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Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. LIBRETTO-001 is a registrational phase I/II, single-arm, open-label study of selpercatinib in patients with RET (REarranged during Transfection)-activated cancers (ClinicalTrials.gov identifier: NCT03157128). We present long-term safety and efficacy from LIBRETTO-001 in patients with RET -mutant medullary thyroid cancer (MTC; n = 324) and RET fusion-positive thyroid cancer encompassing different histological subtypes (TC; n = 66). At the data cutoff of January 2023, the objective response rate was 82.5% among patients with cabozantinib/vandetanib-naïve MTC and 95.8% among patients with treatment-naïve TC. At a median follow-up time of 42.4 and 44.0 months in patients with cabozantinib/vandetanib-naïve and pretreated MTC, the median progression-free survival (PFS) was not reached and 41.4 months, respectively. At a median follow-up time of 24.9 and 30.4 months in patients with treatment-naïve and pretreated TC, the median PFS was not reached and 27.4 months, respectively. Three-year PFS rates were 75.2% and 87.3% among patients with cabozantinib/vandetanib-naïve MTC and treatment-naïve TC, respectively. Median PFS was similar to median duration of response for each patient group. The safety profile of selpercatinib was consistent with previous reports. With an additional follow-up of 37 months and 228 more patients from the last disclosure, selpercatinib continued to provide durable and robust responses in treatment-naïve and previously treated patients with RET -mutant MTC and RET fusion-positive TC.

Purpose: Third-generation epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitors (TKIs) are effective in acquired resistance (AR) to early-generation EGFR TKIs in EGFR-mutant lung cancer. However, efficacy is marked by interindividual heterogeneity. We present the molecular profiles of pretreatment and post-treatment samples from patients treated with third-generation EGFR TKIs and their impact on treatment outcomes., Methods: Using the databases of two lung cancer networks and two lung cancer centers, we molecularly characterized 124 patients with EGFR p.T790M-positive AR to early-generation EGFR TKIs. In 56 patients, correlative analyses of third-generation EGFR TKI treatment outcomes and molecular characteristics were feasible. In addition, matched post-treatment biopsy samples were collected for 29 patients with progression to third-generation EGFR TKIs., Results: Co-occurring genetic aberrations were found in 74.4% of EGFR p.T790-positive samples (n = 124). Mutations in TP53 were the most frequent aberrations detected (44.5%; n = 53) and had no significant impact on third-generation EGFR TKI treatment. Mesenchymal-epithelial transition factor ( MET ) amplifications were found in 5% of samples (n = 6) and reduced efficacy of third-generation EGFR TKIs significantly (eg, median progression-free survival, 1.0 months; 95% CI, 0.37 to 1.72 v 8.2 months; 95% CI, 1.69 to 14.77 months; P ≤ .001). Genetic changes in the 29 samples with AR to third-generation EGFR TKIs were found in EGFR (eg, p.T790M loss, acquisition of p.C797S or p.G724S) or in other genes (eg, MET amplification, KRAS mutations)., Conclusion: Additional genetic aberrations are frequent in EGFR-mutant lung cancer and may