PL02.11 Overall Survival with Durvalumab Plus Etoposide-Platinum in First-Line Extensive-Stage SCLC: Results from the CASPIAN Study

Abstract

Background: No targeted therapy is currently approved for patients with RET fusion-positive non-small cell lung cancer (NSCLC). LOXO-292 is a highly selective RET inhibitor with activity against diverse RET fusions, activating RET mutations and brain metastases. Based on initial data from LIBRETTO-001, LOXO-292 received FDA Breakthrough Designation for the treatment of RET fusion-positive NSCLC in August 2018. Method: This global phase 1/2 study (87 sites, 15 countries) enrolled patients with advanced RET-altered solid tumors including RET fusion-positive NSCLC (NCT03157128). LOXO-292 was dosed orally in 28-day cycles. The phase 1 portion established the MTD/RP2D (160 mg BID). The phase 2 portion enrolled patients to one of six cohorts based on tumor type, RET alteration, and prior therapies. The primary endpoint was ORR (RECIST 1.1). Secondary endpoints included DoR, CNS ORR, CNS DoR, PFS, OS, safety and PK. Result: As of 17-June 2019, 247 RET fusion-positive NSCLC patients were treated. The primary analysis set (PAS) for LOXO-292 registration, as defined with the US FDA, consists of the first 105 consecutively enrolled RET fusion-positive NSCLC patients who received prior platinum-based chemotherapy; 54 patients (51%) also received prior immune checkpoint inhibitors (ICIs). The majority of PAS responders have been followed for !6 months from first response. Of the remaining 142 patients, 74 previously treated with platinum-based chemotherapy have not had sufficient follow-up, 56 did not receive prior platinum-based chemotherapy and 12 did not have measurable disease at baseline. Among PAS patients, the investigator-assessed ORR was 70% (95% CI 60-78%, n¼73/105, 3 PRs pending confirmation). Responses did not differ by fusion partner or the type or number of prior therapies, including chemotherapy, ICIs and multikinase inhibitors with anti-RET activity. The median DoR was 20.3 months (95% CI 16.6-NR) with a median follow-up of 7.5 months (range 1.9-21.1 months); as evidenced by the wide confidence interval, this DoR estimate is not statistically stable due to a low number of events (12 of 70 confirmed responders). The intracranial ORR was 90% (n¼9/10: 2 confirmed CRs, 7 confirmed PRs) for patients with measurable brain metastases at baseline. The ORR in evaluable treatment naïve RET fusion-positive NSCLC patients was 88% (95% CI 72-97%, n¼29/33, 10 PRs pending confirmation). In the safety data set of all 247 patients, 5 treatment-related AEs occurred in !15% of patients: dry mouth, AST increased, diarrhea, ALT increased, and hypertension. Most AEs were grade 1-2. Only 3 of 247 (1.2%) NSCLC patients discontinued LOXO-292 for treatment-related AEs. Updated data will be presented at the meeting. Conclusion: LOXO-292 had marked antitumor activity in RET fusion-positive NSCLC patients and was well tolerated. These data will form the basis of an FDA NDA submission later this year.

Anti-SOX1 Antibodies in Paraneoplastic Neurological Syndrome

“…The median survival time from the diagnosis of SCLC was shorter than 1 year, and the overall survival rate at 5 years was less than 10% due to its early metastasis. 76 The current study identified only one patient with squamous-cell lung cancer with a clinical outcome, and he fully recovered from PLE after 15 days of treatment without further follow-up. 17 In general, PNS in association with anti-SOX1 abs remains a therapeutic challenge, with the main beneficial interventions being stabilization of the neurological deficits, while symptomatic amelioration was only observed in subsets of patients.…”

In This Issue/Research Watch/News-in-Brief/News from 002the IASLC Tobacco Control Committee

“…For pediatric patients 12 years or older with NTRK gene fusion-positive solid tumors, the prescribing information provides dosage recommendations based on body surface area. Similarly, during the WCLC 2019, Paz-Ares et al 3 reported the intracranial activity of entrectinib in patients with NTRK-positive solid tumors (n ¼ 54) or ROS1þ NSCLC (n ¼ 53) with CNS disease at baseline (14). Time to CNS progression was 17.0 months (95% CI: 14.3eNE) for NTRK-positive solid tumor patients (and 20.9 months for those without brain metastases at baseline) and NE (95% CI: 15.1eNE) for ROS1þ NSCLC.…”

“…1 It appears that most of the cases have been associated with the recent use of e-cigarette type devices and the possibility of a vaping-related pneumonitis has been raised. There have been multiple reports from various major news sites [2][3][4] and the first case series was published in the New England Journal of Medicine on September 6. 5 This article identified key features of the disease:…”

“…2 and that presented results of a survey of smokers, created ecosystem maps and infused its message with the language, visuals and theoretical frameworks of public health. A flurry of publications followed the foundation launch largely offering criticism [3][4][5] , but in at least one case 3 refraining from advising a full boycott of the Foundation although pessimistic about its promises. The President of the Foundation has had several opportunities to voice the views of the Foundation 6,7 and, true to a background in public health and (disconcertingly) global tobacco control 8,9 writes with conviction and authority on these issues with the erudite competence of a professional.…”

“…The results of this study reiterate the findings observed in the IASLC dataset. Hence, rather than the adoption of 5 subdivisions for N1/N2 disease, the use of a smaller number (3)(4)) of subdivisions appears more appropriate.…”