Characterizing tumor shrinkage as a measure of clinical benefit for immune checkpoint inhibitors.

BACKGROUND: We explored whether the effectiveness of immune checkpoint inhibitors (ICIs) can be characterized by incorporating a composite of duration of response (DOR) to complement traditional Response Evaluation Criteria in Solid Tumors (RECIST) criteria for objective response rate (ORR) in an intent-to-treat (ITT) population. Furthermore, the correlation of this novel endpoint, characterized by the restricted mean time in response (RMTR), with overall survival (OS) will be examined. METHODS: We analyzed ORR alone or in combination with DOR (RMTR) in available phase I, II, and III trials evaluating nivolumab monotherapy or in combination with ipilimumab across solid tumor types. ORR was evaluated per RECIST V.1.1. DOR was estimated using individual patient data in ITT populations regardless of RECIST response, with non-responders imputed as zero. Associations between ORR alone or RMTR and OS were evaluated in the ITT population. DOR curves were generated using the Kaplan-Meier product limit method, and 6-month RMTR, a measure of response durability, was derived from the area under the curves. For ORR and RMTR in the ITT population, the strength of association with OS was analyzed using Pearson correlation coefficients (r). RESULTS: Nivolumab treatment was associated with longer response durations than active control in responder and ITT populations. Similarly, ORR and RMTR were both significantly correlated with OS (ORR vs OS: r=0.684, p=0.02; RMTR vs OS: r=0.695, p=0.018). CONCLUSIONS: Combining ORR and DOR (RMTR) to objectively characterize tumor shrinkage in an ITT patient population is a novel approach that appears to correlate well with OS in patients treated with nivolumab monotherapy or in combination with ipilimumab. This endpoint may provide a more complete characterization of tumor shrinkage to incorporate into the design of future ICI clinical trials. However, confirmation of this approach will require further research.

Current Status and Future Perspectives on Neoadjuvant Therapy in Lung Cancer.

This Review Article provides a multi-stakeholder view on the current status of neoadjuvant therapy in lung cancer. Given the success of oncogene-targeted therapy and immunotherapy for patients with advanced lung cancer, there is a renewed interest in studying these agents in earlier disease settings with the opportunity to have an even greater impact on patient outcomes. There are unique opportunities and challenges with the neoadjuvant approach to drug development. To achieve more rapid knowledge turns, study designs, endpoints, and definitions of pathologic response should be standardized and harmonized. Continued dialogue with all stakeholders will be critical to design and test novel induction strategies, which could expedite drug development for patients with early lung cancer who are at high risk for metastatic recurrence.

Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer.

PURPOSE: The phase III Iressa Survival Evaluation in Lung Cancer (ISEL) trial compared gefitinib with placebo in 1,692 patients with refractory advanced non-small-cell lung cancer. We analyzed ISEL tumor biopsy samples to examine relationships between biomarkers and clinical outcome after gefitinib treatment in a placebo-controlled setting. METHODS: Biomarkers included epidermal growth factor receptor (EGFR) gene copy number by fluorescence in situ hybridization (n = 370); EGFR (n = 379) and phosphorylated Akt (p-Akt) protein expression (n = 382) by immunohistochemistry; and mutations in EGFR (n = 215), KRAS (n = 152), and BRAF (n = 118). RESULTS: High EGFR gene copy number was a predictor of a gefitinib-related effect on survival (hazard ratio [HR], 0.61 for high copy number and HR, 1.16 for low copy number; comparison of high v low copy number HR, P = .045). EGFR protein expression was also related to clinical outcome (HR for positive, 0.77; HR for negative, 1.57; comparison of high v low protein expression HR, P = .049). Patients with EGFR mutations had higher response rates than patients without EGFR mutations (37.5% v 2.6%); there were insufficient data for survival analysis. No relationship was observed between p-Akt protein expression and survival outcome, and the limited amount of data collected for KRAS and BRAF mutations prevented any meaningful evaluation of clinical outcomes in relation to these mutations. CONCLUSION: EGFR gene copy number was a predictor of clinical benefit from gefitinib in ISEL. Additional studies are warranted to assess these biomarkers fully for the identification of patients most likely to benefit from gefitinib treatment.