Selpercatinib in Patients With RET Fusion–Positive Non–Small-Cell Lung Cancer: Updated Safety and Efficacy From the Registrational LIBRETTO-001 Phase I/II Trial

Selpercatinib; Lung cancer; SafetySelpercatinib; Cáncer de pulmón; SeguridadSelpercatinib; Càncer de pulmó; SeguretatPURPOSE Selpercatinib, a first-in-class, highly selective, and potent CNS-active RET kinase inhibitor, is currently approved for the treatment of patients with RET fusion–positive non–small-cell lung cancer (NSCLC). We provide a registrational data set update in more than double (n = 316) of the original reported population (n = 144) and better characterization of long-term efficacy and safety. METHODS Patients were enrolled to LIBRETTO-001, a phase I/II, single-arm, open-label study of selpercatinib in patients with RET-altered cancers. An analysis of patients with RET fusion–positive NSCLC, including 69 treatment-naive and 247 with prior platinum-based chemotherapy, was performed. The primary end point was objective response rate (ORR; RECIST v1.1, independent review committee). Secondary end points included duration of response (DoR), progression-free survival (PFS), overall survival, and safety. RESULTS In treatment-naive patients, the ORR was 84% (95% CI, 73 to 92); 6% achieved complete responses (CRs). The median DoR was 20.2 months (95% CI, 13.0 to could not be evaluated); 40% of responses were ongoing at the data cutoff (median follow-up of 20.3 months). The median PFS was 22.0 months; 35% of patients were alive and progression-free at the data cutoff (median follow-up of 21.9 months). In platinum-based chemotherapy pretreated patients, the ORR was 61% (95% CI, 55 to 67); 7% achieved CRs. The median DoR was 28.6 months (95% CI, 20.4 to could not be evaluated); 49% of responses were ongoing (median follow-up of 21.2 months). The median PFS was 24.9 months; 38% of patients were alive and progression-free (median follow-up of 24.7 months). Of 26 patients with measurable baseline CNS metastasis by the independent review committee, the intracranial ORR was 85% (95% CI, 65 to 96); 27% were CRs. In the full safety population (n = 796), the median treatment duration was 36.1 months. The safety profile of selpercatinib was consistent with previous reports. CONCLUSION In a large cohort with extended follow-up, selpercatinib continued to demonstrate durable and robust responses, including intracranial activity, in previously treated and treatment-naive patients with RET fusion–positive NSCLC.Supported by Loxo Oncology, a wholly owned subsidiary of Eli Lilly and Company. A.D. was supported in part by funding from the National Cancer Institute of the National Institutes of Health: 1R01CA251591- 01A1 and P30 CA008748. Partial support was likewise provided by LUNGevity

Early Circulating Tumor DNA Dynamics and Efficacy of Lorlatinib in Patients With Treatment-Naive, Advanced, ALK-Positive NSCLC

Introduction: Circulating tumor DNA (ctDNA) has been used as a biomarker for prognostication and response to treatment. Here, we evaluate ctDNA as a potential biomarker for response to lorlatinib, a third-generation ALK tyrosine kinase inhibitor in patients with treatment-naive, advanced, ALK-positive NSCLC in the ongoing phase 3 CROWN study (NCT03052608). Methods: Molecular responses were calculated using mean variant allele frequency (VAF), longitudinal mean change in VAF (dVAF), and ratio to baseline. Efficacy assessments (progression-free survival [PFS] and objective response rate) were paired with individual patient ctDNA and analyzed for association. Results: Compared with baseline, mean VAF at week 4 was decreased in both treatment arms. Considering all detected somatic variants, a reduction in dVAF (≤0) was associated with a longer PFS in the lorlatinib arm. The hazard ratio (HR) for a dVAF less than or equal to 0 versus more than 0 was 0.50 (95% confidence interval [CI]: 0.23–1.12) in the lorlatinib arm. A similar association was not observed for crizotinib (HR = 1.00, 95% CI: 0.49–2.03). Comparing molecular responders with nonresponders, patients treated with lorlatinib who had a molecular response had longer PFS (HR = 0.37, 95% CI: 0.16–0.85); patients treated with crizotinib who had a molecular response had similar PFS as those without a molecular response (HR = 1.48, 95% CI: 0.67–3.30). Conclusions: In patients with treatment-naive, advanced, ALK-positive NSCLC, early ctDNA dynamics predicted better outcome with lorlatinib but not with crizotinib. These results suggest that ctDNA may be used to monitor and potentially predict efficacy of lorlatinib treatment.</p

