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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.

over-treatment and unnecessary toxicity are paramount. Surgical resection for cure is standard of care for early stage non-small cell lung cancer (NSCLC), however, the five year survival following complete resection is sub-optimal, ranging from w85% for patients with stage IA tumors to w20% in patients with stage IIIA. Following surgery, 10-15% of patients may experience a local recurrence, while 15-60% experience a distant recurrence, and these events often lead to death. The use of advanced molecular profiling approaches on individual patient tumor tissues to arrive at rationally-derived therapy decisions for that patient's cancer (vs. categorical therapy assignments) are now being pursued in several advanced clinical trials. Delivering this "right" cancer treatment to the right patient at the right dose and the right time, is a next logical step and a seminal aspect of adjuvant therapy decision making. Methods: The clinical trial protocol has been approved by the IRB and implemented. Next generation sequencing (NGS) and digital droplet PCR (ddPCR) approaches are used for the analysis of patient tumor samples, which includes surgically resected tumor as well as preoperative and postoperative blood/plasma. Results: Patient enrollment is ongoing. A variety of novel and complex bioinformatic approaches, designed to address the needs of the clinical trial, have been developed and continue to be enhanced. Solid tumor material and cfDNA from preoperative and ongoing postoperative blood draws are subjected to molecular profiling with NGS and ddPCR with results being compared, contrasted, and integrated. Conclusion: In order to improve outcomes for cancer patients, there is an urgent need for advanced clinical trials utilizing: i) innovative assays, and ii) molecular profiling with cutting-edge bioinformatics. Such a clinical trial is in progress in the State of Arkansas. Monitoring cfDNA through the perioperative period will improve detection of minimal residual disease and recurrence while potentially guiding adjuvant therapy.

months. Among patients who discontinued brigatinib, 100 (59.9%) received subsequent ALK-TKIs. Lorlatinib was the most common next ALK TKI (57.0%), followed by brigatinib retreatment (16.0%), alectinib (13.0%), ceritinib (10.0%), and crizotinib (4.0%). The median (95% CI) TTD of the post-brigatinib ALK TKI was 7.2 (3.9-13.8) months. In patients who received crizotinib then brigatinib, the median (95% CI) TTD of the post-brigatinib ALK TKI was 6.7 (3.7-22.2) months. In patients who received lorlatinib after brigatinib was discontinued, median (95% CI) lorlartinib TTD was 8.0 (3.9-not reached) months.Conclusions: These results indicate that brigatinib has real-world durable clinical effects for patients. Treatment with subsequent TKIs, can still bring benefit to patients after discontinuing brigatinib. More formalized prospective data are needed to establish sequencing recommendations.