Cellular Therapy in NSCLC: Between Myth and Reality.

PURPOSE OF REVIEW: In this paper, we review the current state and modalities of adoptive cell therapies (ACT) in non-small cell lung carcinoma (NSCLC). We also discuss the challenges hampering the use of ACT and the approaches to overcome these barriers. RECENT FINDINGS: Several trials are ongoing investigating the three main modalities of T cell-based ACT: tumor-infiltrating lymphocytes (TILs), genetically engineered T-cell receptors (TCRs), and chimeric antigen receptor (CAR) T cells. The latter, in particular, has revolutionized the treatment of hematologic malignancies. However, the efficacy against solid tumor is still sparse. Major limitations include the following: severe toxicities, restricted infiltration and activation within the tumors, antigen escape and heterogeneity, and manufacturing issues. ACT is a promising tool to improve the outcome of metastatic NSCLC, but significant translational and clinical research is needed to improve its application and expand the use in NSCLC.

Current Approaches to Neoadjuvant Immunotherapy in Resectable Non-small Cell Lung Cancer.

PURPOSE OF REVIEW: For decades, early-stage resectable non-small cell lung cancer (NSCLC), while potentially curable, has been marred by unacceptably high recurrence rates. RECENT FINDINGS: Anti-PD(L)1 immune checkpoint blockade (ICB) has revolutionized the treatment of advanced NSCLC, and with recent approvals in the peri-operative space, is now poised to transform the systemic treatment paradigm for localized and locally-advanced NSCLC. In this review, we focus on neoadjuvant ICB in resectable NSCLC, highlighting the pre-clinical rationale for neoadjuvant ICB, early clinical trials, randomized phase 3 trial data, and future directions for resectable NSCLC.

Neoadjuvant Immunotherapy: A Promising New Standard of Care.

Neoadjuvant immunotherapy has emerged as a promising approach in the treatment of various malignancies, with preclinical studies showing improved immune responses in the preoperative setting. FDA-approved neoadjuvant-immunotherapy-based approaches include triple-negative breast cancer and early non-small cell lung cancer on the basis of improvement in pathological response and event free survival. Nevertheless, current trials have only shown benefits in a fraction of patients. It is therefore crucial to identify predictive biomarkers to improve patient selection for such approaches. This review aims to provide an overview of potential biomarkers of neoadjuvant immunotherapy in early triple-negative breast cancer, bladder cancer, melanoma, non-small cell lung cancer, colorectal cancer and gastric cancer. By the extrapolation of the metastatic setting, we explore known predictive biomarkers, i.e., PD-L1, mismatch repair deficiency and tumour mutational burden, as well as potential early-disease-specific biomarkers. We also discuss the challenges of identifying reliable biomarkers and the need for standardized protocols and guidelines for their validation and clinical implementation.

Risk of SARS-CoV2-Related Mortality in Non-Small Cell Lung Cancer Patients Treated with First-Line Immunotherapy Alone or in Combination with Chemotherapy.

BACKGROUND: The impact of systemic anticancer treatments on SARS-CoV-2-related mortality is still debatable. METHODS: By a retrospective analysis of patients with non-small-cell lung cancer (NSCLC) treated with first-line Pembrolizumab or in combination with chemotherapy (ChT) during the first surge of the pandemic. RESULTS: The adjusted risk of death was higher in patients treated with ChT + Pembrolizumab (HR 4.6, 1.2-17.4, p = 0.02). The SARS-CoV-2-related mortality rate was higher in patients treated with ChT + Pembrolizumab (p = 0.03), ≥70 years (p = 0.03) and current smokers (p = 0.17). CONCLUSIONS: The addition of ChT to immunotherapy could be associated with increased risk of mortality and higher SARS-CoV-2-related mortality rate.

Biological Rationale for Peripheral Blood Cell-Derived Inflammatory Indices and Related Prognostic Scores in Patients with Advanced Non-Small-Cell Lung Cancer.

