Part 1: Challenges of Choosing Single-Agent Immunotherapy for NSCLC

CASE SUMMARY:

A 72-year-old white man presented with chest discomfort, cough, and dyspnea. He had a history of mild chronic obstructive pulmonary disorder and was a former smoker who quit 25 years ago and had 10 pack-years of exposure.​ A CT scan of the chest and abdomen revealed a 9.0-cm spiculated mass in the left lower lobe​, loculated pleural effusion in the left hemithorax​, and right adrenal metastasis. ​

PET/CT scan showed 18 fluorine-fluorodeoxyglucose uptake in the left lung mass, pleura, and right adrenal gland. A brain MRI showed a solitary brain lesion of 1.5 cm but no central nervous system (CNS) symptoms​.

Physical examination was notable for decreased breath sounds in the left lung base. His ECOG performance score was 1. The laboratory work was unremarkable with normal organ function and blood counts​.

An image-guided biopsy of the lung mass showed a poorly differentiated adenocarcinoma of the lung​. Immunohistochemistry showed PD-L1 tumor proportion score (TPS) of 95%.​ Tissue next-generation sequencing (NGS) was negative for molecular aberrations in EGFR, ROS1, BRAF, ALK, RET, MET, ERBB2, NTRK, but was positive for KRAS G12C mutation​. The disease was microsatellite stable.

CASE DISCUSSION:

• What agents would you consider for this patient in the first line?
• What factors support a decision to use checkpoint immunotherapy (ICI) monotherapy instead of chemotherapy plus ICI in this patient with metastatic non–small cell lung cancer (NSCLC) and very high PD-L1 expression (95%)?

RAVI SALGIA, MD, PHD: We have a number of immunotherapies that are available, such as pembrolizumab [Keytruda], atezolizumab [Tecentriq], and now cemiplimab [Libtayo] as well, in terms of single agents. You can use combinations such as the IMpower150 (NCT02366143) regimen of atezolizumab plus bevacizumab [Avastin], taxane, and carboplatin, which is quite intense, or you can go to single-agent immunotherapy. The red herring in this case was the KRAS G12C mutation. I think we just want to emphasize that indeed you can go with a single agent, but don’t go to the targeted therapy yet.

RUPESH PARIKH, MD: Do the 2 negative studies of immunotherapy by themselves [CheckMate 026 (NCT02041533) and MYSTIC (NCT02453282)] bother you in the decision to use a single agent?^1,2

SALGIA: Was the appropriate biomarker chosen? Nivolumab (Opdivo) has a biomarker of 28-8 instead of the 22C3. You have to keep that in mind. Then the tumor or the TPS is important. Does it bother us that every trial is not positive? It doesn’t bother me, especially in the context of the PD-L1 selection, greater than or equal to 5% versus greater than or equal to 25%. I think it depends on the TPS. It depends on the combined positive score [CPS]. In my mind, there’s no great tumor biomarker that’s available for us for immunotherapy at this moment in time. We’ll take the greater than 95% and that’s where some of the other studies really prove their point to be very significant.

PARIKH: A secondary question: is 1 immunotherapy better than the others upfront?

SALGIA: Whichever one the payors will pay for is OK. It’s so important. If you’re in love with pembrolizumab, but let’s say cemiplimab is the one that the payors are going to pay for, I would choose cemiplimab. Again, I’m not wedded to any IO [immune-oncology], to be honest, and I’m not big for buying any IO, but I do [believe] is there are enough data for central nervous system [CNS] [activity] for cemiplimab that I might’ve chosen that just because of the CNS lesion.³ Pembrolizumab certainly has efficacy.⁴ Nivolumab has efficacy with ipilimumab.⁵ A lot of data translates over from melanoma, but NSCLC is just ahead of the curve now as well.

KATHLEEN KERRIGAN, DO: I was hoping to get your opinion on where you see the quadruplet regimens fitting in. I think it’s hard to potentially recommend a 4-drug regimen with more toxicity that may not have the same or better efficacy.

