Search

Background: While targeted therapies have transformed the treatment landscape of oncogene-addicted non-small cell lung cancer (NSCLC), the influence of sex on treatment outcomes remains insufficiently understood., Objectives: This systematic review aimed to investigate the impact of sex on clinical outcomes in patients with NSCLC harboring driver fusions treated with targeted therapies enrolled in clinical trials., Data Sources and Methods: A comprehensive literature search was conducted using PubMed, Embase, and relevant conference abstracts to identify phase III randomized and early clinical trials that reported sex-specific data, including progression-free survival (PFS), overall survival (OS), overall response rate, and adverse events (AEs), in patients with fusion-positive NSCLC treated with tyrosine kinase inhibitors (TKIs)., Results: This review involved 10 studies reporting PFS data and 3 studies with OS data, focusing on first-line treatments for ALK fusion (9 studies) and RET fusion-positive (1 study) NSCLC. Pooled analysis of hazard ratios (HRs) for PFS and OS in ALK inhibitors trials revealed no significant differences in survival outcomes based on sex. Additionally, none of the studies provided data on sex-based differences in response rates or toxicities, highlighting a significant knowledge gap regarding the impact of sex on secondary outcomes in targeted therapy., Conclusion: This review found no significant sex-related differences in survival outcomes among patients treated with ALK inhibitors. However, the lack of data on sex-specific response and toxicity emphasizes the need for future research to better understand the role of sex in modulating treatment outcomes and treatment decisions with TKIs., Competing Interests: E.A.—Lectures and educational activities: MSD, Janssen; Consulting, Advisory role: from Amgen and Sanofi; Travel, Accommodations: Amgen, Ipsen. D.M.: Lectures and educational activities: Astellas Pharma, PharmaMar, Roche; Travel, Accommodations: Novartis, Lilly, Bristol-Myers Squibb, Merck. D.I.—Lectures and educational activities: Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, F. Hoffmann-La Roche, Johnson & Johnson, Lilly, MSD, Pfizer, Pharmamar, Takeda; Consulting, advisory role: AbbVie, Amgen, AstraZeneca, Bayer, BMS, Beigene, Boehringer Ingelheim, F. Hoffmann-La Roche, Johnson & Johnson, Lilly, Merck, MSD, Pfizer, Pharmamar, Sanofi, Takeda; Clinical Trials: AbbVie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Daiichi Sankyo, F. Hoffmann-La Roche, GSK, Johnson & Johnson, Lilly, Merck, Mirati, MSD, Novartis, Pfizer, Pharmamar, Sanofi; Research Grants: AstraZeneca, BMS, F. Hoffmann-La Roche, GSK. G.L.R.—Consulting, advisory role: Merck Sharp and Dohme, Takeda, Amgen, Eli Lilly, BMS, F. Hoffmann-La Roche, Italfarmaco, Novartis, Sanofi, Pfizer, AstraZeneca. L.M.—Lectures and educational activities: Bristol-Myers Squibb, AstraZeneca, Roche, Takeda, Janssen, Pfizer, MSD, Radonova; Consulting, advisory role: Roche, Takeda, Janssen, MSD; Research Grants: Inivata, AstraZeneca, Gilead; Travel, Accommodations, Expenses: Bristol-Myers Squibb, Roche, Takeda, AstraZeneca, Janssen. All other authors declare no conflicts of interest., (© The Author(s), 2024.)