PURPOSE OF REVIEW: To describe the biological rationale of peripheral blood cells (PBC)-derived inflammatory indexes and assess the related prognostic scores for patients with advanced non-small cell lung cancer (aNSCLC) treated with immune-checkpoint inhibitors (ICI). RECENT FINDINGS: Inflammatory indexes based on PBC may indicate a pro-inflammatory condition affecting the immune response to cancer. The lung immune prognostic index (LIPI), consisting of derived neutrophils-to-lymphocyte ratio (NLR) and lactate dehydrogenase, is a validated prognostic tool, especially for pretreated aNSCLC patients, where the combination of NLR and PD-L1 tumour expression might also be predictive of immunotherapy benefit. In untreated high-PD-L1 aNSCLC patients, the Lung-Immune-Prognostic score (LIPS), including NLR, ECOG PS and concomitant steroids, is prognostic, and its modified version might indicate patients with favourable outcomes despite an ECOG PS of 2. NLR times platelets (i.e., SII), included in the NHS-Lung score, might improve the prognostication for combined chemoimmunotherapy. PBC-derived inflammatory indexes and related scores represent accurate, reproducible and non-expensive prognostic tools with clinical and research utility.

SAKK 19/17: safety analysis of first-line durvalumab in patients with PD-L1 positive, advanced nonsmall cell lung cancer and a performance status of 2.

INTRODUCTION: The safety of first-line (1L) durvalumab in patients with advanced nonsmall-cell lung cancer (NSCLC) and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 (PS2) is unknown. This is an interim unplanned safety analysis of the study SAKK 19/17 for patients with metastatic NSCLC with programmed death-ligand 1 (PD-L1) expression in ≥ 25% of tumor cells and an ECOG PS2 treated with 1L durvalumab. This safety analysis was triggered by the SAKK data and safety monitoring board due to a high mortality rate observed after the recruitment of the first 21 patients. METHODS: This single-arm phase II study recruited patients with metastatic NSCLC with PD-L1 in ≥ 25% and ECOG PS2. Patients received durvalumab 1500 mg every four weeks. The trial aims to recruit 48 patients in total. This report includes safety analyses only. Adverse events (AEs) were assessed using National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) Version 5.0. Efficacy data including the primary endpoint overall survival at 6 months and secondary endpoints (objective response rate, progression-free survival, and quality of life) will be reported at a later time point. RESULTS: The data from 21 patients were available at this interim safety analysis. Among these, 13 deaths (13/21; 62%) were reported, including one treatment-related fatal colonic perforation at 9 months after treatment initiation (1/13; 8%). Twelve deaths were not treatment-related (12/13; 92%), and mostly attributed to tumor progression (10/13; 77%). Of note, seven deaths (7/13; 54%) occurred during the first 5 weeks (range 0.6-4.7 weeks) after treatment initiation. Four (4/7; 57%) were respiratory failures attributed to tumor progression. One of these patients (25%) had pre-existing COPD, and three (75%) had baseline dyspnea grade 2-3 related to the tumor. Grade ≥ 3 treatment-related AEs (TRAEs) included colonic perforation (grade 5), abdominal pain, and colitis (grade 3 each) in one patient, and fatigue (grade 3) in another. Other Grade ≥ 3 AEs unrelated to treatment were all of pulmonary origin: lung infections (19%), dyspnea (24%), cough (5%), and bronchial obstruction (5%). CONCLUSIONS: 1L durvalumab in patients with ECOG PS2 and metastatic NSCLC with PD-L1 expression ≥ 25% resulted in an unexpectedly high number of fatal early events due to rapid tumor progression. We recommend to avoid treatment with 1 L durvalumab of patients who are highly symptomatic from the tumor, particularly those with respiratory symptoms. The study is continuing its accrual after an amendment excluding these patients.

The Role and Impact of Minimal Residual Disease in NSCLC.

PURPOSE OF REVIEW: There has been a huge development in the assessment of malignancies through liquid biopsies last years, especially for NSCLC, where its use has become part of clinical practice in some settings. We aim to summarize current evidence about minimal residual disease and its use in lung cancer. RECENT FINDINGS: Recent studies using ctDNA in NSCLC but also in other types of cancer found strong correlations between the presence of ctDNA and the risk of disease progression or death after curative intent, despite current technical difficulties in performing this analysis (high sensitivity and specificity required). Evaluation of MRD in NSCLC, especially through ctDNA, could be an important point in future trial designs and could permit a more "targeted" adjuvant treatment.

