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IntroductionOsimertinib is an effective treatment for metastatic NSCLC. Occasionally, thoracic radiation therapy (TRT) is delivered to patients receiving osimertinib to treat residual or progressing pulmonary tumors. Anecdotal reports suggest that the delivery of TRT in combination with osimertinib may be associated with a high risk of severe pneumonitis.MethodsA retrospective study was performed at a single academic medical center in the United States to investigate the incidence of severe pneumonitis among patients treated with combined TRT and osimertinib between June 2016 and December 2021. Baseline patient characteristics, tumor size and location, and dosimetric parameters were evaluated. The highest grade of radiation pneumonitis that developed within 6 months of treatment was scored in accordance with the Common Terminology Criteria for Adverse Events version 5.0.ResultsA total of 16 patients were identified who were treated with combined TRT and osimertinib. All had a diagnosis of metastatic NSCLC. Treatment-related grade greater than or equal to 2 pneumonitis developed in 56%, grade greater than or equal to 3 in 37.5%, and grade 4 in 6.3%; no patient developed grade 5 pneumonitis. Median time to any-grade pneumonitis was 29 days (1-84 d); all patients had symptom resolution with expectant management or oral steroid therapies. All patients discovered to have grade greater than or equal to 3 pneumonitis (n = 6) received TRT to tumors located within 2 cm of the proximal bronchial tree, including tumors abutting the proximal bronchial tree (n = 2) and within the mediastinum (n = 1).ConclusionsThe combination of TRT with osimertinib was associated with a high rate of severe pneumonitis that required oral steroid medications. Larger studies are needed to validate these findings and to understand the clinical and treatment factors that influence this risk and how they can be mitigated.

IntroductionEstrogen receptors (ER) (ERα, ERβ) and aromatase (key enzyme for estrogen synthesis) are expressed in most human NSCLCs. High intratumoral estrogen levels and elevated aromatase expression in NSCLC predict poor outcome. This open-label, phase 1b, single-center study evaluated the safety and tolerability of escalating doses of the aromatase inhibitor, exemestane, in combination with carboplatin and pemetrexed in postmenopausal women with stage IV nonsquamous NSCLC.MethodsPatients received exemestane (starting 1-wk before chemotherapy) at 25 mg orally (PO) daily (cohort 1) or 50 mg PO daily (cohort 2) combined with carboplatin (area under the curve 6 mg × min/mL) and pemetrexed (500 mg/m2) intravenously every 3 weeks for four cycles. Thereafter, patients were eligible for continued therapy with exemestane and pemetrexed or pemetrexed alone.ResultsA total of 10 patients consented for therapy, and two patients failed in the screening. Four patients completed the therapy in cohort 1 and four patients in cohort 2. The median number of cycles administered was 15 (range: 1-54). Maximum tolerated dose was exemestane 50 mg PO daily with combination chemotherapy. Intention-to-treat analysis revealed an objective response rate (ORR) of 62.5% (five of eight patients with partial response) and a clinical benefit rate of 87.5% (seven of eight patients with either stable disease or partial response). ORR was associated with aromatase expression (p = 0.02). Circulating estrogen levels decreased with exemestane use, and quality of life measurements did not significantly change during the treatment. There were no adverse events.ConclusionsThe combination of carboplatin, pemetrexed, and exemestane in postmenopausal women with metastatic NSCLC is safe and well tolerated. Biomarker studies revealed that ORR correlates with tumor aromatase expression. These findings support future clinical trials to confirm the antitumor efficacy with this combination therapy.