Introduction: LIPI has been strongly correlated with immunotherapy (IT) outcomes in advanced NSCLC. Limited data is available for upfront chemotherapy (CT) + IT combinations. We aimed to study its prognostic value in 1st-line CT +/- IT +/- antiangiogenics., Methods: Data from patients with wild-type EGFR/ALK aNSCLC included in IMpower150, IMpower131, and IMpower130 (international phase 3 multicenter studies) treated with 1st-line CT +/- atezolizumab and/or bevacizumab were retrospectively analysed. LIPI was calculated based on the neutrophil/(leucocytes-neutrophils) (dNLR) ratio and serum LDH: good (dNLR < 3 and LDH < ULN), intermediate (dNLR ≥ 3 or LDH ≥ ULN) and poor (dNLR ≥ 3 and LDH ≥ ULN)., Results: Out of 2540 patients, 48.6 % were LIPI good, 40.8 % intermediate and 10.6 % poor. LIPI was significantly associated with treatment outcomes (PFS, OS) in the overall cohort (p < 0.001) and in each treatment cohort (all p < 0.001). After adjustment for age, smoking status, number of metastatic sites, brain or liver involvement and performance status, LIPI remained an independent prognostic factor for PFS and OS. In the LIPI good group (n = 1235), longer PFS was observed in patients treated with CT + IT + AA (median [m] PFS 11.3 vs. < 7.6 months with other regimens, p < 0.001), with a trend for OS (mOS 26.1 vs 20.7 months, p = 0.08). No regimen demonstrated significant PFS benefit in the LIPI poor group compared to chemotherapy. LIPI-good + PD-L1 ≥ 50 % (n = 105) showed long responses (mPFS of 11.1 months, mOS not reached)., Conclusions: LIPI was prognostic for PFS and OS in prospective trials in aNSCLC, regardless of the treatment regimen. LIPI poor patients derived no benefit from combination treatment. LIPI combined to PD-L1 may improve the upfront treatment selection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Responses to first-line programmed cell death protein 1 inhibition vary among patients with metastatic NSCLC and a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) greater than or equal to 50%. We previously reported improved clinical outcomes to first-line programmed cell death protein 1 inhibition in patients with metastatic NSCLC with a PD-L1 TPS of greater than or equal to 90% versus 50% to 89% in a pilot study. Here, we report the three-year survival with first-line pembrolizumab and cemiplimab in two large independent cohorts of patients with PD-L1 TPS greater than or equal to 90% versus 50% to 89% and characterize genomic and immunophenotypic differences between these PD-L1 expression groups, which were largely unknown., Methods: We analyzed three-year outcomes of the following two independent cohorts: (1) a multicenter cohort of patients from four academic centers in the United States treated with pembrolizumab and (2) EMPOWER-Lung 1, randomized, phase III trial comparing first-line cemiplimab with chemotherapy. Tumor genomic profiling and multiplexed immunofluorescence were performed to evaluate genomic and immunophenotypic correlates of very high PD-L1 expression., Results: At three years of follow-up, progression-free survival (hazard ratio [HR], 0.69; p < 0.001) and overall survival (HR, 0.70; p < 0.01) to first-line commercial pembrolizumab were significantly improved in patients with a PD-L1 TPS greater than or equal to 90% versus 50% to 89%. In the EMPOWER-Lung 1, patients assigned to the cemiplimab arm with a PD-L1 TPS greater than or equal to 90% also had significant improvements in progression-free survival (HR, 0.53; p < 0.0001) and overall survival (HR, 0.63; p  = 0.007) compared with those with a PD-L1 of 50% to 89%. Tumor genomic profiling of 553 NSCLC samples revealed that mutations in STK11 and SMARCA4 were significantly more frequent in tumors with a PD-L1 TPS of 50% to 89% compared with those with a PD-L1 TPS greater than or equal to 90% (Q < 0.15), whereas BRCA2 was enriched in NSCLC samples with a PD-L1 TPS greater than or equal to 90% (Q < 0.15). Multiplexed immunofluorescence on 93 NSCLC samples identified higher intratumoral CD8 + PD1 + T cells ( p  = 0.02) in tumors with PD-L1 TPS greater than or equal to 90% versus 50% to 89%., Conclusion: Pembrolizumab and cemiplimab were found to have long-term survival benefit and