A New Generation of Vaccines in the Age of Immunotherapy.

PURPOSE OF REVIEW: Cancer vaccines are one of the most extensively studied immunotherapy type in solid tumors. Despite favorable presuppositions, so far, the use of cancer vaccines has been associated with disappointing results. However, a new generation of vaccines has been developed, promising to revolutionize the immunotherapy field. RECENT FINDINGS: In this review, we aim to highlight the advances in cancer vaccines and the remaining hurdles to overcome. Cancer vaccination has experienced tremendous progress in the last decade, with myriad promising developments. Future efforts should focus on optimization of target identification, streamlining of most appropriate vaccination strategies, and adjuvant development, as well as predictive biomarker identification. Cautious optimism is warranted in the face of early successes seen in recent clinical trials for oncolytic vaccines. If an approach were to prove successful, it could revolutionize cancer therapy the way ICIs did in the previous decade.

The METeoric rise of MET in lung cancer.

Over the years, there has been a continuous increase in clinically relevant driver mutations in patients with non-small cell lung cancer (NSCLC). Among these, dysregulated activation of the MET tyrosine kinase receptor has gained importance due to the recent development of quite effective treatments. MET dysregulation encompasses a heterogeneous array of alterations leading to the prolonged activation of the cellular MET (c-MET or MET) receptor and downstream proliferation pathways. It can arise through several mechanisms, including gene amplification, overexpression of the receptor and/or its ligand hepatocyte growth factor, and the acquisition of activating mutations. MET mutations are found in approximately 3% to 5% of patients with NSCLC, mainly adenocarcinoma, and are overrepresented in the sarcomatoid subtype. De novo MET amplifications are found in 1% to 5% of NSCLC cases, also predominantly in adenocarcinoma. In the current review, the authors discussed the biology of MET, how to diagnose clinically relevant alterations, and the rising clinical importance of these alterations in light of the emergence of multiple targeted therapies, both within the context of MET as a driver of resistance and in its own right.

Outcomes with immune checkpoint inhibitors for relapsed small-cell lung cancer in a Swiss cohort.

OBJECTIVES: Early clinical trials showed promising outcomes with immune-checkpoint inhibitors (ICI) in a subset of patients with relapsed small-cell lung carcinoma (SCLC). The aim of this retrospective analysis was to assess the efficacy and safety of ICI for relapsed SCLC in a real-world patient population. METHODS: Nine cancer centres in Switzerland contributed data to this cohort. Responses were assessed by the local investigators using standard RECIST v1.1 criteria. Progression-free survival (PFS) and overall survival (OS) were analysed by the Kaplan-Meier method. Associations between potential predictive markers and survival endpoints were probed by Cox proportional hazards. RESULTS: Forty-five patients were included in the analysis. Median age was 63 years, 73% were males and 18% had an ECOG performance status (PS) ≥ 2. ICIs were given as second-line treatment in 60%. Twenty-four patients (53%) received ipilimumab with nivolumab. Twenty-eight patients (62%) had undergone irradiation (RT) prior to or during ICI. Overall response rate (ORR) was 29% and median PFS and OS were 2.3 and 6.5 months, respectively. Median duration of response was 9 months (95% CI 2.8-NA). Five patients maintained their response for > 6 months, all of them receiving combination treatment. There were no new safety signals. CONCLUSION: This is the first report of "real-world" data on ICI in relapsed SCLC also including patients with poor PS. Promising durable responses were observed. No biological prognostic marker could be identified.

Impact of performance status on non-small-cell lung cancer patients with a PD-L1 tumour proportion score ≥50% treated with front-line pembrolizumab.

