Proposal for multiple new lesions as complement of hyperprogressive disease in NSCLC patients treated with PD-1/PD-L1 immunotherapy.

BACKGROUND: Hyperprogressive disease (HPD) is a progression pattern of rapid increase in tumor burden during immunotherapy. However, current HPD definitions are mainly based on the diameter of target lesions. How to take new lesions into account remains unknown. METHODS: In this retrospectively analysis, 393 patients received PD-1/PD-L1 inhibitors monotherapy. 237 patients were eligible for HPD evaluation based on tumor growth rate (TGR) ratio, ΔTGR or tumor growth kinetic (TGK) ratio. Among them, 214 patients were eligible for evaluation of new lesions. The impact of new lesions on overall survival (OS) was investigated by Kaplan-Meier methods. The optimal threshold for new lesion number was investigated by one-year time-dependent receiver operating characteristic (ROC) curves. Developing more than one new lesions (n ≥ 2) was defined as multiple new lesions (MNL). New HPD was redefined as both developing MNL and meeting the requirement of current HPD definitions (TGR ratio, ΔTGR or TGK ratio). The survival difference between the newly defined HPD and non-HPD patients was investigated. RESULTS: HPD occurred in 5.1-18.1 % patient based on current definitions (TGR ratio, 15.6 %; ΔTGR, 5.1 %; TGK ratio, 18.1 %). However, there is no significant difference between OS of HPD and non-HPD patient. New lesion was associated with a shorter median OS in PD（with or without HPD) patients (6.1 vs 18.9 months, p = 0.001). Time-dependent ROC analysis suggested that the optimal threshold for new lesion number in survival prediction was two. After the redefinition of HPD, New HPD patients had a significantly shorter median OS compared with non-HPD patients (TGR ratio with MNL: 5.6 vs 11.8 months, p < 0.001; ΔTGR with MNL: 5.0 vs 11.4 months, p = 0.034; TGK ratio with MNL: 5.7 vs 12.3 months, p < 0.001; respectively). CONCLUSIONS: Current HPD definitions had a better prognostic value when complemented with MNL. MNL should be integrated into the new definition of HPD.

Landscape and Predictive Significance of the Structural Classification of EGFR Mutations in Chinese NSCLCs: A Real-World Study.

Background: Non-classical EGFR mutations demonstrate heterogeneous and attenuated responsiveness to EGFR TKIs. Non-small cell lung cancer (NSCLC) patients with atypical EGFR mutations have limited therapeutic options. A recent study established a novel structural-based classification of EGFR mutations and showed its value in predicting the response to TKI. We sought to interrogate the distribution of different structural types and to validate the predictive value in Chinese NSCLCs. Methods: A total of 837 tumor samples were retrospectively recruited from 522 patients with unresectable EGFR-mutant NSCLC. EGFR mutations were classified into four groups: classical-like, T790M-like, Ex20ins-L, and PACC. Treatment information and clinical outcomes were obtained from 436 patients. The time to treatment failure (TTF) was determined on a per-sample basis. Results: Of the 837 EGFR-mutant samples, 67.9%, 18.5%, 9.0%, and 3.1% harbored classical-like, T790M-like, PACC, and Ex20ins-L mutations, respectively. Thirteen (1.6%) samples carried mutations beyond the four types. Among the 204 samples with atypical mutations, 33.8%, 36.7%, 12.7%, and 10.3% were classical-like, PACC, Ex20ins-L, and T790M-like, respectively. In patients with PACC mutations, second-generation TKIs demonstrated a significantly longer TTF than first-generation TKIs (first-line: 15.3 vs. 6.2 months, p = 0.009; all-line: 14.7 vs. 7.1 months, p = 0.003), and a trend of longer TTF than third-generation TKIs (all-line: 14.7 vs. 5.1 months, p = 0.135). Conclusions: Our study depicted the landscape of structural types of EGFR mutations in Chinese NSCLC patients. Our results also suggest that the structural classification can serve as a predictive marker for the efficacy of various EGFR TKIs, which would guide therapeutic decision making.