Impact of KRAS mutations on adjuvant carboplatin/paclitaxel in surgically resected stage IB NSCLC: CALGB 9633.

Abstract

7008 Background: CALGB 9633 randomized surgically resected stage IB NSCLC patients to carboplatin/paclitaxel (CP) or observation (OBS). A retrospective assessment suggested a survival benefit in patietns with tumors > 4.0 cm in size (G. Strauss JCO 2008). KRAS mutations were associated with lack of benefit from adjuvant chemotherapy in the JBR.10 trial. The impact of KRAS mutations on outcome in CALGB 9633 was evaluated. Methods: Pretreatment tumor specimens from CALGB 9633 were evaluated for presence of KRAS (codons 12, 13, 61) mutations using mass spectrometry. Outcomes based on presence/absence of KRAS mutations were evaluated. Results: Tumor specimens were available for KRAS genotyping from 267/344 (78%) patients (CP: 139; OBS: 128). KRAS mutations were detected in 71 (27%) of all KRAS evaluable patients: CP: 35 pts (25%); OBS 36 pts (28%). KRAS mutations were more common in adenocarcinomas vs. non-adeno (41% vs. 11%; p < 0.0001) and in ≥ 4.0 cm vs. < 4 cm (32% vs. 18%; p = 0.0144). 5 yr OS (90% CI) for all pts receiving CP: KRAS WT: 62% (53-69) Mut: 55% (35-63); HR 1.2 (p = 0.581). 5 yr OS for pts with ≥ 4.0 cm tumors receiving chemo. KRAS WT: 73% (62-82); Mut: 38% (23-54); HR = 2.3 (p = 0.011). 5 yr OS (90% CI) for all pts on OBS: KRAS WT: 59% (50-67) Mut: 67% (52-78); HR 1.1 (p = 0.747). 5 yr OS for pts with ≥ 4.0 cm tumors on OBS. KRAS WT: 66% (54-76); Mut: 61% (42-75); HR = 1.4 (p = 0.366). Interaction for KRAS mutations and tumor size (≥ 4.0 cm vs. < 4 cm) is significant (p=0.0036) in a multivariate analysis including all patients and adjusting for treatment, KRAS, tumor size and their interactions. Adjuvant CP in KRAS WT pts with > 4.0 cm tumors was suggestively associated with a benefit (HR = 0.69; p = 0.18) while in KRAS mut pts there was no benefit (HR = 1.2; p = 0.5457) However a three-way interaction between KRAS mutation, treatment and tumor size was not significant. Conclusions: KRAS mutations may identify a subset of stage IB NSCLC pts, especially those with ≥ 4.0 cm tumors, that have a worse prognosis and derive less benefit from adjuvant CP. No significant financial relationships to disclose.