Objectives: We retrospectively analysed patients with advanced non-small-cell lung cancer (NSCLC) harbouring high PD-L1 expression (>50%) and treated with front-line pembrolizumab, comparing outcomes of patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2 to those with PS 0-1.Methods: Data were collected by 16 participating centres. All patients with NSCLC and high PD-L1, treated with first-line pembrolizumab were included. We collected medical data from patient files, pathology and laboratory reports. Patient characteristics, comorbidities, PS, and tumour characteristics were reported. Overall survival (OS), progression-free survival (PFS) and response rate (RR) were calculated.Results: 302 patients were included, 246 with PS 0-1, 56 with PS 2. RR was 72% among patients with PS 0-1 compared to 45% with PS2 (odds ratio (OR) 0.31 (95% CI: 0.17-0.57), p < .001). Median PFS was 2.6 months (95% CI: 1.9-5.1) among patients with PS2 and 11.3 months (95% CI: 8.5-14.4) among those with PS 0-1. Median OS was 7.8 months (95% CI: 2.5-10.7) in the PS2 group, not reached in the PS 0-1 group. PS 2 remained predictive of poor outcomes in multivariate analysis.Conclusion: PS 2 is a strong independent predictor of poor response and survival in NSCLC patients with high PD-L1, treated with front-line pembrolizumab. Prospective randomised trials comparing immunotherapy to chemotherapy in this population would be welcome.

Targeted Therapies in Early Stage NSCLC: Hype or Hope?

Non-small-cell lung cancer (NSCLC) represents roughly 85% of lung cancers, with an incidence that increases yearly across the world. The introduction in clinical practice of several new and more effective molecules has led to a consistent improvement in survival and quality of life in locally advanced and metastatic NSCLC. In particular, oncogenic drivers have indeed transformed the therapeutic algorithm for NSCLC. Nearly 25% of patients are diagnosed in an early stage when NSCLC is still amenable to radical surgery. In spite of this, five-year survival rates for fully resected early stage remains rather disappointing. Adjuvant chemotherapy has shown a modest survival benefit depending on the stage, but more than half of patients relapse. Given this need for improvement, over the last years different targeted therapies have been evaluated in early-stage NSCLC with no survival benefit in unselected patients. However, the identification of reliable predictive biomarkers to these agents in the metastatic setting, the design of molecularly-oriented studies, and the availability of novel potent and less toxic agents opened the way for a novel era in early stage NSCLC treatment. In this review, we will discuss the current landscape of targeted therapeutic options in early NSCLC.

[A new hope in the treatment of hepatocellular carcinoma]. / Nouveaux espoirs thérapeutiques dans le carcinome hépatocellulaire.

Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related mortality worldwide. It most often develops in cirrhosis, the etiology varying based on regional risk factors. Multidisciplinary treatment is the cornerstone of the management of HCC, with surgical or local treatments available for early-stage disease. In advanced disease, there was no progress for many years, with sorafenib in the first-line, and, more recently, regorafenib in selected second-line patients. In the last 2 years, multiple treatment options have surfaced, making the therapeutic decisions both more promising and complex.

Le carcinome hépatocellulaire (CHC) est la deuxième cause de décès par cancer dans le monde. Il se développe le plus souvent sur un terrain de cirrhose, dont l'étiologie varie notamment en fonction des zones d'habitation. Sa prise en charge repose sur une discussion multidisciplinaire, avec des traitements par résection chirurgicale ou gestes ciblés pour les stades localisés. Dans les stades avancés, pendant de nombreuses années les traitements systémiques disponibles étaient très limités, avec le sorafénib puis le régorafénib en cas de progression ou intolérance. Mais depuis 2 ans, nous assistons à une augmentation du nombre de molécules validées pour la prise en charge du CHC rendant les choix thérapeutiques plus complexes et prometteurs.

[Metastatic hormone-sensitive prostate cancer: more than just androgen-deprivation therapy]. / Cancer de la prostate métastatique hormonosensible: l'hormonothérapie, oui, mais pas seulement !

For decades, androgen deprivation was the standard of care for metastatic prostate cancer. Chemotherapy, then novel anti-androgen therapies, changed the treatment paradigm. Large phase III randomized clinical trials were conducted over the course of the last decade, first among patients with castration resistant prostate cancer, then among those with hormone-sensitive disease. Today, androgen deprivation therapy alone is no longer the gold standard and should be associated either with chemotherapy in high-volume disease, or novel anti-androgen therapy. As such, each case should be discussed with a specialist to choose the most appropriate treatment.

