Search

In the immunotherapy era, considering the prolonged survival benefit and responses observed with immunecheckpoint inhibitors (ICI) in many cancer types, the identification of patients with rapid progression (PD) and deaths upon ICI has found some skepticism and resistance among the scientific community. Nevertheless, an acceleration of tumour during ICI, defined as hyperprogressive disease (HPD), has been recognized across different cancer types and evidence regarding rapid PDs and deaths are emerging in patients with malignant pleural mesothelioma (MPM), small cell lung cancer (SCLC) and thymic malignancies and in uncommon non-small cell lung cancer (NSCLC) populations. Of note, PD and early deaths (ED) rates upon single agent ICI were up to 60% and 30% in MPM and 70% and 38% in SCLC patients, respectively. Similarly, rapid PDs and deaths were observed in clinical trials and retrospective studies including patients with poor performance status (PS), HIV infection and rare NSCLC histologies. Atypical patterns of response, such as pseudoprogression (PsPD) may also occur in other thoracic malignancies (MPM) and in some uncommon populations (i.e., HIV patients), however probably at lower rate compared to HPD. The characterizations of HPD and PsPD mechanisms and the identification of common definition criteria are the next future challenges in this area of cancer research., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-20-636). The series “Immunotherapy in other thoracic malignancies and uncommon populations” was commissioned by the editorial office without any funding or sponsorship. Dr. RF reports personal fees from MSD, outside the submitted work. Dr. DS reports personal fees and non-financial support from Astra Zeneca, personal fees and non-financial support from Merck Sharp & Dohme, personal fees and non-financial support from Bristol Myers Squibb, non-financial support from Roche, outside the submitted work. Dr. CP reports personal fees and other from ROCHE, personal fees and other from BMS, other from MSD, outside the submitted work. Dr. AP reports personal fees from Roche, personal fees from AstraZeneca, personal fees from BMS, outside the submitted work. Dr. MCG reports grants and personal fees from Eli Lilly, personal fees from Boehringer Ingelheim, grants and personal fees from Otsuka Pharma, grants and personal fees from Astra Zeneca, grants and personal fees from Novartis, grants and personal fees from BMS, grants and personal fees from Roche, grants and personal fees from Pfizer, grants and personal fees from Celgene, grants and personal fees from Incyte, personal fees from Inivata, personal fees from Takeda, grants from Tiziana Sciences, grants from Clovis, grants from Merck Serono, grants and personal fees from Bayer, grants and personal fees from MSD, grants and personal fees from GlaxoSmithKline S.p.A., grants and personal fees from Sanofi-Aventis, grants and personal fees from Spectrum Pharmaceutcials, grants and personal fees from Blueprint Medicine, personal fees from Seattle Genetics, personal fees from Daiichi Sankyo, grants from United Therapeutics Corporation, grants from Merck KGaA, personal fees from Janssen, non-financial support from MSD, non-financial support from Eli-Lilly, grants from Turning Point, grants from Ipsen, grants from MedImmune, grants from Exelisis, grants from Array (Pfizer), personal fees from Mirati Therapeutics, outside the submitted work. Dr. GLR reports personal fees from MSD, other from BMS, personal fees from AstraZeneca, other from ROCHE, outside the submitted work. The authors have no other conflicts of interest to declare., (2021 Translational Lung Cancer Research. All rights reserved.)

