Non-small cell lung cancer (NSCLC) treatment strategies are evolving to address the challenges posed by specific mutations, particularly in patients with concurrent KRAS and STK11 mutations. Recent discussions among experts at Duke Cancer Institute highlight the potential benefits of dual immunotherapy and chemoimmunotherapy approaches in these challenging cases, where single-agent PD-L1 inhibitors often show limited efficacy.
Addressing KRAS and STK11 Mutations in NSCLC
In a panel discussion led by Neal E. Ready, MD, PhD, the complexities of treating NSCLC adenocarcinoma with KRAS and STK11 mutations were examined. A clinical scenario involving a 47-year-old former smoker with metastatic NSCLC, positive for KRAS G12D and STK11 mutations but PD-L1 negative, sparked a debate on optimal treatment strategies. Joel Rivera Concepcion, MD, JD, presented the case, emphasizing the importance of biomarker testing in guiding treatment decisions.
Ready questioned the likelihood of response to single-agent PD-L1 immune checkpoint therapy in patients with these specific mutations. Concepcion noted that the presence of STK11 mutations, especially in conjunction with low PD-L1 expression, correlates with poor response to single-agent immunotherapy. "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%," Concepcion stated.
The Role of CTLA-4 Inhibitors and Chemoimmunotherapy
Recent research published in the Journal of Thoracic Oncology suggests that chemoimmunotherapy may be a more effective approach for this patient population. The study retrospectively analyzed data from phase 3 trials, including POSEIDON (NCT03164616), CheckMate 9LA (NCT03215706), and KEYNOTE-189 (NCT02578680), to assess the impact of STK11 and KEAP1 mutations on treatment outcomes. The analyses indicated that the addition of a CTLA-4 inhibitor might offer some benefit, particularly in PD-L1-negative patients with concurrent mutations.
The consensus among the panel was to consider a chemoimmunotherapy-based approach for patients with KRAS and STK11 mutations. "The whole idea is that chemoimmunotherapy should take precedence in this population," Concepcion explained.
Investigating AXL Inhibitors
Another promising strategy involves the use of AXL inhibitors in combination with chemotherapy and immunotherapy. Concepcion shared that the patient was enrolled in a phase 2a trial (NCT05469178) evaluating bemcentinib, an AXL inhibitor, in the frontline setting. The trial combines chemotherapy, pembrolizumab, and bemcentinib.
Ready noted that "There is some evidence that AXL inhibitors may overcome STK11 mutation, loss of LKB1." Several clinical trials are currently investigating the potential of AXL inhibitors to enhance immunotherapy responses in patients with STK11 mutations.
Clinical Trial Considerations
The discussion also touched on the practical aspects of implementing these treatment strategies, including insurance coverage and patient access to clinical trials. Laura Alder, MD, mentioned an ongoing frontline trial for patients with STK11 alterations, highlighting the importance of clinical trial participation in advancing treatment options for this challenging patient population. Afreen Idris Shariff, MD, MBBS, emphasized the need to reexamine treatment methods for patients with concurrent KRAS mutations, as they often do not respond well to single-agent immunotherapy.