Introduction: EGFR gene mutations are drivers of NSCLC. The RELAY double-blind, placebo (PBO)-controlled phase 3 study revealed superior progression-free survival (PFS) for ramucirumab plus erlotinib (RAM + ERL) versus PBO (PBO + ERL) in patients with untreated advanced NSCLC and an EGFR- activating mutation. This exploratory analysis evaluated potential associations between EGFR exon 19 deletion (ex19del) variants and clinical outcomes., Methods: Patients (N = 449) were randomized (1:1) to RAM plus ERL or PBO plus ERL. Plasma samples were collected at baseline, on treatment, and at 30-day post-study treatment discontinuation follow-up. Baseline and treatment-emergent gene alterations were investigated by Guardant360 next-generation sequencing. Patients with a valid baseline plasma sample and ex19del were included (RAM + ERL, n = 62; PBO + ERL, n = 72)., Results: The most common ex19del variant was E746_A750del (67.2%); EGFR E746 deletions (E746del) occurred more frequently than L747 deletions (74.6% versus 25.4%, respectively). TP53 mutations were the most frequently co-occurring baseline gene alterations. With treatment arms combined, median PFS was 18.0 months versus 12.5 months for patients with uncommon (non-E746_A750del, n = 44) versus common (E746_A750del, n = 90) ex19del variants (hazard ratio [HR] = 1.657 [95% confidence interval or CI:1.044-2.630]). Median PFS was longer with RAM plus ERL versus PBO plus ERL for patients with the common (15.2 versus 9.9 mo; HR = 0.564 [95% CI: 0.344-0.926]) and E746del (15.4 versus 9.9 mo; HR = 0.587 [95% CI: 0.363-0.951]) variants. Treatment-emergent post-progression EGFR T790M rates were higher in the common versus uncommon and E746del versus L747 deletion subgroups., Conclusions: RAM plus ERL provides benefit and improves treatment outcomes for patients with metastatic NSCLC with EGFR ex19del variants., Competing Interests: Dr. Nishino reports grants or contracts to their institution from AbbVie, Amgen, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Company, Limited, Eisai Co., Ltd., Eli Lilly Japan K.K., Janssen Pharmaceutical K.K., Merck Biopharma Co., Ltd., Merus N.V., Merck Sharp & Dohme, Novartis, Ono Pharmaceutical Co., Ltd., Pfizer, Sanofi K.K., Taiho Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Company Limited; payments or honoraria from AstraZeneca, Bristol-Myers Squibb, Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Janssen Pharmaceutical K.K., Merck, Nippon Boehringer Ingelheim Co., Ltd., Nippon Kayaku Co., Ltd., Novartis, Pfizer, and Roche Diagnostics; and participation on safety/advisory boards with AstraZeneca, Eli Lilly Japan K.K., and Pfizer. Dr. Shih reports grants or contracts from Genconn Biotech and Roche; payments or honoraria from ACT Genomics, Amgen, AstraZeneca, Bayer Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical Co., Ltd., CStone Pharmaceuticals, Eli Lilly and Company, Genconn Biotech, GlaxoSmithKline, Janssen, Lotus, Merck Sharp & Dohme, Mundipharma, Novartis, Orient EuroPharma, Ono Pharmaceutical Co., Ltd., Pfizer, Roche, Takeda Pharmaceutical Company Limited, and TTY Biopharm; and support for attending meetings and/or travel from AstraZeneca, Chugai Pharmaceutical Co., Ltd., and Roche. Dr. Nakagawa reports grants or contracts to their institution from Amgen, Ascent Development Services, Astellas Pharma Inc., AstraZeneca K.K., Bayer Yakuhin, Ltd., Bristol-Myers Squibb, Chugai Pharmaceutical Co., Ltd., CMIC Co., Ltd., Daiichi Sankyo Company, Limited, Eisai Co., Ltd., Eisai Inc., Eli Lilly Japan K.K., EP-CRSU Co., Ltd., EPS Corporation, GlaxoSmithKline K.K., Iqvia Services Japan K.K., Janssen Pharmaceutical K.K., Japan Clinical Research Operations, Kissei Pharmaceutical Co., Ltd., Kobayashi Pharmaceutical Co., Ltd., Labcorp Development Japan K.K. (Covance Japan Co., Ltd.), Mebix, Inc., Medical Research Support, Mochida Pharmaceutical Co., Ltd., Merck Sharp & Dohme K.K., Nippon Boehringer Ingelheim Co., Ltd., Nippon Kayaku Co., Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Parexel International Corp., Pfizer Japan Inc., Pfizer R&D Japan G.K., PPD-SNBL K.K., PRA Health Sciences, Sanofi K.K., Shionogi & Co., Ltd., SRL, Inc., SymBio Pharmaceuticals Limited, Syneos Health Clinical K.K., Sysmex Corporation, Taiho Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Company Limited; consulting fees from Eli Lilly Japan K.K. and Ono Pharmaceutical Co., Ltd.; payments or honoraria from 3H Clinical Trial Inc., Amgen, AstraZeneca K.K., Bayer Yakuhin, Ltd., Bristol-Myers Squibb K.K., CareNet, Inc., Chugai Pharmaceutical Co., Ltd., CMIC Co., Ltd., CMIC ShiftZero K.K., Daiichi Sankyo Company, Limited, Eli Lilly Japan K.K., Incyte Biosciences Japan, Janssen Pharmaceutical K.K., Japan Clinical Research Operations, Kyowa Kirin Co., Ltd., Life Technologies Japan, Medical Mobile Communications Co., Ltd., Medical Review Co., Ltd., Merck Biopharma Co., Ltd., Merck Sharp & Dohme K.K., Neo Communication A.G., Nikkei Business Publications, Inc., Nippon Boehringer Ingelheim Co., Ltd., Nippon Kayaku Co., Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Taiho