Author of

• 11745

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  P2.11 - Poster Session 2 - NSCLC Novel Therapies (ID 209)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Medical Oncology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/29/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 11771

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    P2.11-026 - RET Fusion-Positive Advanced Lung Cancers: Response to First-Line Chemotherapy and Survival in Comparison to ROS1 and ALK Fusion-Positive and EGFR- and KRAS-Mutant Lung Cancers (ID 1964)

    09:30 - 09:30  |  Author(s): E.J. Cho
    • Abstract

    Background
    RET fusions are novel targetable drivers in non-small cell lung cancers. While the clinicopathologic profile of patients with RET fusion-positive tumors has been described in early-stage disease, little is known regarding clinical behavior in advanced unresectable disease.

    Methods
    Patients with advanced unresectable (stage IIIB/IV) pan-negative lung adenocarcinomas (absence of mutations in EGFR, KRAS, NRAS, BRAF, MAP2K1, ERBB2, PIK3CA, and AKT, and fusions of ALK or ROS1) were screened for RET fusions via dual-probe break apart FISH testing. Upstream partners were identified via RT-PCR and next-generation sequencing whenever possible. A retrospective review of patient records was conducted to determine response to systemic therapy and overall survival (OS). OS was calculated from diagnosis of metastatic disease and compared to patients with ALK and ROS1 fusion-positive, and EGFR- and KRAS-mutant lung cancers. Survival curves were estimated using the Kaplan-Meier method. Differences in survival between groups were assessed by the log-rank test.

    Results
    A RET fusion was found in 16% (n=12/76, 95%CI 8%-24%) of pan-negative tumors and 19% (n=10/48, 95%CI 10%-33%) of pan-negative tumors from never-smokers. Patients with RET fusion-positive tumors were predominantly never-smokers (83%, n=10/12, 2 patients with 7 and 10 pack-year histories, respectively) with advanced-stage disease at diagnosis (92%, n=11/12 stage IIIB/IV). Fusion partners were identified in 6 patients (4 KIF5B-RET, 1 TRIM33-RET, 1 NCOA4-RET). Eight patients (67%) received first-line platinum-based therapy, 6 of whom (50%) received maintenance pemetrexed and/or bevacizumab. Partial responses (PRs) were seen in 3 patients (38%) and stable disease (SD) in 5 patients (62%). 1-year OS on chemotherapy and median progression-free survival were 47% and 7.3 months, respectively. 1-year and 2-year OS for patients whose tumors harbored RET, ROS1, or ALK fusions, or EGFR or KRAS mutations is summarized below (Table). OS was not significantly different between RET, ROS1, ALK, or EGFR cohorts when RET was compared to each of the latter three cohorts separately. The presence of a RET fusion was associated with improved OS compared to the presence of a KRAS mutation (HR 0.39, 95%CI 0.21-0.74, p=0.004). Of the 11 patients with RET fusion-positive lung cancers, 4 patients (36%) were treated with cabozantinib on a phase 2 protocol (NCT01639508) with disease shrinkage of -66%, -32%, -23%, and -19% via RECIST v1.1.

    Driver Detected	OS 1-year [95%CI]	OS 2-year [95%CI]
    RET (n=12)	100%	71% [25%-92%]
    ROS1 (n=9)	88% [39%-99%]	88% [39%-99%]
    ALK (n=44)	91% [77%-97%]	73% [55%-85%]
    EGFR (n=102)	85% [76%-91%]	58% [47%-67%]
    KRAS (n=117)	60% [50%-66%]	26% [18%-35%]

    Conclusion
    Response to platinum-based first-line therapy in patients with RET fusion-positive tumors is comparable to historical controls. Survival in patients with RET fusion-positive disease is comparable to patients with EGFR mutations and other recurrent gene fusions (ROS1 and ALK) and improved compared to patients with KRAS mutations. Cabozantinib is worthy of further study in RET fusion-positive lung cancers.