Citations

e20554 Background: The paradigm for locally advanced non-small cell lung cancer has been markedly altered to include maintenance durvalumab (D) post completion of definitive chemoradiation (CRT) following the publication of the Pacific trial in 2018. The toxicity of this treatment has not been well evaluated in the real-world setting. Methods: We identified 42 patients (pts) with Stage IIB-IIIC NSCLC treated at Mayo Clinic Rochester between 6/1/2018 and 10/1/2020 who received definitive CRT followed by maintenance D. Data were abstracted by retrospective chart review under an IRB approved protocol. Results: Median age was 66 yrs (range 47-90) and 62% were women. Primary lung cancer histology included 19 adenocarcinoma, 20 squamous cell, and 3 adenosquamous. The distribution of stages was: IIB (4/42), IIIA (15/42), IIIB (19/42), IIIC (4/42). Approximately half of patients had PDL1 expression > 25% (20/42). With a median follow up of 12.2 months (calculated from first cycle of D; range 4.2-30.5 months), 14 had completed one year of maintenance D, 16 were receiving ongoing D, and 10 stopped D early with 6/12 discontinuing due to disease progression (4/6 local progression, 2/6 distant progression). Other reasons for discontinuation (5/10) included grade 3 colitis, grade 2 hepatitis, aspergillus lung infection, and flare of autoimmune disorders. One quarter of patients experienced grade 2 radiation pneumonitis (RP; 10/42) with median time to development of RP 78 days from end of CRT and 45 days from start of D. RP was determined by multidisciplinary review of imaging and treatment fields. 17/42 patients developed immune related adverse events (see Table for details). There was minimal overlap between the patients who experienced pneumonitis and immune related toxicity; 2/17 had both pneumonitis and immune related toxicity (hepatitis, thyroiditis). Conclusions: In our early experience with the Pacific regimen, 29% of patients did not complete D due to either toxicity or progression during D administration. Pneumonitis was common (10/42 patients) although there were no grade 3 events. Nearly half of the patients developed an immune-related adverse event. Further analysis is needed to evaluate the real-world toxicity of this treatment as well as oncologic outcomes.[Table: see text]

9089 Background: RET fusions are targetable oncogenic drivers in 1–2% of non-small cell lung cancer (NSCLC). ARROW (NCT03037385) supported the US FDA approval of pralsetinib, a highly potent oral selective RET inhibitor for RET-altered NSCLC and thyroid cancer. Here, we present updated results for a larger population of patients with RET fusion–positive NSCLC enrolled in ARROW. Methods: ARROW is a phase 1/2 open-label study conducted at 84 sites in 13 countries. Phase 2 expansion cohorts included patients with RET fusion–positive NSCLC. Initially, all treatment-naïve patients were not candidates for platinum-based therapy, a requirement removed by protocol amendment in July 2019. Primary objectives are overall response rate (ORR; blinded independent central review [BICR] per RECIST v1.1), assessed for patients with baseline measurable disease, and safety. Results: Updated analyses were completed as of Nov 6, 2020 (data cut-off), for patients who initiated pralsetinib 400 mg QD by May 22, 2020 (enrollment cut-off). Efficacy results, including analyses for treatment-naïve patients enrolled after eligibility criteria were revised to allow candidates for platinum-based therapy, are shown in the Table. Conclusions: Pralsetinib showed rapid, potent, and durable clinical activity in patients with RET fusion-positive NSCLC (regardless of prior therapies), including poor prognosis patients not eligible for platinum-based therapy. Overall, pralsetinib was well-tolerated. These data highlight the need for RET testing early in the course of disease to identify candidates who may benefit from treatment with pralsetinib. Clinical trial information: NCT03037385. [Table: see text]

