Evaluating Immunotherapy Options Based on Mutations for NSCLC

As part of a Satellite Sessions program focused on Duke Cancer Center, CancerNetwork hosted a panel discussion on non–small cell lung cancer (NSCLC). The program was conducted to assess the efficacy and durability of immunotherapy responses in patients with NSCLC. Immunotherapy options, particularly in combination with chemotherapy, were discussed, along with comparing dual and single-agent immunotherapy measures.

The expert panel

The panel was led by Neal E. Ready, MD, PhD, professor of medicine and member of the Duke Cancer Institute. Panelists included Joel Rivera Concepcion, MD, JD, assistant professor of medicine and member of the Duke Cancer Institute; Jeffrey Melson Clarke, MD, associate professor of medicine and member of the Duke Cancer Institute; Laura Alder, MD, assistant professor of medicine and member of the Duke Cancer Institute; and Afreen Idris Shariff, MD, MBBS, associate professor of medicine, Medicine, Endocrinology, Metabolism, and Nutrition, and member of the Duke Cancer Institute.

Clinical Scenario Discussion of NSCLC Adenocarcinoma

Concepcion / This is a case I had…I initially [received] this patient and then [enrolled] them in a clinical trial. This is a 47-year-old [woman], a former smoker. Her set of symptoms [included] lower back pain. She was [experiencing] weakness in the lower extremities and loss of sensation. She also had left arm pain. When they did the imaging, especially looking for lower back pain, they found multiple diseases in multiple organs, specifically in the left lung mass. It was a 5-cm left lung mass, with metastasis in the bones, liver, right adrenal gland, and especially the lower back. The pain was because she had [an] L3, 4-cm lesion that was pressing on the spinal cord.

Because of the mass and symptoms, she was initially seen by neurosurgery, [which] was using decompression, and then using that tissue was where we did the pathology, which was positive for adenocarcinoma, and it was CTF1 positive. All the clinical signs and histology we discussed with pathologists just to be sure, and we all felt that it was of a lung primary. When we did the biomarker testing, we found out that it was a KRAS G12D, but also [that it carries] STK11-positive mutation, and it was PD-L1 negative.

[W]hat will be the ideal treatment? It is either chemotherapy plus pembrolizumab [Keytruda], chemotherapy plus cemiplimab-rwlc [Libtayo], ipilimumab [Yervoy] plus nivolumab [Opdivo], chemotherapy plus nivolumab and ipilimumab, or chemotherapy plus durvalumab [Imfinzi] and tremelimumab [Imjudo].

Ready / Based on the KRAS and STK11, what are the chances of responding to single-agent PD-L1 immune checkpoint therapy?

Concepcion / One of the ideas is not only the STK11 prognosis factor but the idea that it does not respond well to immunotherapy. It also correlates with the PD-L1 negative/PD-L1 less than 1%. It is always hard to know how much association there is, but even with the negative PD-L1 and with STK11, when using single-agent immunotherapy, there is no strong advice for that.

[An article] was recently published in the Journal of Thoracic Oncology….¹ They look into the STK11 and KEAP1 mutations in stage IV NSCLC and went through all the data, especially the phase 3 POSEIDON [NCT03164616], the phase 3 CheckMate 9LA [NCT03215706], and also the phase 3 KEYNOTE-189 [NCT02578680] [trials], which had a small group of studies.^2-4 It was mostly retrospective and exploratory in view—[we] looked into that and tried to assess if having CTLA-4 would show some benefit or not. In POSEIDON, it initially did…as have some of your analyses that show a tendency for improvement. [It did] in KEYNOTE-189. There was another factor that they saw.

The whole idea is that chemoimmunotherapy should take precedence in this population. They also mentioned that in patients who are PD-L1 negative, not all STK11 [mutations] are the same, especially when they have concurrent mutations as well. If they have a KRAS mutation as well as the STK11, or maybe a KIP1, or the quantum mutations with loss of heterogeneity, or truncated mutation, specific in certain actions of STK11, or missing mutations, and this whole idea that not all STK11 [mutations] are the same, and maybe in those populations with negative PD-L1; maybe have a triplet that is like STK11, KIP1, KRAS, PD-L1 negative 1%, that could be some idea of using the CTLA-4. The consensus was [considering] a chemoimmunotherapy-based approach.

Inhibitors and Mutations Drive the NSCLC Conversation

Ready / There [are] some data that dual immunotherapy may be better for patients with KRAS/STK11 [mutations] because single-agent responses are very low. There [are] some exploratory data from dual immunotherapy that it may be better. This patient went on a clinical trial.

Concepcion / [The patient went on a phase 2a trial] with bemcentinib [NCT05469178], the AXL inhibitor; it is [done in the frontline setting].⁵ It is chemotherapy, pembrolizumab, and then they add the AXL inhibitors.

Ready / There is some evidence that AXL inhibitors may overcome STK11 mutation, loss of LKB1. There are some upfront clinical trials looking at immunotherapy plus the AXL inhibitor. We have a trial open.

Clarke / Have you ever gotten any pushback from insurance?

Concepcion / No, but I cannot remember a specific instance where I felt that I needed to carry on with the chemotherapy, but no, generally not.

Clarke / OK, the last time I did that, I had to write a letter to justify my decision.

Alder / I have the STK11 alteration frontline trial; if anyone has any patients, send them my way. Unfortunately, [my patient] just got her first cycle of chemotherapy, and her bone disease has blown up. She got the first cycle of chemotherapy a few days ago, and now her shoulder is all eaten up with this cancer.

Clarke / Is it not the trial reaction?

Shariff / It is not the trial reaction. She is in a lot of pain, unfortunately. Hopefully, better days are ahead.

Clarke / Is this a study worth traveling for, given the portal option?

Shariff / I am glad that you brought up the concurrent KRAS mutations, with those being so prevalent within the NSCLC patient population. We have to reexamine other methods from them because they do not respond well to the single-agent immunotherapy, so I appreciate that.

References

1. Ricciuti B, Garassino MC. Precision immunotherapy for STK11/KEAP1-mutant NSCLC. J Thorac Oncol. 2024;19(6):877-882. doi:10.1016/j.jtho.2024.03.002
2. Paz-Ares L, Ciuleanu TE, Cobo M, et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(2):198-211. doi:10.1016/S1470-2045(20)30641-0
3. Johnson ML, Cho BC, Luft A, et al; POSEIDON investigators. Durvalumab with or without tremelimumab in combination with chemotherapy as first-line therapy for metastatic non–small-cell lung cancer: the phase III POSEIDON study. J Clin Oncol. 2023;41(6):1213-1227. doi:10.1200/JCO.22.00975
4. Garassino MC, Gadgeel S, Speranza G, et al. Pembrolizumab plus pemetrexed and platinum in nonsquamous non–small-cell lung cancer: 5-year outcomes from the phase 3 KEYNOTE-189 study. J Clin Oncol. 2023;41(11):1992-1998. doi:10.1200/JCO.22.01989
5. Veluswamy R, Bhalla S, Mehra R, et al. Phase 1b/2a safety and tolerability study of bemcentinib (BEM) with pembrolizumab/carboplatin/pemetrexed in first line (1L) advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) without/with a STK11 mutation. J Clin Oncol. 2023;41(suppl 16):TPS9154. doi:10.1200/JCO.2023.41.16_supp.TPS9154