Sex-Based Differences in Tumor Response to Neoadjuvant Immunotherapy in Non-Small Cell Lung Cancer
Friday, January 24, 2025
5:35pm – 5:42pm PT
Location: Exhibit Hall Theater 2
M. Sewell1, N. Toumbacaris2, K. Tan1, P. Adusumilli2, T. Boerner1, G. Rocco2, B. Park2, J. Huang2, J. Isbell2, M. Bott3, S. Sihag2, K. Gray2, D. Jones2, D. Molena2 1Memorial Sloan Kettering Cancer Center, New York City, New York 2Memorial Sloan Kettering Cancer Center, New York, New York 3Memorial Sloan-Kettering Cancer Center, Ho-Ho-Kus, New Jersey
Disclosure(s):
Marisa Sewell, MD: No financial relationships to disclose
Purpose: There are known sex-specific differences in NSCLC. Additionally, evidence suggests that females and males respond differently to immunotherapy, which has gained relevance with pathologic response as a common trial endpoint. We aimed to determine whether sex was associated with tumor response in patients with resectable NSCLC who received neoadjuvant immunotherapy. Methods: Patients with clinical stage Ib-IV NSCLC who underwent neoadjuvant immunotherapy with or without chemotherapy followed by complete surgical resection between January 2010 and December 2023 were retrospectively identified in our institutional database. Demographic, staging, pathologic, and treatment characteristics were summarized using descriptive statistics. Major pathologic response was defined as less than 10% viable tumor. Categorical variables were compared using the chi-square test or Fisher’s exact test. Continuous variables were compared using Wilcoxon rank-sum test. Univariable and multivariable linear regression were used to evaluate associations of sex and percent viable tumor as a surrogate for pathologic response. Genetic evaluation was done routinely on every specimen after 2016 utilizing our institutional hybridization capture-based sequencing assay, which targets all exons and select introns of key cancer genes in fixed tumors Results: We identified 163 patients, including 105 females and 58 males, who met inclusion criteria. Smoking status, clinical stage, and grade were not different between groups (Table 1). The rate of adenocarcinoma was higher in females than males (82 (78%) v. 29 (50%) p < 0.01). The rate of mPR was higher in females (33(31%) v. 8(14%) p=0.01), but the rate of pCR was similar (6(10%) v. 14(13%) p=0.5). When examined as a continuous variable, females had significantly lower percent viable tumor (30% v 61%, p< 0.01), which persisted on multivariable analysis controlling for age, sex, grade, and clinical stage (p=0.02).
Data from our institutional sequencing assay was available for 64%, or 105 total patients. The overall proportion of EGFR (19% v. 27%, p=0.299), and ALK (3% v. 1.9%, p=0.9) alterations did not differ between females and males. There were significantly more KRAS alterations in females than males (44% v. 25%, p=0.034). However, there was no difference in the frequency of KRAS G12C mutations between females and males (21% v. 7%, p=0.06). Lastly, there was no difference in the frequency of EGFR L858R mutations (9.4% v 9.8%, p=0.990) between females and males. Conclusion: In patients with resectable NSCLC, female sex may be associated with improved tumor response to neoadjuvant immunotherapy. This evidence underscores the importance of achieving sex-based parity in clinical trial enrollment. As new and targeted immunotherapeutics are developed, a deeper understanding of the genetic, hormonal, and environmental factors influencing immunotherapy response in NSCLC is important.
Identify the source of the funding for this research project: This study was supported by the National Institutes of Health/National Cancer Institute (P30 CA008748 to Memorial Sloan Kettering Cancer Center).