Background: Malignant pleural mesothelioma (MPM) is an aggressive tumor but approximately 12% of patients survive more than 3 years. The biological differences underlying better outcomes are not known. Several targeted agents and immunotherapy have been ineffective. Hedgehog (Hh) is one emerging pathway. We compared the biological profiles of patients with different survival, investigating the most frequently altered genes, including the Hh pathway., Methods: We analyzed 56 MPM. A 36-month overall survival (OS) cut-off divided patients into 32 normo (NS) and 24 long (LS) survivors. We used next generation sequencing to test 21 genes, immunohistochemistry to evaluate SMO expression. Mutation differences between NS and LS and their associations with clinical features were analysed by Fisher's test, OS with the Kaplan-Meier method and its association with mutations by univariate and multivariate Cox proportional hazard models., Results: Clinical features were similar in both groups. Eighteen out of 56 patients (32%) were wild-type for the genes analysed. At least five had mutations in BAP1 , NF2 , TP53 , SMO and PTCH1 with no significant differences between the groups except for SMO . SMO , a member of the Hh pathway, was mutated only in NS (15.6%) and only SMO mutations were significantly associated with poor prognosis at univariate (HR =4.36, 95% CI: 2.32-8.18, P<0.0001) and multivariate (HR =9.2, 95% CI: 3.0-28.4, P=0.0001) analysis. All SMO mutated patients expressed high protein levels., Conclusions: SMO mutations were clearly associated with worse prognosis. SMO may be a therapeutic target but this needs to be confirmed in a prospective trial., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-19-425). DS reports personal fees from Astra Zeneca, BMS, Lilly, Boehringer Ingelheim, non-financial support from Astra Zeneca, Roche, MSD, Pfizer outside the submitted work. CP reports personal fees from BMS, MSD outside the submitted work. MT reports personal fees from Astra Zeneca, Pfizer, Eli-Lilly, BMS, Novartis, Roche, MSD, Boehringer Ingelheim, Otsuka, Takeda, Pierre Fabre, grants from Astra Zeneca, Boehringer Ingelheim outside the submitted work. MT serves as an unpaid editorial board member of Translational Lung Cancer Research from Dec 2019 to Nov 2021. GP reports ADVISOR/CONSULTANT: BOEHRINGER ING, AstraZeneca, Roche, BMS, MSD, LILLY ONC. GLR reports personal fees from BMS, MSD, Astra Zeneca outside the submitted work. AP reports personal fees from Roche, AstraZeneca, BMS outside the submitted work. FdB reports personal fees from TIZIANA LIFE SCIENCES, BMS, CELGENE, SERVIER, PHARMA RESEARCH, DAIICHI SANKYO, IGNYTA, NOVARTIS, AMGEN, PFIZER, OCTIMET ONCOLOGY, INCYTE, PIERRE FABRE, ELI LILLY, ROCHE, ASTRA ZENECA, GENTILI, DEPHAFORUM, NOVARTIS, MSD, BAYER, FONDAZIONE MENARINI, SANOFI outside the submitted work. Dr. G Gatta reports grants from AIRC during the conduct of the study. MCG reports grants and personal fees from Eli Lilly, Otsuka Pharma, Astra Zeneca, Novartis, BMS, Roche, Pfizer, Celgene, Incyte, Bayer, MSD, GlaxoSmithKline S.p.A., Spectrum Pharmaceutcials, Blueprint Medicine, personal fees from Boehringer Ingelheim, Inivata, Takeda, Sanofi-Aventis, Seattle Genetics, Daiichi Sankyo, Jannesen, grants from Tiziana Sciences, Clovis, Merck Serono, UNITED THERAPEUTICS CORPORATION, Merck KGaA, TURNING POINT, IPSEN, Medlmmune, EXELISIS, non-financial support from MSD, Pfizer, Eli-Lilly outside the submitted work. MG reports grants from MOH, during the conduct of the study. The other authors have no conflicts of interest to declare., (2020 Translational Lung Cancer Research. All rights reserved.)

The identification of prognostic and predictive biomarkers for high-programmed cell death-ligand 1 (PD-L1) advanced non-small cell lung cancer (aNSCLC) treated with first-line pembrolizumab could support the decision-making about possible combination therapies. To explore the baseline neutrophil-to-lymphocyte ratio (NLR) with the possible addition of PD-L1 tumour proportion score (TPS) level or lactate dehydrogenase (LDH) as possible prognostic biomarkers by a multicenter retrospective exploratory analysis aiming at identifying favourable-risk patients. Baseline NLR was available for all 132 high PD-L1 aNSCLC patients, PD-L1 level and LDH for 81 (61%) and 85 (64%) patients, respectively. NLR, PD-L1 and LDH cut-offs by receiver operating characteristic (ROC) curves were 4.9, 77.5% and 268.5, respectively. Seventy-one patients (54%) had NLR <5; 25 out of 81 NLR <5 (31%) had PD-L1 >80%, 26 out of 85 (31%) NLR <5 and normal LDH (nLDH). Median follow-up was 16.3 months. As compared to NLR >5, significantly better 2-year overall survival (OS) and progression-free survival (PFS) were observed with NLR <5 [62% vs . 41%, P=0.005, hazard ratio (HR) 0.45, and median of 12.0 vs . 