherapy], 6 to 9 months post PACIFIC, or even toward the end of the 12 months of PACIFIC. That is a group where it’s potentially useful.

There are a couple of mutations in nonsquamous lung cancer that appear to predict the lack of sensitivity to PD-1. Those would be KEAP1 and STK11. If they are present, at least in retrospective analysis, that seems to predict lack of response to PD-1 therapy. I had a patient recently who had lung adenocarcinoma [that was PD-L1 negative] and had a KEAP1 mutation. That’s a group where I think they have a little bit of data, although relatively small numbers, with PD-1/CTLA-4 suggesting that the combination might be better.⁴

I treated him with this CheckMate 9LA regimen. He’s actually done quite well, but I think we need more studies. I agree…[that with] metastases in the kidney or skin, those patients tend to do quite poorly with standard therapies. Those…tend to be quite refractory to treatment.

ZOGHBI: On this trial, did they allow patients with small [brain metastases] to be untreated, and then gave the systemic therapy and followed those patients? Or were those patients treated by SRS [stereotactic radiosurgery] or [other] radiation therapy and then treated after?

FORDE: I think they allowed either those with treated brain metastases or those [whose metastases] were asymptomatic and controlled.¹ When you’re doing these trials, it’s often a vague definition. I don’t think they specifically required radiation for the brain metastases, but they had to be asymptomatic, maybe with 1 or 2 small brain metastases.

It’s always a gratifying thing to see the brain metastases responding to a systemic therapy rather than [needing] radiation therapy [From the Data⁵]. But yes, some studies do [require treatment]. The KEYNOTE-407 study [NCT02775435] required that they be treated, whereas CheckMate 9LA allowed them on provided they were asymptomatic.^1,6

LOBINS: With immunotherapy, one of the worries that I always have…especially in these patients who are older and don’t have the best immune system in the world, is [whether] their T cells are worn out. In melanoma, they are looking at LAG-3, which reenergizes the T cells. Are you looking at anything that would enhance therapy, such as LAG-3 or something like that?

FORDE: LAG-3 is being studied with the same drug [as in melanoma], relatlimab. They’re doing a first-line study [NCT04623775] in lung cancer. They did study it at a lower dose, about half the dose of the melanoma-approved dose.⁷ It didn’t appear particularly active in that first study, but now they’re looking at it at the melanoma dosing with nivolumab in the first-line setting.

There is a drug called ceralasertib, which is an ATR [ataxia telangiectasia and RAD3-related] inhibitor. It’s an oral drug that’s being combined with durvalumab for patients who are PD-1 resistant or refractory; patients, for example, who progressed on pembrolizumab and go on to durvalumab plus ceralasertib.⁸ That’s looking relatively promising.

What’s most promising for patients who are not immune sensitive are the antibody-drug conjugates [ADCs] like trastuzumab deruxtecan [Enhertu]. As in breast cancer, patients who respond may not even have the HER2 mutation.

There is a class of drugs called TROP2 ADCs, which are intravenous drugs given once every 3 weeks. They look very promising. They’re in phase 3 trials in the first- and second-line settings in lung cancer at the moment. We have those trials open. Those are the ones I see as the most practical and the most promising out there for metastatic lung cancer.

FORDE: If anyone has any thoughts on management of AEs— is it challenging still, or has it improved since these drugs have become more widely used? What are you seeing in your practices?

LOBINS: Everybody uses immunotherapies now, so we’re getting accustomed to some of the AEs. The neurological AEs are the ones that [are difficult]. The endocrine AEs are actually the easiest because you just give them what they need. I had one patient who had a neurological event that looked like a stroke, but she never had a stroke.

FORDE: Those are tough ones. I’ve had 3 patients in the past 10 years cured of extensive-stage small cell lung cancer [SCLC]. One of them had 2 doses of nivolumab/ipilimumab and went into complete remission but developed a severe paraneoplastic neurologic syndrome. She is in complete remission but still has residual neurological symptoms. [Are your] colleagues in medicine becoming more familiar—for example, in pulmonology and the different specialties?

