Quantitating pathologic response to neoadjuvant chemotherapy in KRAS-mutated versus nonmutated lung cancers.

Abstract

7014 Background: Trials of neoadjuvant chemotherapy in non-small cell lung cancers (NSCLC) have demonstrated that pathologic response correlates with downstaging and survival. There is controversy as to whether KRAS mutated patients (pts) have the same benefit with adjuvant chemotherapy as non-mutated pts however the impact of KRAS mutations on response to neoadjuvant therapy has not been reported. Methods: Pts with resectable stage I-III non-squamous NSCLCs were treated with 4 cycles of cisplatin, docetaxel, and bevacizumab, followed by surgical resection. Tumors were tested for KRAS mutations. Percent treatment effect (necrosis, inflammation, fibrosis) was quantified histologically. Pts were followed until disease recurrence and/or death. Binary variables were compared using the Fisher’s Exact Test. Survival was assessed by pathological response based on the literature (≥90 vs <90%) using the Kaplan-Meier method, stratified by stage (IB-IIB vs. III) and by KRAS mutation. Results: We accrued 51 pts. 34/51 (67%) had clinical stage IIIA disease. 48 had molecular testing: 14/48 (29%) had KRAS mutations and 4/48 (8%) had EGFR mutations. The median follow-up was 2 years (yr) (range, 3-63 months). 41 pts had resection and analysis for pathological response. The 2 yr disease free survival (DFS) and overall survival (OS) were superior in the 11/41 (27%) with ≥90% versus those with <90% treatment effect: DFS 91% vs. 56%, p=0.029 and OS 100% vs. 60%, p=0.013. These outcomes remained significant when adjusted for stage. For pts with KRAS mutations, 0 of 10 tumors analyzed had ≥90% treatment effect whereas 11 of 31 (35%) pts with wild-type KRAS had ≥90%, p=0.039. There was an inferior median OS for KRAS mutated pts (22 months) compared to pts without a known KRAS mutation, (Not Reached, p=0.03). Conclusions: Following neoadjuvant chemotherapy, pts with tumors having ≥90% necrosis had improved survival. There were no patients with KRAS mutation that achieved ≥90% treatment effect in response to cisplatin, docetaxel, and bevacizumab. Adaptive adjuvant trial strategies to improve upon outcomes of those with <90% necrosis at resection and new approaches specifically targeting KRAS-mutated NSCLCs are needed.