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While the discovery of oncogenic driver mutations has personalized the metastatic non-small cell lung cancer (NSCLC) treatment landscape with effective targeted therapies, implementation of new treatments in resectable NSCLC has been limited due to the long follow-up needed for overall survival (OS). Until recently, treatment for patients with early-stage resectable NSCLC has been limited to perioperative chemotherapy, which provides modest benefits. However, the regulatory acceptance of two surrogate endpoints for OS has allowed recent approval of both adjuvant osimertinib and atezolizumab, providing patients with new treatment options to improve outcomes. In phase 3 oncology trials, OS has historically been viewed as the gold-standard efficacy measure, but disease-free survival and event-free survival (EFS) are now validated surrogate endpoints for OS in clinical trials and should be considered when mature OS data is unavailable. Another potential surrogate endpoint in the adjuvant NSCLC setting is circulating tumor DNA (ctDNA)-based minimal residual disease (MRD), although prospective validation is needed. For neoadjuvant targeted therapies, EFS, major pathologic response and ctDNA-based MRD are potential surrogate endpoints. To fully translate the success of the personalized treatment advances in the metastatic setting to earlier-stage disease, prospective validation studies of these potential surrogate endpoints that can accelerate the evaluation of drug efficacy are needed. A collaborative effort is also needed from all clinical and regulatory parties to collate surrogate endpoint data for large-scale validation. In this review we discuss the trends in surrogate endpoints used in oncology trials, with a focus on considerations for selecting appropriate primary endpoints in early-stage resectable EGFR-mutant NSCLC, an area of unmet need for novel treatment options., Competing Interests: Declaration of Competing Interest C.B. has been on an advisory council or committee for Blueprints Medicines; received consulting fee from Amgen; grants or funds from AstraZeneca, Novartis, Mirati, Spectrum, Roche, and Takeda. W.W. has received consulting fees from AstraZeneca. L.B. has ownership of stocks and shares from Roche and Novartis; been on an advisory council or committee for Amgen, AstraZeneca, Takeda, Boehringer Ingelheim, Bayer, Eli Lilly, and Merck Sharpe & Dohme; received honoraria from AstraZeneca, Bayer, Amgen, and Takeda; consulting fee from Johnson & Johnson; and grants and funds from Thermo Fisher and Systems Oncology. J.H. has no conflict of interest. M.M. has received honoraria from Merck Sharpe & Dohme, Boehringer Ingelheim, AstraZeneca, Roche AG, Kyowa Kyrin, Pierre Fabre, Takeda Pharmaceutical, Bayer AG, Amgen, Helsinn, Janssen, and Sanofi; consulting fees from Roche and AstraZeneca; and grants or funds from Bristol-Myers Squibb, Roche, and AstraZeneca. Y.S. has no conflict of interest. J.C. has received consulting fees from Merck, AstraZeneca, Genentech, Flame Biosciencea, Guardant Health, Janssen, Novartis, Arcus Biosciences, Bristol-Myers Squibb, and Regeneron-Sanofi; and grants or funds to institution from AstraZeneca, Bristol-Myers Squibb, Merck, Genetech, and Novartis., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The impact of peripheral blood immune measures and radiation-induced lymphopenia on outcomes in non-small cell lung cancer (NSCLC) patients treated with concurrent chemoradiation (cCRT) and immune check point inhibition (ICI) has yet to be fully defined., Methods: Stage III NSCLC patients treated with cCRT and ≥1 dose of durvalumab across a cancer center were examined. Peripheral blood counts were assessed pre-cCRT, during cCRT and at the start of ICI. These measures and risk-scores from two published models estimating radiation dose to immune-bearing organs were tested for association with disease control., Results: We assessed 113 patients treated with cCRT and a median of 8.5 months of durvalumab. Median PFS was 29 months (95% CI 18-35 months). A lower pre-cCRT ALC (HR: 0.51 (95% CI: 0.32-0.82), p = 0.02) and a higher pre-cCRT ANC (HR: 1.14 (1.06-1.23), p = 0.005) were associated with poor PFS. Neither ALC nadir, ALC at ICI start, ANC at ICI start or the normalized change in ALC from pre-cCRT to nadir were significantly associated with PFS (p = 0.07-0.49). Also, risk scores from the two radiation-dose models were not associated with PFS (p = 0.14, p = 0.21) but were so with the ALC Nadir (p = 0.001, p = 0.002). A higher pre-cCRT NLR was the strongest predictor for PFS (HR: 1.09 (1.05-1.14), p = 0.0001). The 12-month PFS in patients with the bottom vs. top NLR tertile was 84% vs 46% (p = 0.000004)., Conclusions: Baseline differences in peripheral immune cell populations are associated with disease outcomes in NSCLC patients treated with cCRT and ICI., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: M. Thor: No COI to report A. F. Shepard: Reports honoraria from ASCO. I. Preeshagul: Reports serving ono advisory board for Pfizer and AstraZeneca. M. Offin: Reports advisory role for PharMar, Novartis and Targeted Oncology. Reports honoraria from Bristol-Myers Squibb and Merck Sharp & Dohme. D. Y. Gelblum: No COI to report. A. J. Wu: Reports research support from CivaTech Oncology, Inc., non-financial support from AlphaTau Medical, personal fees from MoreHealth, and personal fees from AstraZeneca. A. Apte: No COI to report. C. B. Simone II: Reports honoraria from Varian Medical Systems. M. D. Hellmann: Reports personal fees from Genentech, grants, personal fees and non-financial support from Bristol Myers Squibb, personal fees from Merck, personal fees and non-financial support from AstraZeneca, personal fees from Mirati, personal fees from Syndax, personal fees and equity from Shattuck Labs, personal fees and equity from Immunai, personal fees from Nektar, personal fees from Blueprint Medicines. In addition, Dr. Hellmann has a pending patent Determinants of Cancer Response to Immunotherapy by PD-1 Blockade (PCT/US2015/062208) licensed to PGDx. A. Rimner: Reports grants from Varian Medical Systems, grants from Boehringer Ingelheim, grants from Pfizer, grants and personal fees from AstraZeneca, grants and personal fees from Merck, personal fees from Research to Practice, personal fees from Cybrexa, non-financial support from Philips/Elekta, personal fees from MoreHealth. J. E. Chaft: Reports both research funding and consulting roles with Bristol-Myers Squibb, Merck, Genentech and AstraZeneca. D. R. Gomez: Reports honoraria from Merck, BMS, AstraZeneca, Reflexion, Medscape, Vindico, US Oncology, and Varian. Reports research support from Merck, BMS, AstraZeneca, and Varian. Serves on advisory board for AstraZeneca. J. Deasy: No COI to report. N. Shaverdian: Reports research funding from Novartis., (Published by Elsevier B.V.)

Objectives: Liquid biopsy for plasma circulating tumor DNA (ctDNA) next-generation sequencing (NGS) can detect ALK fusions, though data on clinical utility of this technology in the real world is limited., Materials and Methods: Patients with lung cancer without known oncogenic drivers or who had acquired resistance to therapy (n = 736) underwent prospective plasma ctDNA NGS. A subset of this cohort (n = 497) also had tissue NGS. We evaluated ALK fusion detection, turnaround time (TAT), plasma and tissue concordance, matching to therapy, and treatment response., Results: ctDNA identified an ALK fusion in 21 patients (3%) with a variety of breakpoints and fusion partners, including EML4, CLTC, and PON1, a novel ALK fusion partner. TAT for ctDNA NGS was shorter than tissue NGS (10 vs. 20 days; p < 0.001). Among ALK fusions identified by ctDNA, 93% (13/14, 95% CI 66%-99%) were concordant with tissue evaluation. Among ALK fusions detected by tissue NGS, 54% (13/24, 95% CI 33%-74%) were concordant with plasma ctDNA. ctDNA matched patients to ALK-directed therapy with subsequent clinical response, including four patients matched on the basis of ctDNA results alone due to inadequate or delayed tissue testing. Serial ctDNA analysis detected MET amplification (n = 2) and ALK G1202R mutation (n = 2) as mechanisms of acquired resistance to ALK-directed therapy., Conclusion: Our findings support a complementary role for ctDNA in detection of ALK fusions and other alterations at diagnosis and therapeutic resistance settings., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and Purpose: Concurrent chemoradiation (cCRT) and durvalumab is standard therapy for patients with unresectable stage III non-small-cell lung cancers (NSCLC). Data is limited on outcomes with this regimen outside of clinical trials. Local-regional control rates remain undefined., Materials and Methods: We reviewed patients with stage III unresectable NSCLCs treated between November 2017 and February 2019 with cCRT and ≥1 dose of durvalumab. We examined 12-month progression-free-survival (PFS), overall-survival (OS), toxicities, and the incidence and pattern of local-regional and metastatic failures., Results: Sixty-two patients (median follow-up 12 months) with median age of 66 years of which 73% had stage IIIB (n = 33) or IIIC (n = 12) disease started durvalumab a median