8569 Background: Immune checkpoint inhibitor (atezolizumab or durvalumab) combined with platinum-etoposide is the standard first-line therapy for patients with extensive-stage small cell lung cancer (ES-SCLC). The phase III clinical trials that led to the approval of chemoimmunotherapy in ES-SCLC, excluded patients with an Eastern Cooperative Group (ECOG) Performance Status (PS) of Two or Greater. Therefore, data on efficacy of this combination in this subgroup of ES-SCLC patients whose performance status two or greater is limited. Methods: A retrospective analysis was performed of patients diagnosed with ES-SCLC who received chemoimmunotherapy (atezolizumab or durvalumab) within the Mayo Clinic Health System between January 2016 and January 2021. Cases were identified from clinical databases at Mayo Clinic. Data on demographics, ECOG-PS, date of diagnosis, date of progression, whole brain radiation, CNS involvement, liver involvement, stereotactic body radiation, chest consolidation, platinum sensitivity, lines of therapy and last follow up date were extracted. Overall Survival (OS) and progression free survival (PFS) for ECOG-PS 2-3 were compared to patients with an ECOG-PS 0-1. Results: A total of 84 patients were identified with a median age of 68.2 (48-88) years old. Of these, 54 patients were identified with an ECOG-PS 0-1 and 30 patients with an ECOG-PS 2-3. The median PFS for the ECOG PS 0-1 cohort was 5.2 months (95% CI 4.6-6.1) while the median PFS for the ECOG-PS 2-3 cohort was 6.0 months (95% CI 4.2-7.7; logrank p = 0.93). The median OS for the ECOG-PS 0-1 cohort was 10.8 months (95% CI 8.5-12.9) while the median OS for the ECOG-PS 2-3 cohort was 10.3 months (95% CI 6.0-14.1; logrank p = 0.39). Hazard ratios of ECOG-PS 0-1 versus 2-3 showed no tendency of increased PFS or OS for either group within cox proportional hazards models. Forty-three percent of ECOG-PS 0-1 achieved a partial response (PR) and 57% of patients who had ECOG-PS 2-3 also achieved a PR (Fisher’s exact p = 0.23). A complete response was found in 4% of ECOG-PS 0-1 compared to 3% in the ECOG-PS 2-3 cohort. For patients who responded to initial therapy, 46% of ECOG-PS 2-3 patients had a platinum sensitive relapse while only 33% of ECOG-PS 0-1 were still platinum sensitive at the time of relapse. Five ECOG-PS 2-3 patients were able to receive a second-line therapy. Conclusions: To our knowledge, this is the first study to evaluate chemoimmunotherapy in the subgroup of ES-SCLC patients with an ECOG-PS 2 or greater. This retrospective study demonstrated no significant difference in PFS, OS, and ability to achieve a least a PR in ECOG-PS 2-3 cohort when compared to ECOG-PS 0-1. Therefore, chemoimmunotherapy should not be reserved for only an ECOG-PS of 0-1 but should be considered for all treatment eligible patients.

PURPOSE BIM activation is essential for epidermal growth factor receptor ( EGFR)-tyrosine kinase inhibitor (TKI)–triggered apoptosis in EGFR-mutant non–small-cell lung cancer (NSCLC). A deletion in the intron two of the BIM gene results in generation of alternatively spliced isoforms that impairs their apoptotic response to TKIs, conferring the NSCLC cells intrinsic resistance to these medications. Patients with both alterations have poor clinical evolution. The current study aimed to investigate the clinical efficacy and tolerability of EGFR-TKIs plus bevacizumab (Bev) versus EGFR-TKIs alone as first-line treatment in advanced NSCLC patients with EGFR mutations and BIM deletions ( BIMdel). MATERIALS AND METHODS A retrospective analysis was conducted. BIMdel was detected using polymerase chain reaction analysis and direct sequencing of DNA. BIM protein expression was investigated by immunohistochemistry, and BIM mRNA levels by reverse transcriptase-polymerase chain reaction. Clinical characteristics, overall survival, progression-free survival (PFS), overall response rate (ORR), and treatment-related adverse events were compared between both groups. RESULTS Thirty-three patients were included; 15 received EGFR-TKIs, and 18 received EGFR-TKIs plus Bev. The median age was 63 years, with a majority of recruited female patients. All included individuals had an Eastern Cooperative Oncology Group performance score of 2 or less. The addition of Bev resulted in a significantly higher ORR (94.4% v 40%, P > .001). Median PFS was longer with the use of the combination therapy (11.12 v 7.87 months; P = .001). Median overall survival tended to be longer in the EGFR-TKIs plus Bev (30.9 v 25.4 months; P = .06) but failed to reach statistical significance. Response in terms of both partial and complete as well as overall favorably affected PFS. CONCLUSION EGFR-TKIs plus Bev conferred a significantly higher ORR and PFS in advanced NSCLC patients with EGFR mutation and BIMdel. Further prospective studies are needed to validate these findings.