5.7 months, P=0.01, HR 0.56, respectively], NLR <5 + PD-L1 >80% (81%, P=0.006, HR 0.20 and median of 14.7, P=0.03, HR 0.44, respectively), and NLR <5 + nLDH (74%, P=0.009, HR 0.25 and median of 14.7, P=0.02, HR 0.40, respectively). NLR <5 and NLR <5 + nLDH significantly associated with PD (P=0.008 and P=0.025, respectively) but not response rate (RR) (P=0.09 and P=0.07, respectively); NLR <5 + PD-L1 >80% both RR (P=0.03) and PD (P=0.02). NLR <5 ± PD-L1 >80% or nLDH could represent easy-to-assess tools to identify high PD-L1 aNSCLC patients with favourable outcome following first-line pembrolizumab monotherapy., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-19-583). MB reports personal fees from Janssen-Cilag, Boehringer Ingelheim, Roche, non-financial support from Bristol-Myers Squibb, AstraZeneca/MedImmune, Pierre Fabre, Ipsen, outside the submitted work. DS reports personal fees and non-financial support from Astra Zeneca, Bristol Myers Squibb, personal fees from Lilly, non-financial support from Merck Sharp & Dohme, Roche outside the submitted work. Dr. Metro reports personal fees from Boehringher-Ingelheim outside the submitted work and serves as an unpaid editorial board member of Translational Lung Cancer Research from Jul 2019 to Jul 2021. ADT reports other from MSD outside the submitted work. AF reports personal fees from Roche, Pfizer, Astellas and Bristol-Myers Squibb outside the submitted work. MCG reports personal fees and other from Eli Lilly, personal fees from Boehringer Ingelheim, Otsuka Pharma, grants, personal fees and other from Astra Zeneca, Novartis, BMS, Roche, Pfizer, Celgene, personal fees from Incyte, Inivata, Takeda, grants and other from Tiziana Sciences, Clovis, Merck Serono, grants and personal fees from Bayer, grants, personal fees and other from MSD, grants and other from GlaxoSmithKline S.p.A., personal fees from Sanofi-Aventis, grants and other from Spectrum Pharmaceutcials, Blueprint Medicine, personal fees from Seattle Genetics, Daiichi Sankyo outside the submitted work. AA reports personal fees from BMS, Astrazeneca, Roche, Pfizer, MSD, Boehringer outside the submitted work. The other authors have no conflicts of interest to declare., (2020 Translational Lung Cancer Research. All rights reserved.)

Background: Several biomarkers have been separately described to select patients for immunotherapy (IO), but few studies integrate these markers. Di Maio, EPSILoN and the plasma microRNA signature classifier (MSC), are three different clinico, biochemical and molecular markers able to independently predict prognosis in non-small cell lung cancer (NSCLC)., Methods: Complete data such as sex, histology, ECOG-PS, stage, smoking status, presence of liver metastasis, LDH and neutrophils-to-lymphocyte ratio were collected to generate Di Maio and EPSILoN. The MSC risk level was prospectively assessed in plasma samples collected at baseline IO. The 3 markers were integrated into the DEMo score system prospectively tested in a cohort of 200 advanced NSCLC patients treated with IO. Endpoints were overall survival (OS), progression-free survival (PFS) and overall response rate (ORR)., Results: DEMo separated patients in 7-risk groups whose median OS had a trend ranging from 29.7 to 1.5 months (P<0.0001). When comparing patients with the lowest (n=29) and the highest (n=35) DEMo scores ORR was 45% and 3%, respectively (P<0.0001). Considering the 53 PD-L1 ≥50% patients, DEMo identified a group of 13 (25%) patients who benefit less from IO in terms of both OS (HR: 8.81; 95% CI: 2.87-20.01) and PFS (HR: 6.82; 95% CI: 2.57-18.10). Twelve out of 111 (11%) patients who most benefit from IO according to OS (HR: 0.21; 95% CI: 0.07-0.62) and PFS (HR: 0.28; 95% CI: 0.12-0.65) were identified by DEMo in the PD-L1 <50% group., Conclusions: The DEMo prognostic score system stratified NSCLC patients treated with IO better than each single marker. The proper use of DEMo according to PD-L1 could improve selection in IO regimens., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-20-231). AP reports grants from Italian Association for Cancer Research during the conduct of the study; personal fees from Roche, AstraZeneca and BMS outside the submitted work; in addition, AP has a patent IT1406672 licensed to Gensignia LS, a patent IT1403685 licensed to Gensignia LS, and a patent IT1406866 licensed to Gensignia LS. CP reports grants from Italian Association for Cancer Research during the conduct of the study; personal fees from BMS and MSD outside the submitted work; in addition, CP has a patent IT1406672 licensed to Gensignia LS, a patent IT1403685 licensed to Gensignia LS, and a patent IT1406866 licensed to Gensignia LS. GLR reports grants from Italian Association for Cancer Research during the conduct of the study; personal fees from BMS, MSD and AstraZeneca outside the submitted work; in addition, GLR has a patent IT1406672 licensed to Gensignia LS, a patent IT1403685 licensed to Gensignia LS, and a patent IT1406866 licensed to Gensignia LS. DS reports grants from Italian Association for Cancer Research during the conduct of the study; personal fees from BMS, AstraZeneca and Boehringer Ingelheim outside the submitted work; in addition, DS has a patent IT1406672 licensed to Gensignia LS, a patent