favorable genomic and immunophenotypic profile in patients with advanced NSCLC with PD-L1 TPS greater than or equal to 90% compared with TPS 50% to 89%., Competing Interests: Dr. Ricciuti reports serving on the consulting/advisory board of AstraZeneca, Amgen, and Regeneron; receiving honoraria from Targeted Oncology; and receiving speaker fees from AstraZeneca. Dr. Lin reports receiving consulting from Genentech, C4 Therapeutics, Blueprint Medicines, Nuvalent, Bayer, Elevation Oncology, Novartis, Mirati Therapeutics, Regeneron, Pfizer, Takeda, Ellipses Pharma, Hyku BioSciences, AnHeart Therapeutics, Claim Therapeutics, Turning Point Therapeutics, Bristol-Myers Squibb, and Daiichi Sankyo; receiving institutional research funding from Hengrui Therapeutics, Turning Point Therapeutics, Neon Therapeutics, 10.13039/100019393Relay Therapeutics, 10.13039/100004326Bayer, Elevation Oncology, 10.13039/100004337Roche, Linnaeus Therapeutics, Nuvalent, and 10.13039/100004336Novartis. Dr. Altan reports receiving research funding (to institution) from Genentech, Nektar Therapeutics, Merck, GlaxoSmithKline, Novartis, Jounce Therapeutics, Bristol-Myers Squibb, Eli Lilly, Adaptimmune, Shattuck Lab, and Gilead; serving on the advisory board of GlaxoSmithKline, Shattuck Lab, Bristol-Myers Squibb, AstraZeneca, and Insightec; receiving speaker fees from AstraZeneca, Nektar Therapeutics, and SITC; and having participation of safety review committee for Nanobiotix-MDA Alliance and Hengenix. Dr. Zhang reports receiving grants from 10.13039/100004334Merck; grants and personal fees from Johnson and Johnson and Novartis; and personal fees from Bristol-Myers Squibb, AstraZeneca, GenePlus, Innovent, Varian, Catalyst, and Hengrui, outside the submitted work. Dr. Gainor has served as a compensated consultant or received honoraria from Bristol-Myers Squibb, Genentech/Roche, Takeda, Loxo/Lilly, Blueprint Medicine, Gilead, Moderna, AstraZeneca, Mariana Therapeutics, Mirati, Jounce, Merus Pharmaceuticals, Nuvalent, Pfizer, Novocure, AI Proteins, Novartis, Merck, iTeos, Karyopharm, and Silverback Therapeutics; has received research support from 10.13039/100004336Novartis, Genentech/Roche, and Takeda; has received institutional research support from 10.13039/100002491Bristol-Myers Squibb, Palleon, Tesaro, 10.13039/100019533Moderna, Blueprint, Jounce, 10.13039/100007174Array Biopharma, Merck, Adaptimmune, Novartis, and Alexo; has equity in AI Proteins; and has an immediate family member who is an employee with equity at Ironwood Pharmaceuticals. Dr. Heymach reports serving on the advisory committees of Genentech, Mirati Therapeutics, Eli Lilly & Co., Janssen Pharmaceuticals, Boehringer-Ingelheim Pharmaceuticals, Regeneron, Takeda Pharmaceuticals, BerGenBio, Jazz Pharmaceuticals, Curio Science, Novartis, AstraZeneca Pharmaceuticals, BioAlta, Sanofi, Spectrum Pharmaceuticals, GlaxoSmithKline, EMD Serono, BluePrint Medicine, and Chugai Pharmaceutical; receiving research support from 10.13039/100004325AstraZeneca, Boehringer-Ingelheim, 10.13039/100006399Spectrum, Mirati, Bristol-Myers Squibb, and Takeda; and receiving licensing/royalties from Spectrum. Dr. Pouliot reports being an employee at Regeneron and a Regeneron shareholder. Dr. McIntyre reports being an employee at Regeneron. Dr. Awad reports receiving research funding from Bristol-Myers Squibb, Lilly, 10.13039/100004328Genentech, AstraZeneca, and Elva J. and Clayton L. McLaughlin Fund for Lung Cancer Research; receiving consulting fees from/serving on the advisory board of Merck, Bristol-Myers Squibb, Genentech, AstraZeneca, Nektar, Maverick, Blueprint Medicine, Syndax, AbbVie, Gritstone, ArcherDX, Mirati, NextCure, and EMD Serono. Dr. Rietschel reports being an employee at Regeneron and a Regeneron shareholder with patent issued PCT/US2018/018747. Dr. Nishino reports receiving research funding from Merck, Canon Medical Systems, AstraZeneca, and 10.13039/501100022274Daiichi Sankyo; receiving consulting fees from Daiichi Sankyo and AstraZeneca; and receiving honoraria from Roche. Dr. Sholl reports receiving consulting fee from Genentech, Lilly, and GV20 Therapeutics. The remaining authors have no conflict of interests to disclose., (© 2024 The Authors.)