SALGIA: I use it in the EGFR population, ALK population, and the ROS1 population. Suppose you’ve exhausted osimertinib [Tagrisso] in an EGFR-mutant population. Let’s say it’s an actionable mutation of L858R and then you look at the mechanism of resistance and it turns out to be C797S, then I might give them afatinib [Gilotrif]. Of course, they develop more resistance and then they’re progressing rapidly. That’s when I use the quadruplet regimen.

ALK is the same thing. Let’s say you try alectinib [Alecensa] and then you try brigatinib [Alunbrig] and then you try lorlatinib [Lorbrena] or ceritinib [Zykadia]. Then you’re running out of choices. For me, I like clinical trials, so any time patients can go on to a clinical trial is a good thing. But these “cold tumors” have a lot of regulatory T cells in them. You can’t activate the immune switch. I don’t tend to use [quadruplet] in other populations. It is pretty toxic, by the way.

SANTHOSH AMBIKA, MD: In cases where you decide to use the single agent, would you look at the STK11 or KEAP mutation and maybe add chemotherapy if their disease is mutated, rather than just going with single-agent immunotherapy?

SALGIA: Yes. They are reported for hyperprogression. We’ve reported that as well. STK11, which is also known as LKB1, and KEAP1, are negative predictors.⁶ MDM2 amplification is also potentially touted as [being associated with] hyperprogression. That’s exactly right. If [I have] that kind of information, I do get concerned and then I end up adding chemotherapy in that scenario. We didn’t get that information on this patient. Not knowing that information, you have to be cautious.

If the payors don’t [cover] next-generation sequencing for STK11, KEAP1, MDM2 amplification, there are some data from University of Chicago that are looking at CDKN2A abnormalities that can be hyperprogressive as well in terms of immune therapies.⁷ I think that will all come into play, but unfortunately all of these data are retrospective. We don’t have prospective data to help us, so I get nervous. You’re right, Dr Ambika, but at the same time, adding chemotherapy is not unreasonable in that patient population.

BELISARIO ARANGO, MD: I’ve used the quadruplet regimen in 2 patients when the data came out of carboplatin/paclitaxel, bevacizumab, and atezolizumab in 2019 with the hope that perhaps adding the VEGF antiangiogenesis would add to it.⁸ Both patients tolerated the treatment remarkably well and anecdotally they both are alive, both on maintenance therapy. Those have been the only 2 cases that I have used the quadruplet regimen upfront, and that was more than 2 years ago when the data were new, and now I’m not using it upfront anymore.

_References:

_{1. Carbone DP, Reck M, Paz-Ares L, et al. First-Line nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med. 2017;376(25):2415-2426. doi:10.1056/NEJMoa1613493}

_{2. Rizvi NA, Cho BC, Reinmuth N, et al. Durvalumab with or without tremelimumab vs standard chemotherapy in first-line treatment of metastatic non-small cell lung cancer: the MYSTIC phase 3 randomized clinical trial. JAMA Oncol. 2020;6(5):661-674. doi:10.1001/jamaoncol.2020.0237}

_{3. Sezer A, Kilickap S, Gumus M, et al.Cemiplimab monotherapy for first-line treatment of advanced non-small-cell lung cancer with PD-L1 of at least 50%: a multicentre, open-label, global, phase 3, randomized, controlled trial. Lancet. 2021;397(10274):592-604. doi:10.1016/S0140-6736(21)00228-2}

_{4. Mok TSK, Wu YL, Kudaba I, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019;393(10183):1819-1830. doi:10.1016/S0140-6736(18)32409-7}

_{5. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med. 2019;381(21):2020-2031. doi:10.1056/NEJMoa1910231}

_{6. Camelliti S, Le Noci V, Bianchi F, et al. Mechanisms of hyperprogressive disease after immune checkpoint inhibitor therapy: what we (don’t) know. J Exp Clin Cancer Res. 2020;39(1):236. doi:10.1186/s13046-020-01721-9}

_{7. Gutiontov SI, Turchan WT, Spurr LF, et al. CDKN2A loss-of-function predicts immunotherapy resistance in non-small cell lung cancer. Sci Rep. 2021;11(1):20059. doi:10.1038/s41598-021-99524-1}

_{8. Socinski MA, Jotte RM, Cappuzzo F, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288-2301. doi:10.1056/NEJMoa1716948}