mediate innate and AR to third-generation EGFR TKIs. MET amplification was strongly associated with primary treatment failure and was a common mechanism of AR to third-generation EGFR TKIs. Thus, combining EGFR inhibitors with TKIs targeting common mechanisms of resistance may delay AR., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Sebastian MichelsHonoraria: Novartis, Pfizer, AstraZeneca, Boehringer Ingelheim, Roche Pharma AG Consulting or Advisory Role: Boehringer Ingelheim, Pfizer, Roche Pharma AG Research Funding: Pfizer (Inst), Novartis (Inst), Bristol-Myers Squibb (Inst) Travel, Accommodations, Expenses: NovartisCarina HeydtHonoraria: AstraZeneca, IlluminaNuria PardoOther Relationship: PfizerKim MonkhorstConsulting or Advisory Role: Pfizer, Roche Molecular Diagnostics, MSD, AstraZeneca, AbbVie, Bristol-Myers Squibb Speakers' Bureau: Quadia Research Funding: AstraZeneca, Roche Molecular Diagnostics, Personal Genome Diagnostics Travel, Accommodations, Expenses: Takeda, Pfizer, RocheVanessa RüsselerTravel, Accommodations, Expenses: Ventana Medical SystemsJan StratmannHonoraria: Bristol-Myers Squibb Travel, Accommodations, Expenses: NovartisFrank GriesingerHonoraria: Genentech, Boehringer Ingelheim, Pfizer, AbbVie, MSD, Bristol-Myers Squibb, Ipsen, Novartis Consulting or Advisory Role: AstraZeneca, Genentech, Pfizer, Boehringer Ingelheim, MSD, Bristol-Myers Squibb, Celgene, Takeda, AbbVie, Novartis, Bayer Research Funding: AstraZeneca (Inst), Boehringer Ingelheim (Inst), Bristol-Myers Squibb (Inst), MSD (Inst), Celgene (Inst), Eli Lilly (Inst), Novartis (Inst), Pfizer (Inst), Roche (Inst), Takeda (Inst)Jana FassunkeHonoraria: AstraZenecaRieke FischerHonoraria: Bristol-Myers Squibb, Roche, MSD Research Funding: Bristol-Myers Squibb (Inst), MSD (Inst) Travel, Accommodations, Expenses: MediolanumOliver GautschiOther Relationship: AstraZeneca, PfizerEva GeissingerHonoraria: MSD Sharp & Dohme Consulting or Advisory Role: NovartisHans-Georg KoppHonoraria: MSD Oncology, Boehringer Ingelheim, LEO Pharma, PharmaMar, Roche, Pfizer, Chugai Pharma, Takeda Consulting or Advisory Role: MSD Oncology, Bristol-Myers Squibb, Sanofi, Roche, AstraZeneca Travel, Accommodations, Expenses: Sanofi, Eli Lilly, Amgen, Novartis, PharmaMar, Boehringer Ingelheim, MSD Oncology, Bristol-Myers SquibbAdrianus J. de LangenConsulting or Advisory Role: AstraZeneca (Inst), Bristol-Myers Squibb (Inst), MSD Oncology (Inst), Roche (Inst), Boehringer Ingelheim (Inst), Pfizer (Inst) Research Funding: AstraZeneca (Inst), Bristol-Myers Squibb (Inst), Merck Serono (Inst), MSD Oncology (Inst), Roche (Inst)Alex Martinez-MartiHonoraria: Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, Boehringer Ingelheim Consulting or Advisory Role: Bristol-Myers Squibb, F. Hoffmann-La Roche, Merck Sharp & Dohme, Pfizer, Boehringer Ingelheim Speakers' Bureau: F. Hoffmann-La Roche, Bristol-Myers Squibb, Boehringer Ingelheim Research Funding: Merck Serono Travel, Accommodations, Expenses: Bristol-Myers Squibb, F. Hoffmann-La Roche, MSD Oncology, Boehringer IngelheimLucia NogovaHonoraria: Pfizer, Celgene, Novartis, Roche, Boehringer Ingelheim, Janssen, Bristol-Myers Squibb Consulting or Advisory Role: Novartis, Boehringer Ingelheim, Bristol-Myers Squibb, Roche, Janssen, Pfizer Research Funding: Pfizer, (Inst), Bristol-Myers Squibb (Inst), Novartis (Inst), MSD (Inst), Janssen (Inst) Travel, Accommodations, Expenses: Novartis, Pfizer, Celgene, Boehringer IngelheimDennis PlenkerStock and Other Ownership Interests: Roche, Foundation Medicine Patents, Royalties, Other Intellectual Property: A patent of NRG1 fusions has been filedMichael PueskenConsulting or Advisory Role: MSD Travel, Accommodations, Expenses: ShireErnst RodermannConsulting or Advisory Role: Amgen, CelgeneAndreas H. ScheelHonoraria: MSD, Bristol-Myers Squibb, Roche, Dako/Agilent Technologies Consulting or Advisory Role: MSD, Bristol-Myers Squibb, Roche, Dako/Agilent TechnologiesMatthias SchefflerHonoraria: Healthcare Consulting Cologne, Boehringer Ingelheim, Takeda Consulting or Advisory Role: Boehringer Ingelheim, Takeda Travel, Accommodations, Expenses: Boehringer IngelheimRuth Seggewiss-BernhardtHonoraria: Novartis, Celgene, Roche, Bristol-Myers Squibb, Ipsen, Pfizer, AstraZeneca Consulting or Advisory Role: MSD, Pfizer Travel, Accommodations, Expenses: Astellas Pharma, Celgene, IpsenMartin SebastianHonoraria: AstraZeneca, Novartis, Pfizer/EMD Serono, MSD, Takeda, Bristol-Myers Squibb, Eli Lilly, Genentech, Boehringer Ingelheim, AbbVie Consulting or Advisory Role: Genentech, MSD, AstraZeneca, AbbVie, Takeda, Eli Lilly, Boehringer Ingelheim, Novartis, Bristol-Myers Squibb, Pfizer, Celgene Travel, Accommodations, Expenses: Pfizer, TakedaMartin L. SosResearch Funding: Novartis, NovartisLukas C. HeukampEmployment: NEO New Oncology, Hämatopathologie Hamburg Honoraria: Roche Pharma, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim Consulting or Advisory Role: Roche Pharma, Bristol-Myers Squibb, NovartisEnriqueta FelipConsulting or Advisory Role: Pfizer, Roche, Boehringer Ingelheim, AstraZeneca, Bristol-Myers Squibb, Celgene, Guardant Health, Novartis, Takeda, AbbVie, Blueprint Medicines, Eli Lilly, Merck KGaA, Merck Sharp & Dohme Speakers' Bureau: AstraZeneca, Bristol-Myers Squibb, Novartis, Boehringer Ingelheim, Merck Sharp & Dohme, Roche, Pfizer, AbbVie, Eli Lilly, Merck KGaA, Takeda Research Funding: Fundación Merck Salud (Inst), EMD Serono (Inst)Sabine Merkelbach-BruseHonoraria: AstraZeneca, Bristol-Myers Squibb, Novartis, Pfizer, Roche Pharma Consulting or Advisory Role: Bristol-Myers Squibb, Novartis, PfizerEgbert F. SmitConsulting or Advisory Role: Eli Lilly, AstraZeneca (Inst), Boehringer Ingelheim (Inst), Genentech (Inst), Bristol-Myers Squibb (Inst), Merck KGaA (Inst), MSD Oncology (Inst), Takeda (Inst), Bayer (Inst) Research Funding: Boehringer Ingelheim (Inst), Bayer (Inst), Genentech (Inst), AstraZeneca (Inst), Bristol-Myers Squibb (Inst)Reinhard BüttnerStock and Other Ownership Interests: Co-founder and CSO for Targos Mol. Pathol. (Kassel/Germany) and TAMP (Atlanta, GA) Honoraria: AstraZeneca, AbbVie, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Merck Serono, MSD, Novartis, Qiagen, Pfizer, Roche Research Funding: Roche (Inst)Juergen WolfHonoraria: AbbVie, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, MSD, Novartis, Roche Consulting or Advisory Role: AbbVie, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Chugai Pharma, Ignyta, Eli Lilly, MSD Oncology, Novartis, Pfizer, Roche Research Funding: Bristol-Myers Squibb, Novartis, Pfizer No other potential conflicts of interest were reported., (© 2019 by American Society of Clinical Oncology.)