The aim of this study was to determine how TERTp mutations impact glioblastoma prognosis., Materials and Methods: TERTp mutations were assessed in a retrospective cohort of 258 uniformly treated glioblastoma patients. RNA-sequencing and whole exome sequencing results were available in a subset of patients., Results: Overall, there were no differences in outcomes between patients with mutated TERTp -wt or TERTp . However, we found significant differences according to the type of TERTp mutation. Progression-free survival (mPFS) was 9.1 months for those with the C250T mutation and 7 months for those with either the C228T mutation or TERTp -wt ( p = 0.016). Overall survival (mOS) was 21.9 and 15 months, respectively ( p = 0.026). This differential effect was more pronounced in patients with MGMTp methylation (mPFS: p = 0.008; mOS: p = 0.021). Multivariate analysis identified the C250T mutation as an independent prognostic factor for longer mOS (HR 0.69; p = 0.044). We found no differences according to TERTp mutation status in molecular alterations common in glioblastoma, nor in copy number variants in genes related to alternative lengthening of telomeres. Nevertheless, in the gene enrichment analysis adjusted for MGMTp methylation status, some Reactome gene sets were differentially enriched, suggesting that the C250T mutation may exert a lesser effect on telomeres or chromosomes., Conclusions: In our series, patients exhibiting the C250T mutation had a more favorable prognosis compared to those with either TERPp -wt or TERTp C228T mutations. Additionally, our findings suggest a reduced involvement of the C250T mutation in the underlying biological mechanisms related to telomeres.

Introduction: Chemotherapy plus immunotherapy is the standard of care for patients with metastatic NSCLC. No study has evaluated the outcomes of second-line chemotherapy treatments after progression following first-line chemo-immunotherapy., Method: This multicenter retrospective study evaluated the efficacy of second line (2L) chemotherapies after progression under first-line (1L) chemo-immunotherapy, measured by overall survival (2L-OS) and progression free survival (2L-PFS)., Results: A total of 124 patients were included. The mean age was 63.1 years, 30.6 % of the patients were female, 72.6 % had an adenocarcinoma and 43.5 % had a poor ECOG-performance status prior to 2L initiation. Sixty-four (52.0 %) patients were considered resistant to first line chemo-immunotherapy. (1L-PFS < 6 months). In 2L treatments, 57 (46.0 %) patients received taxane monotherapy, 25 (20.1 %) taxane plus anti-angiogenic, 12 (9.7 %) platinum-based chemotherapy and 30 (24.2 %) other chemotherapy. At a median follow-up of 8.3 months (95 %CI: 7.2-10.2), post initiation of 2L treatment, the median 2L-OS was 8.1 months (95 % CI: 6.4-12.7) and the median 2L-PFS was 2.9 months (95 %CI: 2.4-3.3). Overall, the 2L-objective response and 2L-disease control rates were 16.0 %, and 42.5 %, respectively. Taxane plus anti-angiogenic and platinum rechallenge achieved longest median 2L-OS: not reached (95 %CI: 5.8-NR) and 17.6 months (95 %CI 11.6-NR), respectively (p = 0.05). Patients resistant to the 1L treatment had inferior outcomes (2L-OS 5.1 months, 2L-PFS 2.3 months) compared with 1L responders (2L-OS 12.7 months, 2L-PFS 3.2 months)., Conclusion: In this real-life cohort, 2L chemotherapy achieved modest activity following progression under chemo-immunotherapy. 