IT1403685 licensed to Gensignia LS, and a patent IT1406866 licensed to Gensignia LS. RF reports grants from Italian Association for Cancer Research during the conduct of the study; in addition, RF has a patent IT1406672 licensed to Gensignia LS, a patent IT1403685 licensed to Gensignia LS, and a patent IT1406866 licensed to Gensignia LS. GG reports grants from Italian Association for Cancer Research during the conduct of the study; in addition, GG has a patent IT1406672 licensed to Gensignia LS, a patent IT1403685 licensed to Gensignia LS, and a patent IT1406866 licensed to Gensignia LS. ADT reports grants from Italian Association for Cancer Research during the conduct of the study; in addition, ADT has a patent IT1406672 licensed to Gensignia LS, a patent IT1403685 licensed to Gensignia LS, and a patent IT1406866 licensed to Gensignia LS. GV reports grants from Italian Association for Cancer Research during the conduct of the study; in addition, GV has a patent IT1406672 licensed to Gensignia LS, a patent IT1403685 licensed to Gensignia LS, and a patent IT1406866 licensed to Gensignia LS. MB reports grants from Italian Association for Cancer Research during the conduct of the study; in addition, Marta B has a patent IT1406672 licensed to Gensignia LS, a patent IT1403685 licensed to Gensignia LS, and a patent IT1406866 licensed to Gensignia LS. RL reports grants from Italian Association for Cancer Research during the conduct of the study; in addition, RL has a patent IT1406672 licensed to Gensignia LS, a patent IT1403685 licensed to Gensignia LS, and a patent IT1406866 licensed to Gensignia LS. BT reports grants from Italian Association for Cancer Research during the conduct of the study; in addition, BT has a patent IT1406672 licensed to Gensignia LS, a patent IT1403685 licensed to Gensignia LS, and a patent IT1406866 licensed to Gensignia LS. FT reports grants from Italian Association for Cancer Research during the conduct of the study; in addition, FT has a patent IT1406672 licensed to Gensignia LS, a patent IT1403685 licensed to Gensignia LS, and a patent IT1406866 licensed to Gensignia LS. VT has a patent IT1406672 licensed to Gensignia LS, a patent IT1403685 licensed to Gensignia LS, and a patent IT1406866 licensed to Gensignia LS. GS reports grants from Italian Association for Cancer Research during the conduct of the study; in addition, GS has a patent IT1406672 licensed to Gensignia LS, a patent IT1403685 licensed to Gensignia LS, and a patent IT1406866 licensed to Gensignia LS. MCG reports grants from Italian Association for Cancer Research during the conduct of the study; personal fees from Roche, AstraZeneca, BMS, MSD, International GmbH, Boehringer Ingelheim Italia S.P.A, Celgene, Eli Lilly, Ignyta, Incyte, Inivata, MedImmune, Novartis, Pfizer, Roche and Takeda outside the submitted work; in addition, MCG has a patent IT1406672 licensed to Gensignia LS, a patent IT1403685 licensed to Gensignia LS, and a patent IT1406866 licensed to Gensignia LS. Mattia B reports grants from Italian Ministry of Health during the conduct of the study; in addition, Mattia B has a patent IT1406672 licensed to Gensignia LS, a patent IT1403685 licensed to Gensignia LS, and a patent IT1406866 licensed to Gensignia LS. The other author has no conflicts of interest to declare., (2020 Translational Lung Cancer Research. All rights reserved.)

Lung cancer is one of the major causes of cancer related mortality worldwide. Brain metastases (BM) complicate clinical evolution of non-small cell lung cancer (NSCLC) in approximately 25-40% of cases, adversely influencing quality of life (QoL) and overall survival (OS). Systemic therapy remains the standard strategy for metastatic disease. Nevertheless, the blood-brain barrier (BBB) makes central nervous system (CNS) a sanctuary site. To date, the combination of chemotherapy with whole brain radiation therapy (WBRT), surgery and/or stereotactic radiosurgery (SRS) represents the most used treatment for patients (pts) with intracranial involvement. However, due to their clinical conditions, many pts are not able to undergo local treatments. Targeted therapies directed against epidermal growth factor receptor (EGFR), such as gefitinib, erlotinib and afatinib, achieved important improvements in EGFR mutated NSCLC with favorable toxicity profile. Although their role is not well defined, the reported objective response rate (ORR) and the good tolerance make EGFR-tyrosine kinase inhibitors (TKIs) an interesting valid alternative for NSCLC pts with BM, especially for those harboring EGFR mutations. Furthermore, new-generation TKIs, such as osimertinib and rociletinib, have already shown important activity on intracranial disease and several trials are still ongoing to evaluate their efficacy. In this review we want to highlight literature data about the use and the effectiveness of EGFR-TKIs in pts with BM from NSCLC., Competing Interests: MC Garassino declares consultancies from AstraZeneca, Roche, Boehringer. The other authors have no conflicts of interest to declare.