Larotrectinib efficacy and safety in TRK fusion cancer: An expanded clinical dataset showing consistency in an age and tumor agnostic approach

Lassen, Ulrik; Albert, Catherine M.; Kummar, Shivaani; Tilburg, Cornelis M. van; Dubois, S.G.; Geoerger, Birgit; Mascarenhas, Leo; Federman, Noah; Schilder, Russell J.; Doz, François; Berlin, Jordan; Oh, Do‐Youn; Bielack, Stefan; McDermott, Ray; Tan, Daniel Shao-Weng; Cruickshank, Scott; Ku, N.C.; Cox, Michael C.; Drilon, Alexander; Hong, David S.

doi:10.1093/annonc/mdy279.397

Cited by 39 publications

(57 citation statements)

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“…Basket trials of larotrectinib in TRK fusion-positive cancers and pembrolizumab in MMRdeficient cancers are characterized by high response rates (Drilon et al, 2018;Lassen et al, 2018;Le et al, 2017). By permutation testing, no subgroup was identified in either trial that was significantly less drug-responsive than the average of all tumors.…”

Section: Discussionmentioning

confidence: 99%

“…In the case of the SUMMIT trial permutation testing was separately applied to reported tumor volume changes and to durations of PFS; in the case of the larotrectinib and pembrolizumab trials (Drilon et al, 2018;Lassen et al, 2018;Le et al, 2017) it was applied only to tumor volume changes (PFS outcomes by tumor type are not available). For imatinib, permutation tests were applied to objective response rates (Heinrich et al, 2008).…”

Section: Methodsmentioning

confidence: 99%

“…Basket trials of the immune checkpoint inhibitor pembrolizumab (Le et al, 2017) and kinase inhibitor larotrectinib (Drilon et al, 2018;Lassen et al, 2018) contrast with trials of neratinib and imatinib because response rates are much higher: both drugs were found to be effective in multiple types of tumors positive for a specific genetic biomarker. In a basket trial of 86 patients and 12 tumor types, tumors with mismatch repair (MMR)-deficiency were found to be highly responsive to PD-1 blockade by pembrolizumab regardless of tissue of origin (Le et al, 2017).…”

Section: Permutation Testing Provides Statistical Support For Tumor-amentioning

confidence: 99%

“…In a basket trial of 86 patients and 12 tumor types, tumors with mismatch repair (MMR)-deficiency were found to be highly responsive to PD-1 blockade by pembrolizumab regardless of tissue of origin (Le et al, 2017). Similarly, high rates of larotrectinib response were observed among 122 patients having 15 different types of tumors expressing TRK fusion proteins (Drilon et al, 2018;Lassen et al, 2018). When data from each of these trials were compared to a no difference null (testing in for both superiority and inferiority), no significant differences were observed for any tumor type represented by three or more patients (this corresponded to eight tumor types for larotrectinib and seven types for pembrolizumab).…”

Section: Permutation Testing Provides Statistical Support For Tumor-amentioning

confidence: 99%

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Comparing the efficacy of cancer therapies between subgroups in basket trials

Palmer

Plana

Sorger

2018

Preprint

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An increase in the number of targeted anti-cancer drugs and growing genomic stratification of patients has led to the development of basket clinical trials in which a single drug is tested simultaneously in multiple tumor subtypes under a master protocol. Basket trials typically involve few patients per type, making it difficult to rigorously compare responses across types. We describe the use of permutation testing to analyze tumor volume changes and Progression Free Survival across subtypes in basket trials for neratinib, larotrectinib, pembrolizumab, and imatinib. Permutation testing is a complement to the standard Simon's two-stage binomial approach and can test for differences among subgroups using empirical null distributions while controlling for multiple hypothesis testing. This approach uncovers examples of therapeutic benefit missed by a binomial test; in the case of the SUMMIT trial, our analysis identifies an overlooked opportunity for use of neratinib in lung cancers carrying ERBB2 Exon 20 mutations.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Permutation Testing Provides Statistical Support For Tumor-amentioning

confidence: 99%

Section: Permutation Testing Provides Statistical Support For Tumor-amentioning

confidence: 99%

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Comparing the efficacy of cancer therapies between subgroups in basket trials

Palmer

Plana

Sorger

2018

Preprint

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“…Furthermore, within these molecular basket trials, control groups are absent, which influences outcome interpretation. Fortunately, additional data is generated in ongoing trials and the resulting data will have to be reevaluated.…”

Section: Evolving Topics In Clinical Variant Classificationmentioning

confidence: 99%

Variant classification in precision oncology

Leichsenring

Horak

Kreutzfeldt

et al. 2019

Intl Journal of Cancer

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Next-generation sequencing has become a cornerstone of therapy guidance in cancer precision medicine and an indispensable research tool in translational oncology. Its rapidly increasing use during the last decade has expanded the options for targeted tumor therapies, and molecular tumor boards have grown accordingly. However, with increasing detection of genetic alterations, their interpretation has become more complex and error-prone, potentially introducing biases and reducing benefits in clinical practice. To facilitate interdisciplinary discussions of genetic alterations for treatment stratification between pathologists, oncologists, bioinformaticians, genetic counselors and medical scientists in specialized molecular tumor boards, several systems for the classification of variants detected by large-scale sequencing have been proposed. We review three recent and commonly applied classifications and discuss their individual strengths and weaknesses. Comparison of the classifications underlines the need for a clinically useful and universally applicable variant reporting system, which will be instrumental for efficient decision making based on sequencing analysis in oncology. Integrating these data, we propose a generalizable classification concept featuring a conservative and a more progressive scheme, which can be readily applied in a clinical setting. What's new?With increasingly comprehensive molecular profiling of cancers, the clinical interpretation of genetic alterations is becoming more and more challenging. Here the authors review several classifications for gene variant interpretation that were recently introduced to guide clinical management. They highlight shared features and differences and point out major influencing factors and unresolved issues that still need to be addressed. Based on this analysis, they propose a unified classification concept that may become broadly implemented when remaining issues are solved.

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