PALKA: I’ve run into a lot of problems. I’m out [a long distance away]. They’ll go to the emergency department, and they’ll call a gastroenterologist [who will] put them on metronidazole [Flagyl] and check for Clostridioides difficile [infection]. Then about 4 days later, they’ll call me to say, “Oh, this diarrhea is not getting any better. Do you have any idea?” Usually, you [can give] some steroids and they’re better in 48 hours. Especially outside of the big cities, I don’t think [most physicians] are familiar with these AEs or with immunotherapy.

FORDE: One thing we’ve done for a few patients is we give them a card, which they hand to the emergency department when they get there, that says, “I’m on immunotherapy.” That can be helpful sometimes—if they haven’t lost the card.

KUZUR: I’ve had a patient with extrapulmonary SCLC, and he had a great response to nivolumab. But he developed excruciating hand pain. We couldn’t explain it. It started in one hand and then the other hand.

FORDE: It’s not some kind of polyneuropathy?

KUZUR: No, it’s a pain where the orthopedic doctors operated on his hand, thinking he had a broken small bone there, but it wasn’t. I stopped the nivolumab, but I’m just not sure. I don’t know if there are any reported cases like that. [This patient] has had SCLC for 5 years now.

FORDE: I’ve had a couple patients with unusual joint problems, so some of my rheumatology colleagues have published on that. You can also get skeletal remodeling as well when [patients] are on immunotherapy. One of my other colleagues did a case series of patients who had skeletal events, not joint problems but actual skeletal issues, but they’re uncommon and underrecognized.

ZOGHBI: I try to have the patient select a physician in every [specialty]. So I have a gastroenterologist who is a go-to person for immune-related AEs, a cardiologist, etc. I think they are becoming more familiar, and sometimes they consult with the university, so…they are getting experience. Of course, [they may need] an immunologist as well as an endocrinologist. There is a learning curve, but I think we are getting there in the community setting.

FORDE: Having a good relationship with someone who sees more of these cases is very helpful. The ones that I find hard are the rarer AEs, like renal abnormalities. Sometimes it can be hard to find a nephrologist who’s seen more than 1 or 2 of them. Building up a relationship with the allied medical specialties is important.

_REFERENCES

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_{2. Waterhouse DM, Garon EB, Chandler J, et al. Continuous versus 1-year fixed-duration nivolumab in previously treated advanced non-small-cell lung cancer: CheckMate 153. J Clin Oncol. 2020;38(33):3863-3873. doi:10.1200/JCO.20.00131}

_{3. Hellmann MD, Rizvi NA, Goldman JW, et al. Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Lancet Oncol. 2017;18(1):31-41. doi:10.1016/ S1470-2045(16)30624-6}

_{4. Ramalingam SS, Balli D, Ciuleanu TE, et al. Nivolumab (NIVO) + ipilimumab (IPI) versus chemotherapy (chemo) as first-line (1L) treatment for advanced NSCLC (aNSCLC) in CheckMate 227 part 1: efficacy by KRAS, STK11, and KEAP1 mutation status. Ann Oncol. 2021;32(suppl 7):S1375-S1376. doi:10.1016/j.annonc.2021.10.020}

_{5. Reck M, Ciuleanu TE, Cobo M, et al. First-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone (four cycles) in advanced non-small-cell lung cancer: CheckMate 9LA 2-year update. ESMO Open. 2021;6(5):100273. doi:10.1016/j. esmoop.2021.100273}

_{6. Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med. 2018;379(21):2040-2051. doi:10.1056/ NEJMoa1810865}

_{7. Schuler MHH, Cuppens K, Ploenes T, et al. A randomized, multicentric phase II study of preoperative nivolumab plus relatlimab or nivolumab in patients with resectable non-small cell lung cancer (NEOpredict-Lung). Ann Oncol. 2022;33(suppl 7):S1404. doi:10.1016/ annonc/annonc1089}

_{8. Hernandez M, Besse B, Awad M, et al. Immuno-modulatory effects of ceralasertib in combination with durvalumab in NSCLC with progression on anti-PD(L)1 treatment (HUDSON). J Thorac Oncol. 2021;16(suppl 3):S350-S351. doi:10.1016/j.jtho.2021.01.553}