Pendant plusieurs décennies, la suppression androgénique seule a été le traitement standard du cancer de la prostate métastatique. La chimiothérapie puis les hormonothérapies de nouvelle génération ont bouleversé ce paradigme, avec d'importantes répercussions thérapeutiques. De grands essais randomisés de phase III ont été conduits ces dernières années, ciblant d'abord les cancers prostatiques métastatiques résistant à la castration puis les cancers prostatiques métastatiques hormonosensibles. Aujourd'hui, la déprivation seule n'est plus le traitement standard; elle est désormais associée soit à une chimiothérapie en cas de maladie à haut volume, soit à une hormonothérapie de nouvelle génération. Ainsi, chaque cas mérite d'être discuté avec un spécialiste, afin de choisir le traitement le plus adapté.

[Granulocyte-Colony Stimulating Factors as adjunctive therapy in patients with neutropenic fever]. / Facteurs de croissance granulocytaire dans le traitement curatif des neutropénies fébriles.

Chemotherapy induced neutropenic fever requires a hospitalization in 20-30 % of cases and is then associated with a mortality above 10 %. Hospitalized patients require strict isolation, which sometimes results in a substantial physical and psychological burden. Granulocyte-colony stimulating factors (G-CSF) are established in the primary and secondary prevention of chemotherapy-induced neutropenia. However, their role as adjunctive therapy in patients with neutropenic fever is less clear. This review resumes current best evidence in this area and discusses current recommendations.

La neutropénie fébrile secondaire à une chimiothérapie nécessite une hospitalisation dans 20 à 30 % des cas, et est alors associée à une mortalité supérieure à 10 %. Les patients hospitalisés pour une neutropénie fébrile nécessitent des mesures d'isolement strictes, avec parfois des répercussions non négligeables sur les plans physique et psychique. Les facteurs de croissance granulocytaire (G-CSF) tiennent une place bien établie dans les préventions primaire et secondaire de la neutropénie liée aux cycles de chimiothérapie. Cependant, la place des G-CSF dans le traitement curatif de la neutropénie fébrile postchimiothérapie semble moins claire. Cet article a pour but de résumer l'évidence et discuter des recommandations actuelles dans cette indication thérapeutique.

BRCA1/BRCA2 germline mutations and chemotherapy-related hematological toxicity in breast cancer patients.

PURPOSE: BRCA1 and BRCA2 proteins are central to DNA repair process through homologous recombination. We hypothesize that BRCA1/BRCA2 mutation carriers may exhibit increased hematological toxicity when receiving genotoxic chemotherapy. METHODS: We included women with primary breast cancers screened for BRCA1/BRCA2 germline mutations and treated with (neo)adjuvant chemotherapy in Geneva (Swiss cohort). The primary endpoint was the incidence of febrile neutropenia following the first chemotherapy cycle (C1). Secondary endpoints were the incidence of grade 3-4 neutropenia, grade 4 neutropenia and hospitalization during C1, G-CSF use and chemotherapy dose reduction during the entire chemotherapy regimen. Long-term toxicities (hematological, cardiac and neuropathy) were assessed in the Swiss cohort and a second cohort of patients from Lyon (French cohort). RESULTS: Overall, 221 patients were assessed for acute hematological toxicity, including 23 BRCA1 and 22 BRCA2 carriers. Following the C1, febrile neutropenia had an incidence of 35% (p = 0.002), 14% (p = 0.562) and 10% among BRCA1, BRCA2 and non-carriers, respectively. Grade 4 neutropenia was found in 57% of BRCA1 (p < 0.001), 14% of BRCA2 (p = 0.861) and 18% of non-carriers. G-CSF support was necessary in 86% of BRCA1 (p = 0.005), 64% of BRCA2 (p = 0.285) and 51% of non-carriers. For long-term toxicity analysis, 898 patients were included (167 BRCA1-, 91 BRCA2- and 640 non-carriers). There was no difference between the 3 groups. CONCLUSIONS: BRCA1 germline mutations is associated with greater acute hematological toxicity in breast cancer patients. These observations could have implication for primary prophylaxis with G-CSF.

Poor-Performance Status Assessment of Patients with Non-small Cell Lung Cancer Remains Vague and Blurred in the Immunotherapy Era.

