OA12.02 Updated Antitumor Activity of Crizotinib in Patients with MET Exon 14-Altered Advanced Non-Small Cell Lung Cancer
Alexander DrilonJeffrey W. ClarkJared WeissSai‐Hong Ignatius OuD. Ross CamidgeBenjamin SolomonGregory A. OttersonLiza C. VillaruzGregory J. RielyRebecca S. HeistGeoffrey I. ShapiroDanielle MurphyS. WangTiziana UsariS. LiKeith D. WilnerPaul K. Paik
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Abstract 957: The ALK inhibitor LDK378 overcomes crizotinib resistance in non-small cell lung cancer
Abstract Non-small cell lung cancers (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangements are sensitive to the ALK tyrosine kinase inhibitor (TKI) crizotinib. However, these cancers invariably relapse due to the development of resistance, and approximately 1/3 of such cancers develop resistance mutations within the ALK tyrosine kinase domain. Here we report the preclinical evaluation of the next-generation ALK TKI, LDK378 in the setting of crizotinib resistance. Using EML4-ALK mutant Ba/F3 cellular models, in vivo models of acquired resistance to crizotinib, and novel cell lines established from biopsies of crizotinib-resistant NSCLC patients, we have examined the efficacy of LDK378 in crizotinib-naïve and -resistant ALK-positive cancers. These studies reveal that LDK378 is more potent than crizotinib and effectively overcomes resistance in vitro and in vivo. In particular, LDK378 inhibits ALK harboring crizotinib resistance mutations, including L1196M, G1269A, I1171T and S1206Y. Cell lines derived from crizotinib-resistant biopsies were sensitive to LDK378, including one that did not harbor an ALK resistance mutation and was also sensitive to crizotinib, suggesting that some crizotinib-resistant cancers with wildtype ALK are still sensitive to complete ALK inhibition. We observed that LDK378 did not effectively overcome two crizotinib-resistant ALK mutations, G1202R and F1174C ALK, and mutations in one of these residues was identified in 5 out of 11 biopsies from patients with acquired resistance to LDK378. Altogether our results demonstrate that LDK378 can overcome many mechanisms of crizotinib resistance, consistent with emerging clinical data showing marked efficacy of LDK378 in patients with crizotinib-resistant disease. Citation Format: Luc Friboulet, Nanxin Li, Ryohei Katayama, Christian C. Lee, Justin F. Gainor, Adam S. Crystal, Pierre-Yves Michellys, Mark M. Awad, Noriko Yanagitani, Sungjoon Kim, AnneMarie Pferdekamper, Jie Li, Shailaja Kasibhatla, Frank Sun, Xiuying Sun, Su Hua, Peter McNamara, Sidra Mahmood, Elizabeth L. Lockerman, Naoya Fujita, Makoto Nishio, Jennifer L. Harris, Alice T. Shaw, Jeffrey A. Engelman. The ALK inhibitor LDK378 overcomes crizotinib resistance in non-small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 957. doi:10.1158/1538-7445.AM2014-957
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9034 Background: Systemic treatment benefit in cancer is usually evaluated using Response Evaluation Criteria in Solid Tumors (RECIST). TGR integrates the time intervals between CT-scan allowing a quantitative assessment of the dynamics and kinetics of the tumor. In NSCLC patients treated with immune checkpoints inhibitors (IC), TGR variations after the introduction of IC, and its association with outcome, remain unknown. We compared the accuracy of TGR and RECIST to assess the benefit of IC in advanced NSCLC patients. Methods: We performed a retrospective case note and radiological review of all NSCLC patients treated by IC in our center between February 2013 and October 2015. Tumor response was assessed every 6-8 weeks according to RECIST 1.1 and irRC. The TGR was computed for the pre IC period (reference) and during the IC period (treatment). TGR was classified as < 0 if TGR during IC was inferior to TGR before IC. We studied the relationship between the TGR of the 2 periods, TGR variations, RECIST tumor response and how these outcomes correlated with PFS and OS. Results: Fifty eight patients had appropriate data for further analysis. Median age was 64 years, 58% were male, 79% ex/current smokers, 51% had adenocarcinoma and 40% squamous cell carcinoma. Median follow-up was 8 months. Average reference TGR was not different according to age, sex, histology, stage and was not related to OS. Treatment TGR was significantly related to OS (p < 10-4). None of 15 patients with a treatment TGR < 0 died during the first 12 months of follow-up, while 31/43 patients with a treatment TGR ≥ 0 died during this period (Logrank test p-value < 0.0001). Prediction of survival was significantly better with TGR than RECIST: among the 21 patients classified as stable disease according to RECIST, treatment TGR < 0 was significantly associated with better survival (p = 0.02). Conclusions: Exploring TGR in patients with advanced NSCLC treated with IC provides clinically relevant information and an improved characterization of drug activity than that offered by RECIST alone. Analysis will be extended to 115 patients at final presentation.
