Delvys Rodriguez-Abreu

Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial

BACKGROUND Erlotinib has been shown to improve progression-free survival compared with chemotherapy when given as first-line treatment for Asian patients with non-small-cell lung cancer (NSCLC) with activating EGFR mutations. We aimed to assess the safety and efficacy of erlotinib compared with standard chemotherapy for first-line treatment of European patients with advanced EGFR-mutation positive NSCLC. METHODS We undertook the open-label, randomised phase 3 EURTAC trial at 42 hospitals in France, Italy, and Spain. Eligible participants were adults (> 18 years) with NSCLC and EGFR mutations (exon 19 deletion or L858R mutation in exon 21) with no history of chemotherapy for metastatic disease (neoadjuvant or adjuvant chemotherapy ending ≥ 6 months before study entry was allowed). We randomly allocated participants (1:1) according to a computer-generated allocation schedule to receive oral erlotinib 150 mg per day or 3 week cycles of standard intravenous chemotherapy of cisplatin 75 mg/m(2) on day 1 plus docetaxel (75 mg/m(2) on day 1) or gemcitabine (1250 mg/m(2) on days 1 and 8). Carboplatin (AUC 6 with docetaxel 75 mg/m(2) or AUC 5 with gemcitabine 1000 mg/m(2)) was allowed in patients unable to have cisplatin. Patients were stratified by EGFR mutation type and Eastern Cooperative Oncology Group performance status (0 vs 1 vs 2). The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. We assessed safety in all patients who received study drug (≥ 1 dose). This study is registered with ClinicalTrials.gov, number NCT00446225. FINDINGS Between Feb 15, 2007, and Jan 4, 2011, 174 patients with EGFR mutations were enrolled. One patient received treatment before randomisation and was thus withdrawn from the study; of the remaining patients, 86 were randomly assigned to receive erlotinib and 87 to receive standard chemotherapy. The preplanned interim analysis showed that the study met its primary endpoint; enrolment was halted, and full evaluation of the results was recommended. At data cutoff (Jan 26, 2011), median PFS was 9·7 months (95% CI 8·4-12·3) in the erlotinib group, compared with 5·2 months (4·5-5·8) in the standard chemotherapy group (hazard ratio 0·37, 95% CI 0·25-0·54; p < 0·0001). Main grade 3 or 4 toxicities were rash (11 [13%] of 84 patients given erlotinib vs none of 82 patients in the chemotherapy group), neutropenia (none vs 18 [22%]), anaemia (one [1%] vs three [4%]), and increased amino-transferase concentrations (two [2%] vs 0). Five (6%) patients on erlotinib had treatment-related severe adverse events compared with 16 patients (20%) on chemotherapy. One patient in the erlotinib group and two in the standard chemotherapy group died from treatment-related causes. INTERPRETATION Our findings strengthen the rationale for routine baseline tissue-based assessment of EGFR mutations in patients with NSCLC and for treatment of mutation-positive patients with EGFR tyrosine-kinase inhibitors. FUNDING Spanish Lung Cancer Group, Roche Farma, Hoffmann-La Roche, and Red Temática de Investigacion Cooperativa en Cancer.

First-Line Nivolumab in Stage IV or Recurrent Non–Small-Cell Lung Cancer

BACKGROUND Nivolumab has been associated with longer overall survival than docetaxel among patients with previously treated non–small‐cell lung cancer (NSCLC). In an open‐label phase 3 trial, we compared first‐line nivolumab with chemotherapy in patients with programmed death ligand 1 (PD‐L1)–positive NSCLC. METHODS We randomly assigned, in a 1:1 ratio, patients with untreated stage IV or recurrent NSCLC and a PD‐L1 tumor‐expression level of 1% or more to receive nivolumab (administered intravenously at a dose of 3 mg per kilogram of body weight once every 2 weeks) or platinum‐based chemotherapy (administered once every 3 weeks for up to six cycles). Patients receiving chemotherapy could cross over to receive nivolumab at the time of disease progression. The primary end point was progression‐free survival, as assessed by means of blinded independent central review, among patients with a PD‐L1 expression level of 5% or more. RESULTS Among the 423 patients with a PD‐L1 expression level of 5% or more, the median progression‐free survival was 4.2 months with nivolumab versus 5.9 months with chemotherapy (hazard ratio for disease progression or death, 1.15; 95% confidence interval [CI], 0.91 to 1.45; P=0.25), and the median overall survival was 14.4 months versus 13.2 months (hazard ratio for death, 1.02; 95% CI, 0.80 to 1.30). A total of 128 of 212 patients (60%) in the chemotherapy group received nivolumab as subsequent therapy. Treatment‐related adverse events of any grade occurred in 71% of the patients who received nivolumab and in 92% of those who received chemotherapy. Treatment‐related adverse events of grade 3 or 4 occurred in 18% of the patients who received nivolumab and in 51% of those who received chemotherapy. CONCLUSIONS Nivolumab was not associated with significantly longer progression‐free survival than chemotherapy among patients with previously untreated stage IV or recurrent NSCLC with a PD‐L1 expression level of 5% or more. Overall survival was similar between groups. Nivolumab had a favorable safety profile, as compared with chemotherapy, with no new or unexpected safety signals. (Funded by Bristol‐Myers Squibb and others; CheckMate 026 ClinicalTrials.gov number, NCT02041533.)

Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer

BACKGROUND First‐line therapy for advanced non–small‐cell lung cancer (NSCLC) that lacks targetable mutations is platinum‐based chemotherapy. Among patients with a tumor proportion score for programmed death ligand 1 (PD‐L1) of 50% or greater, pembrolizumab has replaced cytotoxic chemotherapy as the first‐line treatment of choice. The addition of pembrolizumab to chemotherapy resulted in significantly higher rates of response and longer progression‐free survival than chemotherapy alone in a phase 2 trial. METHODS In this double‐blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) 616 patients with metastatic nonsquamous NSCLC without sensitizing EGFR or ALK mutations who had received no previous treatment for metastatic disease to receive pemetrexed and a platinum‐based drug plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance therapy. Crossover to pembrolizumab monotherapy was permitted among the patients in the placebo‐combination group who had verified disease progression. The primary end points were overall survival and progression‐free survival, as assessed by blinded, independent central radiologic review. RESULTS After a median follow‐up of 10.5 months, the estimated rate of overall survival at 12 months was 69.2% (95% confidence interval [CI], 64.1 to 73.8) in the pembrolizumab‐combination group versus 49.4% (95% CI, 42.1 to 56.2) in the placebo‐combination group (hazard ratio for death, 0.49; 95% CI, 0.38 to 0.64; P<0.001). Improvement in overall survival was seen across all PD‐L1 categories that were evaluated. Median progression‐free survival was 8.8 months (95% CI, 7.6 to 9.2) in the pembrolizumab‐combination group and 4.9 months (95% CI, 4.7 to 5.5) in the placebo‐combination group (hazard ratio for disease progression or death, 0.52; 95% CI, 0.43 to 0.64; P<0.001). Adverse events of grade 3 or higher occurred in 67.2% of the patients in the pembrolizumab‐combination group and in 65.8% of those in the placebo‐combination group. CONCLUSIONS In patients with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK mutations, the addition of pembrolizumab to standard chemotherapy of pemetrexed and a platinum‐based drug resulted in significantly longer overall survival and progression‐free survival than chemotherapy alone. (Funded by Merck; KEYNOTE‐189 ClinicalTrials.gov number, NCT02578680.)

Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC

BACKGROUND The cancer‐cell–killing property of atezolizumab may be enhanced by the blockade of vascular endothelial growth factor–mediated immunosuppression with bevacizumab. This open‐label, phase 3 study evaluated atezolizumab plus bevacizumab plus chemotherapy in patients with metastatic nonsquamous non–small‐cell lung cancer (NSCLC) who had not previously received chemotherapy. METHODS We randomly assigned patients to receive atezolizumab plus carboplatin plus paclitaxel (ACP), bevacizumab plus carboplatin plus paclitaxel (BCP), or atezolizumab plus BCP (ABCP) every 3 weeks for four or six cycles, followed by maintenance therapy with atezolizumab, bevacizumab, or both. The two primary end points were investigator‐assessed progression‐free survival both among patients in the intention‐to‐treat population who had a wild‐type genotype (WT population; patients with EGFR or ALK genetic alterations were excluded) and among patients in the WT population who had high expression of an effector T‐cell (Teff) gene signature in the tumor (Teff‐high WT population) and overall survival in the WT population. The ABCP group was compared with the BCP group before the ACP group was compared with the BCP group. RESULTS In the WT population, 356 patients were assigned to the ABCP group, and 336 to the BCP group. The median progression‐free survival was longer in the ABCP group than in the BCP group (8.3 months vs. 6.8 months; hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.52 to 0.74; P<0.001); the corresponding values in the Teff‐high WT population were 11.3 months and 6.8 months (hazard ratio, 0.51 [95% CI, 0.38 to 0.68]; P<0.001). Progression‐free survival was also longer in the ABCP group than in the BCP group in the entire intention‐to‐treat population (including those with EGFR or ALK genetic alterations) and among patients with low or negative programmed death ligand 1 (PD‐L1) expression, those with low Teff gene‐signature expression, and those with liver metastases. Median overall survival among the patients in the WT population was longer in the ABCP group than in the BCP group (19.2 months vs. 14.7 months; hazard ratio for death, 0.78; 95% CI, 0.64 to 0.96; P=0.02). The safety profile of ABCP was consistent with previously reported safety risks of the individual medicines. CONCLUSIONS The addition of atezolizumab to bevacizumab plus chemotherapy significantly improved progression‐free survival and overall survival among patients with metastatic nonsquamous NSCLC, regardless of PD‐L1 expression and EGFR or ALK genetic alteration status. (Funded by F. Hoffmann–La Roche/Genentech; IMpower150 ClinicalTrials.gov number, NCT02366143.)