of 1.5 months from the end of cCRT and were treated with a median of 8 months of durvalumab. Common reasons for stopping durvalumab included disease progression (32%, 20/62) and toxicity (24%, 15/62). The estimated 12-month PFS and OS were 65% (95% CI: 51-79%) and 85% (95% CI: 75-95%), respectively. The cumulative 12-month incidence of local-regional and distant failures were 18% (95% CI: 5.9-30%) and 30% (95% CI: 16.3-44.5%), respectively. Among patients with distant metastatic disease (n = 17), 47% had oligometastatic disease. High tumor mutation burden (≥8.8 mt/Mb) or PD-L1 (≥1% or PD-L1 ≥ 50%) did not predict improved PFS., Conclusions: Outcomes with cCRT and durvalumab in practice align with the PACIFIC trial. A substantial minority of patients are candidates for metastasis-directed therapies at progression. Local regional outcomes appear improved to historical data of cCRT alone., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Durvalumab after concurrent chemoradiation has significantly improved survival in stage III non-small cell lung cancer (NSCLC). However, there is limited data evaluating the utilization and challenges to deliver durvalumab consolidation in the real world. We assessed the use of consolidative durvalumab at a large academic center to examine clinical limitations to delivery of this practice-changing regimen. We found that despite incorporating consolidative durvalumab into standard practice for stage III unresectable NSCLC, 27% patients did not initiate this treatment, largely due to disease progression or toxicity from chemoradiation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: Occult primary non-small cell lung cancer (OP-NSCLC) involving mediastinal lymph nodes without an identifiable primary tumor is a rare presentation, with little known about how outcomes compare to typical Stage III NSCLC. We reviewed our experience treating OP-NSCLC with definitive radiotherapy and compared outcomes to a contemporary cohort of stage III NSCLC patients., Materials and Methods: We reviewed 605 patients with stage III NSCLC staged with PET-CT and treated with definitive radiotherapy between 1998 and 2013. Overall survival, intrathoracic control, and freedom from distant metastasis were computed using Kaplan-Meier method and logrank comparison. Cox hazard ratios were used to perform univariate and multivariate analyses., Results: Twenty-one patients were identified with OP-NSCLC (3.5%). Patients with OP-NSCLC, as compared to known primary NSCLC, had significantly better 5-year rates of intrathoracic control (83.5% vs. 24.2%, P < 0.001), freedom from distant metastasis (59.0% vs. 26.3%, P = 0.003), and overall survival (61.6% vs. 15.2%, P < 0.001). Multivariate analyses confirmed occult primary as an independent prognostic factor associated with a 70% reduction in risk of intrathoracic failure, a 55% reduction in risk of distant metastasis, and a 70% reduction in risk of death., Conclusion: To our knowledge, this is the largest reported series of OP-NSCLC and the first to compare it to a contemporary cohort of Stage III NSCLC with known primary lesion. Definitive radiation therapy was associated with favorable locoregional control and survival, particularly compared with typical stage III NSCLC. This difference suggests that occult primary NSCLC may be a distinct entity with different biology than typical NSCLC., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: Reports of the prognostic significance of ALK-rearrangement in resected non-small cell lung cancer (NSCLC) have been contradictory. We aimed to determine the prognosis of early-stage ALK-positive lung cancers relative to KRAS- and EGFR-mutant lung cancers., Material and Methods: We reviewed medical records of patients with resected NSCLC harboring an ALK rearrangement (n = 29) or a driver mutation in EGFR (n = 255) or KRAS (n = 480). Recurrence-free survival (RFS) was estimated for each genotype with the differences reported as a hazard ratio (HR)., Results: Among the 764 patients, 555 (73%), 101 (13%), and 108 (14%) had stage I, II, and III NSCLC, respectively. ALK-positive patients were distributed across all stages: 10 (34%) stage I, 6 (21%) stage II, and 13 (45%) stage III. Median RFS was not reached for EGFR-mutant patients, 24.3 months (95%CI 11.4-65.3) for ALK-positive patients, and 72.9 months (95%CI 59.7 to undefined) for KRAS-mutant patients. When adjusted for stage, ALK-positive NSCLC remained associated with worse RFS compared to EGFR-mutant (HR 1.8, 95%CI: 1.1-3.1), but not when compared to KRAS-mutant (HR 1.3, 95%CI: 0.8-2.1) NSCLC., Conclusions: In this large series of