PURPOSE OF REVIEW: In the latest decade, the introduction of immune-checkpoint inhibitors (ICIs) has dramatically improved the prognosis of patients with NSCLC. First-line ICIs or chemo-ICI trials have demonstrated OS advantages but the accrual was limited to Eastern Cooperative Oncology Group (ECOG) performance status (PS)0-1 patients. ICI studies have for the vast majority excluded patients with poor performance status. PS 2 particularly is known as a negative prognostic factor for survival and a predictive factor of adverse events and poor response to treatments. Data on the activity of ICIs in PS2 patients are limited and come from heterogeneous meta-analyses and small phase II or expanded access trials. Often, terms such as "unfit" or "frail" ascertain the eligibility of patients to undergo cytotoxic chemotherapy, without specifying PS. RECENT FINDINGS: Other tools exist to aid in decision-making, and one simple, rapid, and validated screening test for frailty is the FRAIL scale consisting of 5 straightforward questions that can be self-administered and may represent an efficient and cost-effective way to screen large groups of patients for frailty. The Comprehensive Geriatric Assessment (CGA) is a widely used method to determine the medical, psychological, and functional capabilities of older patients. However, CGA is time-consuming and this could represent a real barrier to its adoption in clinical practice. For this reason, a quick screening tool, the G8 questionnaire, has been developed and demonstrated validity also in a younger population. A complementary tool to assess patients' frailty is Charlson comorbidity index (CCI) which has become the most widely used clinical index for a variety of disorders and cancers. Yet, none of these tools has been validated as predictive in ICI. In conclusion, solid data regarding the benefit of ICIs in ECOG PS2 NSCLC patients are currently lacking and the role of immunotherapy remains uncertain for PS2 patients. Prospective randomized trials addressing this question are warranted or ongoing. However, we are concerned that without a more extensive and objective assessment of patients' fitness and frailty by using and validating appropriate tools a clear answer may not come to light.

Diagnosis and Treatment of ALK Aberrations in Metastatic NSCLC.

OPINION STATEMENT: There has been rapid progress in the use of targeted therapies for ALK-positive which has led to improve dramatically PFS and OS in the metastatic ALK-rearranged NSCLC patients. There are several molecules now available (crizotinib, ceritinib, brigatinib, alectinib, and lorlatinib) and others in development. Such an improvement in treatment efficacy has even more highlighted the importance of an adequate identification of ALK alterations. Efficient and easily accessible testing tools are required to identify eligible patients in a timely fashion. Different methods for detecting ALK+ NSCLC patients are now available, with fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) currently representing validated diagnostic techniques for the initial assessment of ALK status. Furthermore the widespread use of next-generation sequencing to detect other possible different activating mutations has allowed to identify individual ALK fusion variants. Several more expensive and time-consuming methods are also available nowadays which have the advantage to detect even rarer uncommon ALK fusion variants and mutations in tumour or blood samples. A review of the evolving testing-treatment landscape is needed to highlight the importance of properly diagnosing and treating this group of patients.

[Supportive care in oncology: a real change for patients?] / Soins de support en oncologie : un vrai changement pour le patient ?

With the increased incidence of cancers due to an aging population, and a prolonged survival thanks to advances in cancer treatments, new therapeutic challenges have arisen. The management of symptoms, the tolerance of increasingly effective oncologic treatments and, finally, quality of life are central concerns of patients and their loved ones. Supportive care in oncology has helped meet these challenges, offering a holistic approach, encompassing somatic, psychiatric and social aid. Inaugurated in 2005, the oncologic supportive care unit of the Geneva University Hospitals allows many cancer patients access to a team of multidisciplinary care-givers to help meet their needs.

Avec le vieillissement de la population à l'origine d'une augmentation de l'incidence des cancers et face aux progrès thérapeutiques qui permettent aux patients atteints de vivre plus longtemps, surgissent de nouveaux défis de prise en charge. La gestion des symptômes, la tolérance aux traitements oncologiques de plus en plus nombreux et efficaces, et finalement la qualité de vie sont au centre des préoccupations des patients et de leurs proches. Les soins de support en oncologie permettent de répondre à ces attentes en proposant une prise en charge globale, aussi bien somatique que psychique et sociale. Inaugurée en 2005, l'unité hospitalière des soins de support en oncologie des HUG permet à de nombreux patients, atteints de cancer, d'avoir accès à une équipe multidisciplinaire de soignants afin de répondre à ces objectifs.