Patient Characteristics Influence Choice of Chemo/IO Regimen in NSCLC

Sandip P. Patel, MD (Moderator)

Professor of Medicine

UC San Diego Health

San Diego, CA

DISCUSSION QUESTIONS

• What patient characteristics would you consider when choosing among immunotherapy plus chemotherapy regimens?​
• How does site of metastases impact the treatment algorithm for non–small cell lung cancer (NSCLC)?​

SANDIP P. PATEL, MD: What patient characteristics would you consider when choosing amongst all these immunotherapy and chemotherapy regimens? Do sites of metastases matter? Brain, liver, other? Are patients typically able to tolerate 4 cycles of chemotherapy, or do you have to dose reduce or dose delay? Do you think about other regimens then?

For patients with brain metastases, do you alter your systemic approach? The response rates in the brain are not so low that I would go with systemic treatment alone. [Chemoimmunotherapy] does not have the level of efficacy of osimertinib [Tagrisso], alectinib [Alecensa], brigatinib [Alunbrig], or lorlatinib [Lorbrena], so typically stereotactic radiosurgery followed by immunotherapy or chemoimmunotherapy is the approach.

ESHA SACHDEV, MD: I noticed with [chemotherapy and] nivolumab [Opdivo] plus ipilimumab [Yervoy] with the brain metastases, the data are quite impressive.¹ If a patient had brain metastases, I would lean towards that. Also, I’m just more familiar with nivolumab/ipilimumab. I have never used [durvalumab (Imfinzi) and tremelimumab (Imjudo)] in any other tumors, either. I would lean towards something that I’m more comfortable with.

PATEL: I think that’s very reasonable. Any other thoughts on the best approach [if] metastases influence your thinking on which regimen one may use? How about STK11/KEAP1, does anyone use that? Or TMB [tumor mutational burden] as the inverse of it to help influence them not whether to do immunotherapy at all, but which immunotherapy backbone to use?

SHERRY HSU, MD: The POSEIDON trial [NCT03164616] put forth the STK11 mutation; they claim durvalumab/tremelimumab seems to have an edge for that and the KEAP1 as well.² [For] the nivolumab/ipilimumab [and chemotherapy], post hoc analysis also shows some advantages in STK11/KEAP1-mutated disease.³ Regarding TMB, I think that there are some data on supporting the bevacizumab [Avastin] regimen.⁴

PATEL: These are great points. We went from having almost no choices to having many choices in NSCLC. I know getting chemotherapy ordered, the platinum part, has been a big issue. Has anyone had the platinum shortage be the impetus to change regimens, meaning you couldn’t get carboplatin or cisplatin for your patient…and the best data were for a different regimen? Has anyone had the logistics of this lead to a treatment change?

HSU: I think it’s more applied to cisplatin. Carboplatin, we can somehow get enough vials.

SAM YEH, MD: What do you think about the TMB? Do you think that’s a surrogate marker for immunotherapy for in lung cancer? Or is it kind of controversial?

PATEL: My view on TMB is TMB only matters if it’s very high or very low. If it’s in the middle, which I include TMB of 10 to 20 muts/Mb as being in the middle, it’s not helpful. If someone’s TMB is 40 muts/Mb, that the patient’s going to do well. I would even consider PD-1 monotherapy in those patients. If someone’s TMB is 1 or 2 muts/Mb, you didn’t get RNA sequenced, and they’re a never-smoker, to me that means there could be a cryptic fusion hiding there, and that patient may be a better targeted therapy candidate, especially if they’re young or a never-smoker.

YEH: Yes, [although] it seems like the anything above 10 is considered high TMB.

PATEL: I think they set it too low. It would be like if you had a frontline [therapy], if you’re going do pembrolizumab [Keytruda] or cemiplimab [Libtayo] or atezolizumab itself for PD-L1 [of at least] 10%. In fact, that was one of the studies. You may remember, [CheckMate 026; NCT02041533], where the PD-L1 cutoff was 5%, was too low to be informative.⁵ I think TMB of 10 muts/Mb is the PD-L1 5% of biomarkers. It’s not discriminating enough between response and non-response.

_References:

_{1. Paz-Ares L, Ciuleanu T, Cobo M, et al. First-line nivolumab plus ipilimumab with chemotherapy versus chemotherapy alone for metastatic NSCLC in CheckMate 9LA: 3-year clinical update and outcomes in patients with brain metastases or select somatic mutations. J Thorac Oncol. 2023;18(2):204-222. doi:10.1016/j.jtho.2022.10.014}

_{2. Peters S, Cho BC, Luft A, et al. Association between KRAS/STK11/KEAP1 mutations and outcomes in POSEIDON: durvalumab ± tremelimumab + chemotherapy in mNSCLC. J Thorac Oncol. 2022;17(9):S39-S41. doi:10.1016/j.jtho.2022.07.073}

_{3. Paz-Ares L, Ciuleanu T, Cobo M, et al. First-line (1L) nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of chemotherapy (chemo) versus chemo alone (4 cycles) in patients (pts) with metastatic non–small cell lung cancer (NSCLC): 3-year update from CheckMate 9LA. J Clin Oncol. 2022;40(suppl_17):LBA9026. doi:10.1200/JCO.2022.40.17_suppl.LBA9026}

_{4. Provencio M, Ortega AL, Coves-Sarto J, et al. Atezolizumab plus bevacizumab as first-line treatment for patients with metastatic nonsquamous non-small cell lung cancer with high tumor mutation burden: A nonrandomized controlled trial. JAMA Oncol. 2023;9(3):344-353. doi:10.1001/jamaoncol.2022.5959}

_{5. 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}