1L-resistant patients remained a refractory population, highlighting a need for new 2L strategies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Immunotherapy using immune checkpoint modulators has revolutionized the oncology field, emerging as a new standard of care for multiple indications, including non-small cell lung cancer (NSCLC). However, prognosis for patients with lung cancer is still poor. Although immunotherapy is highly effective in some cases, not all patients experience significant or durable responses, and further strategies are needed to improve outcomes. Therapeutic cancer vaccines are designed to exploit the body's immune system to activate long-lasting memory against tumor cells that ensure tumor regression, with minimal toxicity. A unique feature of cancer vaccines lies in their complementary approach to boost antitumor immunity that could potentially act synergistically with immune checkpoint inhibitors (ICIs). However, single-line immunization against tumor epitopes with vaccine-based therapeutics has been disappointingly unsuccessful, to date, in lung cancer. The high level of success of several recent vaccines against SARS-CoV-2 has highlighted the evolving advances in science and technology in the vaccines field, raising hope that this strategy can be successfully applied to cancer treatments. In this review, we describe the biology behind the cancer vaccines, and discuss current evidence for the different types of therapeutic cancer vaccines in NSCLC, including their mechanisms of action, current clinical development, and future strategies.

Background: Pleural effusion (PE) is a common metastatic site of NSCLC, associated with poor outcomes. As very few data are available about immune checkpoint inhibitors (ICI) and PE, we aimed to assess the clinical outcome of PE in NSCLC treated with ICI., Method: Multicenter international retrospective study of patients with metastatic NSCLC treated with ICI, between 2012 and 2019. Stratification according to the presence of PE at ICI baseline or appearance under ICI treatment (PE group) versus no history of PE (non-PE group). Primary endpoints were overall survival (OS) and early death rate (EDR, OS ≤ 3 months)., Results: A total of 538 patients were included: 196 in the PE group and 342 in the non-PE group. In the PE group, median age was 64, 31.6 % were female, 77.6 % had non-squamous histology, PD-L1 was ≥50 % in 38.6 % of cases (95 missing). PE was more likely associated with >2 metastatic sites (70.4 % vs. 50 %) and worse performance status (PS ≥ 2, 30.8 % vs 23.1 %). Globally, the overall median OS was 9.7 months [95 %CI: 8.1-11.8]; 6.3 [95 % CI: 4.0-8.6] in PE vs. 11.4 [95 %CI: 9.7-13.8] in the non-PE respectively, P = 0.002. Overall the EDR was 31.4 %; higher in the PE group (38.3 % vs. 27.5 %; OR 1.63, 95 %CI: 1.13-2.37, P = 0.01). In the PE PD-L1≥50 % group, EDR was 33.3 %. In multivariate analysis, after adjustment on PS, liver/intracranial/bone metastasis, ICI line and dNLR, PE remained an independent prognostic factor for OS [HR: 1.38, 95 %CI: 1.09-1.74, P = 0.007]. In the PE group, PE appeared under ICI for 31 patients (16.4 %). We observed lower EDR in this group compared to patients whom PE was already present (29.0 % vs 40.5 %, P = 0.2)., Conclusion: PE is associated with worse immunotherapy outcomes in NSCLC treated with ICI, including in patients with ≥50 % PD-L1 tumors. Thus, in these patients, combination strategies should be explored., (Copyright © 2021. Published by Elsevier B.V.)