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e19069 Background: Early determination of therapeutic failure can potentially spare a pt ineffective and toxic treatment. We previously reported in a retrospective study the use of CT within 4 weeks of initiation of chemotherapy in advanced NSCLC to assess response and progression by RECIST (Bruzzi et al. JTO 2006). Here, we prospectively assess whether CT imaging after the first cycle of pemetrexed in advanced NSCLC has a role in evaluating response and management. Methods: We accrued pts with PS 2 or 3 advanced NSCLC receiving at least one dose of 1 st or 2 nd line pemetrexed. A repeat CT prior to a 2nd course was required. Pts with progression by RECIST were to come off study. CT scans were done using multislice CT technology (GE Lightspeed Plus), and images were reconstructed with slice thicknesses of 3.75mm or less. All images were reviewed using a PACs workstation (Stentor iSite) and measurements were done with electronic calipers. RECIST criteria: progression, an increase in the tumor's longest dimension by 20%, response, a decrease by 30%. Results: Thirty pts had a median age of 68 years (45 - 81). PS 2/3, 1 st /2 nd line, and F/M were 16/14, 17/13, and 12/18 respectively. Pts received 1–8 cycles (median 2). Twelve pts received only 1 course of whom 7 pts had f/u CTs at a median of 20 days (12–25) after 1 st chemo dose. Of these pts, 5/7 had progression by RECIST and the other 2/7 pts had stable disease with 1 pt who came off due to serial PEs and 1 pt who opted off for reasons of travel. Two of the 5 pts who had progression by CT had no detectable change by CXR. Of 5/12 pts treated with only 1 course without f/u CT, 2 pts died, 2 pts had progression by CXR, and 1 pt stopped after treatment for pneumonia. All 18 pts receiving ≥2 cycles had a repeat CT prior to their 2 nd course. Conclusions: The results of this prospective trial support earlier retrospective findings that short-term follow-up using CT in pts with advanced NSCLC can detect tumor progression and impact patient management. We will also present f/u CTs in pts who received ≥ 1course to determine whether early signs of progression predict later RECIST determined progression. [Table: see text]
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The treatment of advanced non-small cell lung cancer (NSCLC) has dramatically changed over the last decade. It has developed from an unspecific approach based on platinum doublet chemotherapy to a personalized, molecularly targeted therapy. Crizotinib is a new tyrosine kinase inhibitor approved for the treatment of NSCLC with gene rearrangement of EML4 and ALK. Despite good initial responses, patients treated with crizotinib relapse after an average of 10 months. In this case report, we present a patient with acquired crizotinib resistance whose adenocarcinoma responded to a second course of crizotinib following a drug holiday and chemotherapy with pemetrexed. This is the second case report to suggest that retreatment with crizotinib is an option for patients with initial benefit from ALK inhibition.
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Although single-agent second-line chemotherapy has limited efficacy in unselected non-small cell lung cancer (NSCLC), its effect in advanced anaplastic Kinase positive (ALK+) NSCLC is uncertain. Crizotinib has marked clinical activity in ALK+ NSCLC [Camidge DR et al. Lancet Oncol 2012; Kim DW et al. ASCO 2012. Abstract 7533]. The PROFILE 1007 [NCT00932893] trial compared the efficacy and safety of crizotinib with standard chemotherapy as second-line therapy in patients with advanced ALK+ NSCLC.
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