Erica C. Nakajima, MD, Analyzes Frontline Immune Checkpoint Inhibitors in KRAS+, PD-L1+ Non-Small Cell Lung Cancer

Erica C. Nakajima, MD
Medical Oncologist, FDA Office of Oncologic Drugs
Washington, DC

Results from a retrospective pooled analysis on the frontline use of immune checkpoint inhibitors (ICI) in KRAS–mutated non-small cell lung cancer (NSCLC) were recently presented in a poster at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting showing that most patients benefit when therapy is administered in combination with chemotherapy, similar to what is seen in KRAS wild-type disease.

Erica C. Nakajima, MD, a medical oncologist at the FDA Office of Oncologic Drugsand lead investigator of this study, spoke with CancerNetwork^® about the efficacy of chemotherapy alone, ICI alone, and ICI in combination with chemotherapy across patients with KRAS-mutated or KRAS wild-type NSCLC.

Results showed an improved objective response rate (ORR) and median overall survival (OS) across all patient subgroups treated with ICI and chemotherapy vs either therapy alone, including in key patient subgroups. For patients with KRAS-mutated NSCLC, the ORR was 46% (95% CI, 39%-53%) with the combination treatment vs 37% (95% CI, 29%-46%) with ICI alone and 35% (95% CI, 28%-42%) with chemotherapy alone. Patients with KRAS wild-type NSCLC, meanwhile, experienced corresponding ORRs of 51% (95% CI, 46%-57%), 33% (95% CI, 27%-40%), and 32% (95% CI, 27%-37%). Investigators suggested that patients with KRAS-mutated NSCLC should receive combination therapy upfront and that future clinical trials in the frontline setting should include ICI plus chemotherapy as the comparator arm for more definitive results.

CancerNetwork^®: What was the rationale for conducting this analysis?

Nakajima: There’s a significant subset of patients with NSCLC that have KRAS mutations, comprising about 30% [of the total population with NSCLC]. In 2021, the FDA approved the RAS GTPase family inhibitor sotorasib [Lumakras] for the treatment of NSCLC with a KRAS G12C mutation, which is found in about 13% of the population with KRAS mutations.2 Prior to the approval of that targeted therapy, there was some debate as to whether patients with KRAS-mutated NSCLC had improved responses to frontline immunotherapy as compared with those patients with KRAS wild-type NSCLC. There had been 2 published retrospective analyses of individual clinical trials [NCT01905657; NCT02578680] that compared KRAS wild-type NSCLC with KRAS-mutated NSCLC, and the results were somewhat mixed. When they examined patients who received frontline immunotherapy alone,3 patients with KRAS-mutated NSCLC appeared to respond better to immunotherapy. A subsequent retrospective study examined patients with KRAS wild-type vs KRAS-mutated NSCLC in response to ICI plus chemotherapy, and the results were equivalent [across mutational status groups].4 The 2 groups both showed a similar ORRs and median OS. The important caveat to both retrospective analyses is that they were based on a single randomized clinical trial in which the patient cohort numbers were low, ranging between 30 and 100 patients. We needed more patient data to establish more definitively whether there’s a difference in response between these 2 populations.

What findings stood out to you most?

Overall, it appears that patients with KRAS-mutated and KRAS wild-type NSCLC respond similarly to immunotherapy alone, to ICI alone, and to ICI plus chemotherapy. Both ORR and median OS were very similar between the 2 mutational subgroups [across the 3 treatment options].

That said, all the subgroups we examined—including KRAS wild-type, KRAS-mutated, and across PD-L1 expression levels—appeared to respond best to the combination of ICI with chemotherapy. But we didn’t see a significant difference between the 2 mutational subgroups.

Where do you foresee research efforts going from here?

There are a lot of caveats to our pooled analysis. We couldn’t control for certain co-mutations that confer resistance to immunotherapy, such as KEAP1 or STK11. Patients [with those mutations] may have been mixed into our sample population without our knowledge because that data weren’t provided in the marketing application. We also know that patients with EGFR and ALK mutations were likely included in the KRAS wild-type subgroup because some of the trials we pulled from didn’t exclude those patients. We are planning to go back and sift through our data to see if we can pull them out because patients with EGFR- and ALK-mutated NSCLC are thought to have poor response to immunotherapy.

[In summary], we need to refine our analysis to have a [more defined] population of patients with KRAS wild-type NSCLC without EGFR or ALK mutations and compare that against those with KRAS-mutated NSCLC. Ideally, we’d be able to define the exact mutation, whether it’s KRAS G12C [or otherwise], because that may impact a patient’s response to ICI as well. What we’d like going forward is for clinical trials to collect that genetic information from the patient’s tumors so we can refine our analysis.

How might this research impact clinical practice?

It’s a great question. There’s a lot of clinical interest in this because oncologists are seeing patients with this KRAS mutation. Our data showed that patients appear to do best with ICI in combination with chemotherapy. That said, this was an exploratory retrospective analysis, and so it’s primarily hypothesis generating. It would be great if future studies defined these populations and selected their control arm carefully so that they could prospectively evaluate whether ICI in combination with chemotherapy is the optimal regimen for these patients. We also need to learn whether there’s a subset of patients with KRAS-mutated NSCLC who may not respond well to ICI and might do best with KRAS-targeted therapy in the front-line. That’s also an active area of investigation.

What do you hope your colleagues took away from this analysis?

Overall, our data [establish] that patients with KRAS-mutated NSCLC generally respond well to frontline immunotherapy. There’s [still] a lot of discussion that needs to happen within the clinic when dealing with individual patients. [You need to ask]: what exactly is their KRAS mutation? What exactly is their PD-L1 score? Do they have a preference about receiving frontline chemotherapy? Do they have frailties that may preclude them from chemotherapy? [In some cases], treatment with ICI alone might be optimal. There are a lot of factors to consider, but generally [our data] indicate that patients show a good response to ICI therapy.

References

1. Nakajima EC, Vallejo JJ, Akinboro O, et al. Outcomes of first-line immune checkpoint inhibitors with or without chemotherapy according to KRAS mutational status and PD-L1 expression in patients with advanced NSCLC: FDA pooled analysis. J Clin Oncol. 2022;40(16):9001. doi:10.1200/JCO.2022.40.16_suppl.9001
2. FDA grants accelerated approval to sotorasib for KRAS G12C mutated NSCLC. News release. FDA. May 28, 2021. Accessed September 2, 2022. https://bit.ly/3KPQBHm
3. Herbst RS, Lopes G, Kowalski DM, et al. Association of KRAS mutational status with response to pembrolizumab monotherapy given as first-line therapy for PD-L1-positive advanced non-squamous NSCLC in Keynote-042. Ann Oncol. 2019;39(suppl 11):LBA4. doi:10.1093/annonc/mdz453.001
4. Gadgeel SM, Rodriguez-Abreu D, Felip E, et al. KRAS mutational status and efficacy in KEYNOTE-189: Pembrolizumab (pembro) plus chemotherapy (chemo) vs placebo plus chemo as first-line therapy for metastatic non-squamous NSCLC. Ann Oncol. 2019;30(11):LBA5. doi:10.1093/annonc/mdz453.002