resected NSCLC, ALK rearrangements were associated with a trend toward inferior disease outcomes compared to other clinically relevant genomic subsets. These data support the need for clinical trials evaluating use of ALK inhibitors among ALK-positive patients with localized or locally-advanced disease., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: Thyroid transcription factor 1 (TTF-1) is routinely tested in the diagnostic evaluation of suspected lung cancers, is commonly expressed by lung adenocarcinomas, and may modulate lung cancer biology. We examined the role of TTF-1 as a predictive and prognostic marker in patients with advanced lung adenocarcinomas., Materials and Methods: We analyzed clinical, pathologic, and molecular features, treatments received, and overall survival obtained from the medical records of 479 consecutive patients at a single site with stage IV lung adenocarcinomas and evaluable TTF-1 expression. TTF-1 expression was determined by immunohistochemistry using antibody 8G7G3/1., Results and Conclusion: TTF-1 expression was evaluable in 479 (75%) of all patients reviewed, and was positive in 383 (80%, 95% CI 76-83%). Clinicopathologic features were similar between TTF-1 positive and TTF-1 negative tumors, except EGFR mutations were more common in TTF-1 positive cases (24% vs 6%, p<0.001). In univariate analysis, overall survival was significantly longer in patients with TTF-1 positive versus TTF-1 negative tumors (18 months vs 9 months, p<0.0001). In multivariate analysis, TTF-1 positivity remained associated with better overall survival (HR=0.38, p<0.0001), exceeding the prognostic impact of Karnofsky performance status >/=80% (HR 0.62, p=0.0003) and receipt of first-line combination chemotherapy or targeted therapy (HR relative to first-line single agent chemotherapy 0.59, p=0.05 and 0.51, p=0.05 respectively). Both patients with TTF-1 positive and TTF-1 negative cancers had longer durations of initial therapy when treated with pemetrexed-based chemotherapy. In patients with advanced lung adenocarcinomas, TTF-1 expression is associated with better survival but is not predictive of distinct benefit from pemetrexed-based chemotherapy., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Human epidermal growth factor receptor 2 (HER2, ERBB2) mutations occur in 3% of lung adenocarcinomas. While case reports and series have shown activity of HER2 targeted agents in these patients, little is known about outcomes of chemotherapies. Patients with stage IV HER2-mutant lung cancers at Memorial Sloan Kettering were reviewed. Patient demographics, types of HER2 mutations, duration of systemic treatments and survival were analyzed. We identified 38 patients with HER2-mutant lung cancers: median age 62; majority were women (n=24), never smokers (n=22), and all had adenocarcinomas. A 12 base pair in-frame insertion YVMA in exon 20 (p.A775&#95;G776insYVMA) was present in 24 (63%, 95% CI 46-78%) patients. In addition, there were four 9 base pair insertions, one 6 base pair insertion, and five 3 base pair insertions in exon 20, and four single bp substitutions (exon 20 L755F, V777L, D769H, exon 8 S310F). The median overall survival from date of diagnosis of stage IV disease was 2.3 years (95% CI 1.2-2.6). The median duration of chemotherapy was 4.3 months (68 treatments, range 0-21 months): 6.2 months for pemetrexed ±platinum/bevacizumab, 4 months for taxane ±platinum/bevacizumab, 2.6 months for gemcitabine, 3.5 months for vinorelbine. The median duration of HER2 tyrosine kinase inhibitors was 2.2 months (28 treatments, range 0.3-16.3 months). As we search for better targeted therapies for patients with HER2-mutant lung cancers, chemotherapy remains an important component of care., Competing Interests: Bob T. Li has received consulting fees from Roche and Biosceptre International Mark G. Kris has received consulting fees from AstraZeneca, and Genentech/Roche All other authors declare no competing interests., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Human epidermal growth factor 2 (HER2, ERBB2) mutations in lung cancers are oncogenic drivers that respond to HER2 targeted therapies. Little is known about the sensitivity of subtypes of HER2 mutant lung cancers to targeted agents. We present a patient with HER2 mutant lung cancer with a 12 base pair insertion YVMA (p.A775&#95;G776insYVMA), who had a long natural history and durable partial response to afatinib. We demonstrate that afatinib has activity in patients with HER2 mutant lung cancers with exon 20 YVMA insertions, the most common variant., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)