Abstract Purpose: The CLASSICAL-Lung clinical trial tested the combination of pepinemab, an IgG4 humanized mAb targeting semaphorin 4D, with the PD-L1 inhibitor avelumab to assess the effects of coupling increased T-cell infiltration and reversal of immune suppression via pepinemab with sustained T-cell activation via checkpoint inhibition. Patients and Methods: This phase Ib/II, single-arm study was designed to evaluate the safety, tolerability, and efficacy of pepinemab in combination with avelumab in 62 patients with advanced non–small cell lung cancer (NSCLC), including immunotherapy-naïve (ION) patients and patients whose tumors progressed following anti-PD-1/L1 monotherapy (IOF). The main objectives were to evaluate safety/tolerability, establish a recommended phase 2 dose (RP2D), obtain a preliminary evaluation of antitumor activity, and investigate candidate biomarker activity. Results: The combination was well tolerated with no major safety signals identified. Pepinemab, 10 mg/kg with avelumab, 10 mg/kg, every 2 weeks, was selected as the RP2D. Among 21 evaluable ION patients, 5 patients experienced partial responses (PR), 4 patients evidenced clinical benefit ≥1 year, and the disease control rate (DCR) was 81%. Notably, overall response rate with the combination therapy was higher than previously reported for single-agent avelumab in the PD-L1-negative/low population. Among 29 evaluable IOF patients, the combination resulted in a DCR of 59%, including 2 PR and 7 patients with durable clinical benefit of ≥23 weeks. Biomarker analysis of biopsies demonstrated increased CD8 T-cell density correlating with RECIST response criteria. Conclusions: The combination of pepinemab with avelumab was well tolerated in NSCLC and showed signs of antitumor activity in immunotherapy-resistant and PD-L1-negative/low tumors.

Abstract Objectives To evaluate SATB2 expression and prognostic implications in a large cohort of thoracic neuroendocrine tumors. Methods Surgical pathology files (1995-2017) and an institutional thymic epithelial tumor database (2010-2020) were searched for resected neuroendocrine tumors. Cases were stained with SATB2 (clone EP281). Percent SATB2-positive tumor cells and expression intensity were scored. Results In the lung, SATB2 was expressed in 5% or more of tumor cells in 29 (74.4%) of 39 small cell carcinomas and 9 (22.5%) of 40 atypical and 26 (40.6%) of 64 typical carcinoid tumors. SATB2 percent tumor cell expression and intensity were higher in small cell carcinomas than in carcinoid tumors (both P < .001, respectively). After adjusting for tumor subtype, SATB2 expression did not correlate with outcome. In the thymus, four (100%) of four atypical carcinoid tumors and one large cell neuroendocrine carcinoma but no small cell carcinoma (n = 2) expressed SATB2 in 5% or more of tumor cells. Conclusions SATB2 (clone EP281) is expressed in a large subset of pulmonary and thymic neuroendocrine tumors and therefore does not appear to be a useful marker to identify the origin of neuroendocrine tumors. Validation studies are needed, specifically including thymic neuroendocrine tumors, as the expression pattern might be different in those tumors.

467 Background: Recent tumor-agnostic drug approvals have resulted in a paradigm shift in cancer treatment away from organ/histology specific indications to biomarker-guided tumor-agnostic approaches. Pralsetinib is a potent and selective RET inhibitor, which has recently been approved by the U.S. Food and Drug Administration (FDA) for the treatment of adults with metastatic RET fusion–positive non-small cell lung cancer (NSCLC) and is under New Drug Application review for RET mutant thyroid cancers by the FDA. RET fusions occur in up to approximately 7‒8% of patients with gastrointestinal malignancies, including pancreatic, liver, and colorectal cancers. There are currently no approved selective RET inhibitors for patients with RET fusion–positive solid tumors other than NSCLC and thyroid cancer. Here, we present data on the clinical activity of pralsetinib in patients with RET fusion–positive solid tumor types other than NSCLC enrolled in the Phase I/II ARROW study (NCT03037385). Methods: ARROW consists of a phase I dose escalation (30–600 mg once [QD] or twice daily) followed by a phase II expansion (400 mg QD) in patients with advanced RET-altered solid tumors. Primary objectives are overall response rate (ORR), per RECICT v1.1 and safety. Results: A total of 13 patients with RET fusion–positive thyroid cancer (12 papillary, 1 poorly differentiated; enrollment cutoff July 11, 2019) and 14 patients with RET fusion–positive solid tumors other than NSCLC and thyroid (3 pancreatic, 3 colon, 2 cholangiocarcinoma, 6 other; enrollment cutoff November 19, 2019) were enrolled in ARROW and received pralsetinib. At the February 13, 2020, data cutoff, the ORR (blinded central review) in response-evaluable patients with RET fusion–positive thyroid cancer was 91% (10/11; 95% CI: 59‒100) and disease control rate was 100% (95% CI: 72‒100). Treatment was ongoing in 7 of 11 patients. In RET fusion–positive solid tumors other than NSCLC and thyroid, ORR (investigator’s assessment) was 50% (6/12; 95% CI: 21‒79) and responses were observed in all patients with pancreatic cancer (3/3) and cholangiocarcinoma (2/2). Treatment was ongoing in 6 of 12 patients, including 2 of 3 patients with pancreatic cancer and 1 of 2 patients with cholangiocarcinoma. Responses were observed across multiple fusion genotypes. In the 27 patients with RET fusion–positive tumors other than NSCLC, most frequent treatment-related adverse events (TRAEs) were grade 1–2, and included anemia (33%), increased aspartate aminotransferase (33%), decreased white blood cell count (33%), hypertension (30%), increased alanine aminotransferase (26%), hyperphosphatemia (19%), and neutropenia (19%). No patients discontinued due to TRAEs. Conclusions: Pralsetinib demonstrated broad and durable antitumor activity across multiple advanced solid tumor types, regardless of RET fusion genotype, and was well tolerated. The study is ongoing. Clinical trial information: NCT03037385.