Pharmaceutical Co., Ltd., Taiyo Pharma Co., Ltd., Takeda Pharmaceutical Company Limited, and Yodosha Company, Ltd.; and patents planned, issued, or pending with Daiichi Sankyo Company, Limited, and their institution. Dr. Reck reports consulting fees from Amgen, AstraZeneca, BeiGene, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo Company, Limited, Eli Lilly and Company, GlaxoSmithKline, Merck, Merck Sharp & Dohme, Mirati Therapeutics, Inc., Novartis, Pfizer, Roche, Samsung Bioepis, and Sanofi; payments or honoraria from Amgen, AstraZeneca, BeiGene, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo Company, Limited, Eli Lilly and Company, GlaxoSmithKline, Merck, Merck Sharp & Dohme, Mirati Therapeutics, Inc., Novartis, Pfizer, Roche, Sanofi, and Samsung Bioepis; support for attending meetings and/or travel from Amgen, AstraZeneca, BeiGene, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo Company, Limited, Eli Lilly and Company, GlaxoSmithKline, Merck, Merck Sharp & Dohme, Mirati Therapeutics, Inc., Novartis, Pfizer, Roche, Sanofi, and Samsung Bioepis; and honoraria for participation on a data safety monitoring board or advisory board from Daiichi Sankyo Company, Limited, and Sanofi. Dr. Garon reports consultant and/or advisory fees from AbbVie, ABL Bio, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Dracen Pharmaceuticals, EMD Serono, Eisai Co., Ltd., Eli Lilly and Company, Gilead Sciences, GlaxoSmithKline, Merck, Natera, Novartis, Personalis, Regeneron, Sanofi, Shionogi, Xilio Therapeutics, and Zymeworks; grant/research support from ABL Bio, 10.13039/100004325AstraZeneca, 10.13039/100002491Bristol-Myers Squibb, 10.13039/501100002336Daiichi Sankyo Company, Limited, Dynavax Technologies, Eli Lilly and Company, 10.13039/100004755EMD Serono, 10.13039/100004328Genentech, 10.13039/100005564Gilead Sciences, Iovance Biotherapeutics, 10.13039/100004334Merck, 10.13039/100016957Mirati Therapeutics, Neon, and 10.13039/100004336Novartis; sponsored independent medical education from Daiichi Sankyo Company, Limited, and Ipsen; and travel support from A2 Biotherapeutics and Novartis. Ms. Carlsen and Dr. Visseren-Grul are employees and minor shareholders of Eli Lilly and Company. Ms. Matsui is an employee of Eli Lilly Japan K.K. and is a minor shareholder of Eli Lilly and Company. Dr. Nadal received research funding from Bristol-Myers Squibb, Merck Serono, Pfizer, and Roche; participated in advisory boards or received honoraria from Amgen, AstraZeneca, Bayer Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo Company, Limited, Eli Lilly and Company, Janssen, Merck Serono, Merck Sharp & Dohme, Pfizer, Pierre Fabre, Qiagen, Roche, Sanofi, and Takeda Pharmaceutical Company Limited; and received travel support from 10.13039/100009947Merck Sharp & Dohme, 10.13039/100004319Pfizer, 10.13039/100004337Roche, and 10.13039/100008373Takeda Pharmaceutical Company Limited., (© 2023 The Authors.)

Introduction: To assess the technical feasibility and safety of repeated percutaneous computed tomography (CT)-guided transthoracic biopsies and intratumoral injections of gene-modified dendritic cells in metastatic NSCLC., Methods: A total of 15 patients with 15 NSCLC lesions measuring greater than 1.0 cm underwent two cycles of intratumoral biopsies and CCL21 dendritic cell injections separated by 7 days. All needle placements and injections were done under CT guidance. Clinical and imaging follow-up was done approximately 4 weeks after the first procedure. Safety and feasibility were determined as: (1) safety and feasibility similar to that of single-needle biopsy, and (2) an absence of serious adverse events defined as grade greater than or equal to three according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0., Results: A total of 30 percutaneous, transthoracic intratumoral biopsies and injections into the lung cancer were performed, two cycles (at d 0 and 7) received by each patient (311 biopsies and 96 intratumoral injections). All percutaneous cases achieved technical success with respect to needle placement for both biopsy and injection of CCL21 dendritic cells. Only minor complications were observed (grade <3), including pneumothorax (n = 10, 33%) and small postbiopsy hemorrhage (n = 2, 7%). Pneumothorax was moderate (n = 1) or trace (n = 9), with resolution of the moderate pneumothorax after manual aspiration without chest tube placement. No patient required chest tube placement. No other complications or serious adverse effects related to the biopsy or dendritic cell injection were noted. All patients were in stable condition after up to 4 hours in the recovery unit and were discharged home on the same day. No procedure-related complications were observed on imaging or clinical follow-up at 4 weeks., Conclusions: Repeated percutaneous, transthoracic CT-guided biopsies and intratumoral gene-modified cell-based immunotherapy injections into lung cancers are technically feasible, safe, and reproducible. There were no procedure-related serious (defined as grade ≥3) adverse events., (© 2021 THE AUTHORS.)