P1.14-58 A Phase II Study to Evaluate Neoadjuvant Osimertinib for Surgically Resectable, EGFR-Mutant Non-Small Cell Lung Cancer

Abstract

(age range, 43-61 years) and all had brain metastases at baseline. All four patients achieved an objective partial response to ensartinib, including one patient with an acquired ALK F1174V crizotinib resistance mutation. Intracranial responses included one partial response, two stable disease, and resolution of a non-target lesion in another patient. The median progression free survival was 12.5 months (range, 8-15 months) and the median decrease in tumor size was 42% (range, 39-48%). Primary sites of disease progression included lung (n¼1), brain (n¼2), both lung and brain (n¼1). No somatic alterations were identified in the two patients who received post-ensartinib ctDNA sequencing. At progression, all patients received brigatinib as subsequent therapy with clinical benefit; one received lorlatinib after brigatinib failure and response is ongoing. Median post-ensartinib survival was 27 months (range, 20-38 months). Two patients remain alive 27 and 95 months after first anti-cancer therapy. The most common adverse events with ensartinib were mild rash, diarrhea, and fatigue that did not require dose reduction. Conclusion: Ensartinib is well tolerated and has clinical activity in advanced ALK-rearranged NSCLC patients with brain metastases, despite previously progressing on crizotinib, with durable post-ensartinib survival on subsequent next-generation ALK inhibitors such as brigatinib and lorlatinib.

Neoadjuvant Osimertinib With/Without Chemotherapy Versus Chemotherapy Alone for EGFR -Mutated Resectable Non-Small-Cell Lung Cancer: NeoADAURA

“…An important consideration for a neoadjuvant agent is that treatment-related toxicities do not interfere with surgery or delay surgery, currently a key factor in determining the timing of neoadjuvant or adjuvant therapy. Preliminary results from the small study mentioned above indicate that neoadjuvant osimertinib was well tolerated, with no SAEs reported, and no unscheduled delay to surgery [36], in line with the well-characterized tolerability profile of osimertinib monotherapy in advanced EGFRm NSCLC [27,28,31,32] and as adjuvant treatment for resected stage IB-IIIA EGFRm NSCLC [17]. While data are limited regarding the combination of osimertinib with chemotherapy, results from the safety run-in (n = 30) of the FLAURA2 study demonstrated that first-line osimertinib plus chemotherapy was well tolerated in patients with advanced/metastatic EGFRm NSCLC with a similar toxicity profile to chemotherapy alone and osimertinib alone, and with no new safety signals identified (Planchard et al Manuscript in preparation).…”

“…• Hemoglobin: ≥9.0 g/dL • Absolute neutrophil count: ≥1.5 × 10 9 /l • Platelet count: ≥100 × 10 9 /l • Serum bilirubin: ≤1.5 ULN • ALT and AST: ≤2.5 × ULN • Creatinine clearance: ≥50 ml/min • Life expectancy of Ͼ6 months prior to randomization • Prior treatment with systemic anti-cancer treatment for NSCLC, EGFR-TKI treatment or pre-operative radiotherapy • Mixed small cell and non-small-cell lung cancer histology • T4 tumors infiltrating the aorta, esophagus and/or heart • Bulky N2 disease • Candidates for segmentectomies or wedge resections only • Medical history of ILD, drug-induced ILD, radiation pneumonitis which required steroid treatment or any evidence of clinically active ILD • Severe or uncontrolled systemic diseases/active infections, history of allogeneic organ transplantation, history of primary immunodeficiency, history of another primary malignancy • Refractory nausea/vomiting, chronic GI disease, significant bowel resection that may prevent absorption of osimertinib • QTc Ͼ470 ms, clinically important abnormalities in resting ECG, factors increasing risk of QTc prolongation or arrhythmias † IASLC Staging Manual in Thoracic Oncology 2016 [37]. Indeed, preliminary data from a small Phase II study (NCT03433469) of five patients with resectable stage I-IIIA EGFRm NSCLC suggest that neoadjuvant osimertinib was well tolerated and could potentially induce pathological responses and downstaging of disease before surgery [36].…”

“…Taken together, these positive osimertinib data in the advanced/metastatic and adjuvant settings and the preliminary data from first- and second-generation EGFR-TKIs in the neoadjuvant setting, strongly support the rationale that neoadjuvant osimertinib may provide clinical benefit for patients with resectable EGFR m NSCLC. Indeed, preliminary data from a small Phase II study (NCT03433469) of five patients with resectable stage I–IIIA EGFR m NSCLC suggest that neoadjuvant osimertinib was well tolerated and could potentially induce pathological responses and downstaging of disease before surgery [ 36 ].…”

Neoadjuvant treatment of stage IIIA-N2 in EGFR-Mutant/ALK-rearranged non-small cell lung cancer

“…To date, there are three ongoing clinical trials exploring the efficacy of osimertinib in a neoadjuvant setting: the phase II ChiCTR1800016948 and NCT03433469, and the phase III NeoADAURA (NCT04351555) (Table 2). Preliminary data from the phase II NCT03433469 study (comprising data from only 5 patients) indicates that 8 weeks of neoadjuvant treatment with osimertinib is well tolerated (no serious AEs reported) with a 60% ORR (no CPR have been observed) (73). The NeoADAURA trial, will randomize (1:1:1) 300 patients with sensitizing EGFR mutations (Ex19del or L858R either alone or in combination with other EGFR mutations) to receive placebo plus chemotherapy (per 3 cycles), osimertinib plus chemotherapy (per 3 cycles) and osimertinib (9 weeks), duration a bit longer than previous neoadjuvant trials with EGFR-TKIs.…”

Anticipating EGFR Targeting in Early Stages of Lung Cancer: Leave No Stone Unturned

“…After the results of the ADAURA trial [10], a new scenario opened for investigating third-generation EGFR TKIs as induction preoperative therapy. Preliminary data from a phase II study (NCT03433469) indicated that neoadjuvant osimertinib (osimertinib 80 mg orally daily for 1-2 months), in surgically resectable EGFR mutant NSCLC, induced pathological responses and downstaging of disease prior to surgery, with a good safety profile [30]. During the International Association for the Study of Lung Cancer (IASLC) 2020 World Conference on Lung Cancer, Tsuboi et al presented the design of NeoADAURA, a phase III, randomized, multicenter study of neoadjuvant osimertinib in EGFR mutant resectable stage II-IIIB NSCLC.…”