Early Circulating Tumor DNA Dynamics and Efficacy of Lorlatinib in Patients With Treatment-Naive, Advanced, ALK-Positive NSCLC

Introduction: Circulating tumor DNA (ctDNA) has been used as a biomarker for prognostication and response to treatment. Here, we evaluate ctDNA as a potential biomarker for response to lorlatinib, a third-generation ALK tyrosine kinase inhibitor in patients with treatment-naive, advanced, ALK-positive NSCLC in the ongoing phase 3 CROWN study (NCT03052608). Methods: Molecular responses were calculated using mean variant allele frequency (VAF), longitudinal mean change in VAF (dVAF), and ratio to baseline. Efficacy assessments (progression-free survival [PFS] and objective response rate) were paired with individual patient ctDNA and analyzed for association. Results: Compared with baseline, mean VAF at week 4 was decreased in both treatment arms. Considering all detected somatic variants, a reduction in dVAF (≤0) was associated with a longer PFS in the lorlatinib arm. The hazard ratio (HR) for a dVAF less than or equal to 0 versus more than 0 was 0.50 (95% confidence interval [CI]: 0.23–1.12) in the lorlatinib arm. A similar association was not observed for crizotinib (HR = 1.00, 95% CI: 0.49–2.03). Comparing molecular responders with nonresponders, patients treated with lorlatinib who had a molecular response had longer PFS (HR = 0.37, 95% CI: 0.16–0.85); patients treated with crizotinib who had a molecular response had similar PFS as those without a molecular response (HR = 1.48, 95% CI: 0.67–3.30). Conclusions: In patients with treatment-naive, advanced, ALK-positive NSCLC, early ctDNA dynamics predicted better outcome with lorlatinib but not with crizotinib. These results suggest that ctDNA may be used to monitor and potentially predict efficacy of lorlatinib treatment.</p

Early Circulating Tumor DNA Dynamics and Efficacy of Lorlatinib in Patients With Treatment-Naive, Advanced, ALK-Positive NSCLC

Introduction: Circulating tumor DNA (ctDNA) has been used as a biomarker for prognostication and response to treatment. Here, we evaluate ctDNA as a potential biomarker for response to lorlatinib, a third-generation ALK tyrosine kinase inhibitor in patients with treatment-naive, advanced, ALK-positive NSCLC in the ongoing phase 3 CROWN study (NCT03052608). Methods: Molecular responses were calculated using mean variant allele frequency (VAF), longitudinal mean change in VAF (dVAF), and ratio to baseline. Efficacy assessments (progression-free survival [PFS] and objective response rate) were paired with individual patient ctDNA and analyzed for association. Results: Compared with baseline, mean VAF at week 4 was decreased in both treatment arms. Considering all detected somatic variants, a reduction in dVAF (≤0) was associated with a longer PFS in the lorlatinib arm. The hazard ratio (HR) for a dVAF less than or equal to 0 versus more than 0 was 0.50 (95% confidence interval [CI]: 0.23–1.12) in the lorlatinib arm. A similar association was not observed for crizotinib (HR = 1.00, 95% CI: 0.49–2.03). Comparing molecular responders with nonresponders, patients treated with lorlatinib who had a molecular response had longer PFS (HR = 0.37, 95% CI: 0.16–0.85); patients treated with crizotinib who had a molecular response had similar PFS as those without a molecular response (HR = 1.48, 95% CI: 0.67–3.30). Conclusions: In patients with treatment-naive, advanced, ALK-positive NSCLC, early ctDNA dynamics predicted better outcome with lorlatinib but not with crizotinib. These results suggest that ctDNA may be used to monitor and potentially predict efficacy of lorlatinib treatment.</p

Minimal information for studies of extracellular vesicles 2018 (MISEV2018):a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines

The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points

Genomic profile of brain metastases from lung adenocarcinomas

Le cancer bronchique est la première cause de mortalité par cancer, notamment parce qu’il est le plus grand pourvoyeur de métastases cérébrales (MC). Une meilleure connaissance de la biologie des cancers bronchiques non à petites cellules (CBNPC) a amélioré le pronostic des patients. Cependant, l’efficacité cérébrale des traitements est variable. Ce travail avait pour objectif une meilleure connaissance de la biologie des MC de CBNPC et de l’hétérogénéité génomique entre la MC et les autres sites tumoraux pour guider la prise en charge thérapeutique des malades.Nous avons montré que l’efficacité intracérébrale de l’immunothérapie était variable et que l’incidence et l’évolution des MC étaient associées au profil mutationnel. Nous avons ensuite comparé le séquençage pan-exomique de paires d’échantillons de tumeurs pulmonaires (TP) et MC de patients atteints de CBNPC et identifié 13 gènes spécifiques des MC.Nous avons ensuite constitué une cohorte prospective de patients atteints de CBNPC avec MC opérées. Dans ces MC, nous avons trouvé un nombre de mutations très élevé, dont 2 mutations des 13 gènes. De plus, l’ADNtc dans le LCR était représentatif des mutations des MC. Ces travaux soulignent l’importance de l’hétérogénéité tumorale entre les MC, les TP et l’ADNtc. Il est difficile d’établir une signature spécifique des MC, notamment du fait du faible nombre d’échantillons disponibles et de la difficulté d’obtenir des paires TP/MC mais l’étude de l’ADNtc dans le LCR peut être une piste. Nous allons ensuite étudier le microenvironnement cérébral et utiliser d’autres approches comme la modélisation mathématique pour une meilleure compréhension de la biologie des MC.Lung cancer is the leading cause of cancer-related deaths, partly because it is the first cause of brain metastases (BM). A better knowledge of non-small cell lung cancer (NSCLC) molecular biology and the development of targeted therapies have improved patients’ outcomes. However, the intracranial efficacy of these new treatments is inconstant. The objective of this work was a better knowledge of BM biology in lung adenocarcinoma and a better knowledge of genomic heterogeneity between BM and PT to guide patients’ treatment strategy.We showed that intracranial efficacy of immunotherapy was inconstant and that BM incidence and recurrence after local treatment was associated with mutation profile. We then compared whole exome sequencing of paired frozen samples from PT and BM of patients with NSCLC and identified 13 genes with recurrent mutations in BM never mutated in PT samples. We then analyzed a prospective cohort of patients with CBNPC and resected BM. In these BM, the number of mutations was high, including 2 genes among the 13 genes identified. Moreover, CSF ctDNA was representative of BM mutation status.This work highlights the importance of tumor heterogeneity between BM, PT and ctDNA. Whereas it is difficult to establish a specific signature of BM because of the poor number of samples available and the difficulty to have paired PT/BM samples for each patient, CSF ctDNA study may be a way to assess BM biology. We plan to study brain microenvironment and use new approaches such as mathematical modeling for a better understanding of BM biology

The Value of Population Screening in Advancing Personalized Medicine in the Field of Lung Cancer

International audienceDuring the past decade, progress has been made in the field of lung cancer molecular biology and onco-immunology, leading to prolonged survival of patients. The combination of increased fundamental knowledge and the pharmaceutical pipeline has allowed the development of various tyrosine kinase inhibitors, targeting numerous molecular alterations. These drugs are now available in daily practice and have transformed survival outcomes for patients harboring EGFR, ALK or ROS1 alterations. Multiple clinical trials are now ongoing in order to increase the number of approved drugs, thus overcoming the issues of rare mutations and tyrosine kinase inhibitors resistance. Immune checkpoint inhibitors development has also changed lung cancer outcomes, but underwhelming response rates highlight the need for immune biomarkers. While PD-L1 expression was the first approved immune biomarker, it has shown several limitations and new biomarkers have to be identified to predict response or resistance to immune checkpoint inhibitors. Testing methods, molecular results and targeted therapeutic schedules will be harmonized in the coming years, with the help of dedicated molecular multidisciplinary boards

Atezolizumab: feasible second-line therapy for patients with non-small cell lung cancer? A review of efficacy, safety and place in therapy

Advanced non-small cell lung cancer (NSCLC) prognosis is still poor and has recently been reformed by the development of immune checkpoint inhibitors and the approval of anti-PD-1 (programmed cell-death 1) treatments such as nivolumab and pembrolizumab in second line. More recently, atezolizumab (MDPL 3280A), a programmed cell-death-ligand 1 (PD-L1) inhibitor, was also studied in this setting. Here, we report a review of the literature assessing the efficacy, safety, and place of atezolizumab in the second-line treatment of advanced NSCLC. We performed a literature search of PubMed, American Society of Clinical Oncology, European Society of Medical Oncology and World Conference on Lung Cancer meetings. Atezolizumab showed a good tolerance profile and efficacy in comparison with docetaxel for second-line treatment of advanced NSCLC. Potential predictive biomarkers also have to be assessed