PURPOSE: IMpower133 (ClinicalTrials.gov identifier: NCT02763579 ), a randomized, double-blind, phase I/III study, demonstrated that adding atezolizumab (anti-programmed death-ligand 1 [PD-L1]) to carboplatin plus etoposide (CP/ET) for first-line (1L) treatment of extensive-stage small-cell lung cancer (ES-SCLC) resulted in significant improvement in overall survival (OS) and progression-free survival (PFS) versus placebo plus CP/ET. Updated OS, disease progression patterns, safety, and exploratory biomarkers (PD-L1, blood-based tumor mutational burden [bTMB]) are reported. PATIENTS AND METHODS: Patients with untreated ES-SCLC were randomly assigned 1:1 to receive four 21-day cycles of CP (area under the curve 5 mg per mL/min intravenously [IV], day 1) plus ET (100 mg/m 2 IV, days 1-3) with atezolizumab (1,200 mg IV, day 1) or placebo, and then maintenance atezolizumab or placebo until unacceptable toxicity, disease progression, or loss of clinical benefit. Tumor specimens were collected; PD-L1 testing was not required for enrollment. The two primary end points, investigator-assessed PFS and OS, were statistically significant at the interim analysis. Updated OS and PFS and exploratory biomarker analyses were conducted. RESULTS: Patients received atezolizumab plus CP/ET (n = 201) or placebo plus CP/ET (n = 202). At the updated analysis, median follow-up for OS was 22.9 months; 302 deaths had occurred. Median OS was 12.3 and 10.3 months with atezolizumab plus CP/ET and placebo plus CP/ET, respectively (hazard ratio, 0.76; 95% CI, 0.60 to 0.95; descriptive P = .0154). At 18 months, 34.0% and 21.0% of patients were alive in atezolizumab plus CP/ET and placebo plus CP/ET arms, respectively. Patients derived benefit from the addition of atezolizumab, regardless of PD-L1 immunohistochemistry or bTMB status. CONCLUSION: Adding atezolizumab to CP/ET as 1L treatment for ES-SCLC continued to demonstrate improved OS and a tolerable safety profile at the updated analysis, confirming the regimen as a new standard of care. Exploratory analyses demonstrated treatment benefit independent of biomarker status.

Abstract Mesothelioma is a universally lethal cancer lacking effective therapy. The spindle poison vinorelbine exhibits clinical activity in the relapsed setting, and in preclinical models requires BRCA1 to initiate apoptosis. However, the mechanisms underlying this regulation and the clinical implications have not been explored. Here, we show that BRCA1 silencing abrogated vinorelbine-induced cell-cycle arrest, recruitment of BUBR1 to kinetochores, and apoptosis. BRCA1 silencing led to codepletion of MAD2L1 at the mRNA and protein levels consistent with its status as a transcriptional target of BRCA1. Silencing of MAD2L1 phenocopied BRCA1 and was sufficient to confer resistance to vinorelbine. This was recapitulated in cell lines selected for resistance to vinorelbine, which acquired loss of both BRCA1 and MAD2L1 expression. Following ex vivo vinorelbine in 20 primary tumor explants, apoptotic response rate was 59% in BRCA1/MAD2L1-positive explants compared with 0% in BRCA1/MAD2L1-negative explants. In 48 patients, BRCA1 and/or MAD2L1 loss of expression was not prognostic; however, in a subset of patients treated with vinorelbine, survival was shorter for patients lacking BRCA1/MAD2L1 expression compared with double-positive patients (5.9 vs. 36.7 months, P = 0.03). Our data implicate BRCA1/MAD2L1 loss as a putative predictive marker of resistance to vinorelbine in mesothelioma and warrant prospective clinical evaluation.