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A. Drilon



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    MA16 - Novel Strategies in Targeted Therapy (ID 407)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Chemotherapy/Targeted Therapy/Immunotherapy
    • Presentations: 1
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      MA16.03 - Global RET Registry (GLORY): Activity of RET-Directed Targeted Therapies in RET-Rearranged Lung Cancers (ID 4325)

      14:26 - 14:32  |  Author(s): A. Drilon

      • Abstract
      • Presentation
      • Slides

      Background:
      GLORY is a global registry of patients with RET-rearranged non-small cell lung cancer (NSCLC). In order to complement ongoing prospective studies, the registry’s goal is to provide data on the efficacy of RET-directed targeted therapies administered outside the context of a clinical trial. We previously reported results from our first interim analysis (Gautschi, ASCO 2016). Following additional accrual into the registry, updated results are presented here, with a focus on an expanded efficacy analysis of various RET inhibitors.

      Methods:
      A global, multicenter network of thoracic oncologists identified patients with pathologically-confirmed NSCLC harboring a RET rearrangement. Molecular profiling was performed locally via RT-PCR, FISH, or next-generation sequencing. Anonymized data including clinical, pathologic, and molecular features were collected centrally and analyzed by an independent statistician. Response to RET tyrosine kinase inhibition (TKI) administered off-protocol was determined by RECIST1.1 (data cutoff date: April 15, 2016). In the subgroup of patients who received RET TKI therapy, the objectives were to determine overall response rate (ORR, primary objective), progression-free survival (PFS), and overall survival (OS).

      Results:
      165 patients with RET-rearranged NSCLC from 29 centers in Europe, Asia, and the USA were accrued. The median age was 61 years (range 28-89 years). The majority of patients were female (52%), never smokers (63%), with lung adenocarcinomas (98%) and advanced disease (91%). The most frequent metastasic sites were lymph nodes (82%), bone (51%) and lung (32%). KIF5B-RET was the most commonly identified fusion (70%). 53 patients received at least one RET-TKI outside of a clinical protocol, including cabozantinib (21), vandetanib (11), sunitinib (10), sorafenib (2), alectinib (2), lenvatinib (2), nintedanib (2), ponatinib (2) and regorafenib (1). In patients who were evaluable for response (n=50), the ORR was 37% for cabozantinib, 18% for vandetanib, and 22% for sunitinib. Median PFS was 3.6, 2.9, and 2.2 months and median OS was 4.9, 10.2, and 6.8 months for cabozantinib, vandetanib, and sunitinib, respectively. Responses were also observed with nintedanib and lenvatinib. Among patients who received more than one TKI (n=10), 3 partial responses were achieved after prior treatment with a different TKI.

      Conclusion:
      RET inhibitors are active in individual patients with RET-rearranged NSCLC, however, novel therapeutic approaches are warranted with the hope of improving current clinical outcomes. GLORY remains the largest dataset of patients with RET-rearranged NSCLC, and continues to accrue patients.

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    OA11 - Angiogenesis in Advanced Lung Cancer (ID 387)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
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      OA11.05 - A Phase 2 Study of Cabozantinib for Patients with Advanced RET-Rearranged Lung Cancers (ID 5731)

      11:35 - 11:45  |  Author(s): A. Drilon

      • Abstract
      • Presentation
      • Slides

      Background:
      RET rearrangements are actionable drivers found in 1-2% of non-small cell lung cancers. We previously reported the efficacy and safety of the multikinase RET inhibitor cabozantinib in 16 patients with RET-rearranged lung cancers in the first stage of our Simon two-stage phase 2 clinical trial (overall response rate 38%; Drilon, ASCO 2015). This study has since completed accrual of both stages, now with 26 patients treated with cabozantinib.

      Methods:
      This was an open-label, single center, phase 2 trial (NCT01639508). Eligibility criteria: stage IV pathologically-confirmed lung cancers, presence of a RET rearrangement, KPS >70%, and measurable disease. RET rearrangements were detected by FISH or next-generation sequencing. Cabozantinib was administered in tablet form at 60 mg daily until progression of disease or unacceptable toxicity. The primary objective was to determine the overall response rate (ORR, RECIST v1.1). Secondary objectives included determining progression-free survival (PFS), overall survival (OS), and toxicity. 5 responses in 25 response-evaluable patients were required to meet the primary endpoint (Simon two-stage minimax design: H~0~ 10% vs H~A~ 30% ORR). All patients who received at least one dose of cabozantinib were evaluable for toxicity.

      Results:
      26 patients with RET-rearranged lung adenocarcinomas were treated with cabozantinib. KIF5B-RET was the predominant fusion type identified in 16 (62%) patients. The median number of prior chemotherapy lines was 1 (0-5). One patient who discontinued therapy in cycle 1 and did not undergo a response assessment was not response-evaluable as per protocol. The study met its primary endpoint with confirmed partial responses observed in 7 (ORR 28% [95% CI 12-49%]) of 25 response-evaluable patients. The median PFS was 5.5 months (95% CI 3.8-8.4). The median OS was 9.9 months (95% CI 8.1-not reached). Response by RET fusion partner: Unknown (FISH+) 2/6 (33%), KIF5B 3/15 (20%), CLIP1 1/1, TRIM33 1/1, CCDC6 0/1, ERC1 0/1. In 26 patients evaluable for toxicity, the most common all-grade treatment-related adverse events were increased alanine aminotransferase in 25 (96%) patients, increased aspartate aminotransferase in 19 (73%) patients, hypothyroidism in 18 (69%) patients, diarrhea in 16 (62%) patients, and palmar plantar erythrodysesthesia in 15 (58%) patients. Nineteen (73%) patients required dose reduction.

      Conclusion:
      This study met its primary endpoint. Cabozantinib is an active agent in patients with RET-rearranged lung cancers. An improved understanding of tumor biology and novel therapeutic approaches will be required to improve outcomes with RET-directed therapy.

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