National Cancer Centre, Singapore, Singapore
Daniel Shao-Weng Tan , Dong-Wan Kim , Michael Thomas , Serafino Pantano , Ying Wang , Sebastian Lukasz Szpakowski , Alejandro Javier Yovine , Ranee Mehra , Laura Q. Chow , Sunil Sharma , Benjamin J. Solomon , Enriqueta Felip , D. Ross Camidge , Johan F. Vansteenkiste , Hans Bitter , Lilli M. Petruzzelli , Margaret Han Dugan , Alice T. Shaw
Background: To better understand genetic determinants of response to ceritinib, tumor biopsies from NSCLC pts treated with ceritinib in ASCEND-1 (NCT01283516) were analyzed by next-generation sequencing (NGS). Methods: Biopsies were assayed by NGS using a Foundation Medicine panel targeting 295 genes. Somatic alterations were correlated with clinical outcome (cut-off 14 Apr 2014). Results: NGS data were generated for 85 pts (ALK inhibitor [ALKi]-pretreated [n=54]; ALKi-naïve [n=31]). Baseline (BL) biopsy collection times differed among pts. The most frequent ALK rearrangements detected were EML4-ALK variant 1 (26/85) and variant 3 (23/85); 6 pts did not carry an EML4-ALK fusion but had an ALK rearrangement with another gene (HIP1 [n=2]; CLTC, CRIM1, STRN and TFG [n=1 each]). Comprehensive analysis correlating genetic landscape with ceritinib efficacy will be presented, including for 2 pts with ceritinib BL and post-progression biopsies. Of 28 pts with biopsies collected during or after prior ALKi treatment (Tx), 10 harbored an ALK tyrosine kinase domain mutation. Among these 10 pts, 8 had BL biopsies collected after (or less than 7 days before) the last day of prior ALKi Tx. All but one of these 8 pts benefited from ceritinib Tx (Table 1). One pt ALKi-naïve had a MET amplification in a ceritinib post-progression biopsy (among other somatic mutations) but not in BL biopsy. Conclusions: This analysis increases our knowledge of the mechanisms of resistance to ALK inhibition and their impact on ceritinib Tx, including the potential role of MET amplification. It also illustrates that ceritinib is active against almost all ALK resistance mutations found in ALKi-pretreated pts.
Pt | ALK mutation(s) | BOR | PFS, days |
---|---|---|---|
1 | E1129V | PR | 337 |
2 | L1196M | PR | 267 |
3 | I1171T, F1174V | PR | 250 |
4b | C1156Y | SD | 246+ |
5 | L1196M | PR | 213 |
6c | C1156Y | PR | 174 |
7 | L1196M | PR | 163 |
8 | G1202R | Unknown | 26 |
aEfficacy per blinded independent review committee. bBiopsy 5 days before end of crizotinib Tx; + pt ongoing without event cBiopsy on last day of crizotinib Tx. BOR, best overall response; PFS, progression-free survival; PR, partial response; SD, stable disease.
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