Accurate identification of ALK positive lung carcinoma patients: Novel FDA-cleared automated fluorescence in situ hybridization scanning system and ultrasensitive immunohistochemistry

Background Based on the excellent results of the clinical trials with ALK-inhibitors, the importance of accurately identifying ALK positive lung cancer has never been greater. However, there are increasing number of recent publications addressing discordances between FISH and IHC. The controversy is further fuelled by the different regulatory approvals. This situation prompted us to investigate two ALK IHC antibodies (using a novel ultrasensitive detection-amplification kit) and an automated ALK FISH scanning system (FDA-cleared) in a series of non-small cell lung cancer tumor samples. Methods Forty-seven ALK FISH-positive and 56 ALK FISH-negative NSCLC samples were studied. All specimens were screened for ALK expression by two IHC antibodies (clone 5A4 from Novocastra and clone D5F3 from Ventana) and for ALK rearrangement by FISH (Vysis ALK FISH break-apart kit), which was automatically captured and scored by using Bioviews automated scanning system. Results All positive cases with the IHC antibodies were FISH-positive. There was only one IHC-negative case with both antibodies which showed a FISH-positive result. The overall sensitivity and specificity of the IHC in comparison with FISH were 98% and 100%, respectively. Conclusions The specificity of these ultrasensitive IHC assays may obviate the need for FISH confirmation in positive IHC cases. However, the likelihood of false negative IHC results strengthens the case for FISH testing, at least in some situations.

Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial

BACKGROUND In the phase 3 KEYNOTE-024 trial, treatment with pembrolizumab conferred longer progression-free survival than did platinum-based therapy in patients with treatment-naive, advanced non-small-cell lung cancer (NSCLC) with a programmed cell death-ligand 1 (PD-L1) tumour proportion score of 50% or greater (PD-L1-positive). Here we report the prespecified exploratory endpoint of pembrolizumab versus chemotherapy on patient-reported outcomes (PROs). METHODS In this multicentre, international, randomised, open-label, phase 3 trial, we recruited patients with treatment-naive, stage IV NSCLC in 102 sites in 16 countries. Eligible patients had measurable disease (per RECIST version 1.1) and an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Patients were randomly assigned (1:1) via an interactive voice response system and integrated web response system to receive either pembrolizumab 200 mg every 3 weeks (35 cycles) or investigator-choice platinum-doublet chemotherapy (4-6 cycles or until documented disease progression or unacceptable toxicity). Randomisation was stratified according to geography, ECOG performance status, and histology. PROs were assessed at day 1 of cycles 1-3, every 9 weeks thereafter, at the treatment discontinuation visit, and at the 30-day safety assessment visit using the European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 items (QLQ-C30), the EORTC Quality of Life Questionnaire Lung Cancer 13 items (QLQ-LC13), and the European Quality of Life 5 Dimensions-3 Level (EQ-5D-3L) questionnaire. The key exploratory PRO endpoints (analysed for all patients who received at least one dose of study treatment and completed at least one PRO instrument at at least one timepoint) were baseline-to-week-15 change in the QLQ-C30 global health status (GHS)/quality-of-life (QOL) score and time to deterioration of the composite of cough, chest pain, and dyspnoea in the QLQ-LC13. This study is registered with ClinicalTrials.gov, number NCT02142738, and is ongoing but no longer enrolling patients. FINDINGS Between Sept 19, 2014, and Oct 29, 2015, 305 patients were randomly assigned to pembrolizumab (n=154) or chemotherapy (n=151). Three patients in each group did not complete any PRO instruments at any timepoints, and so 299 patients were included in the full analysis set. Of these patients, one in each group did not complete any PRO instruments before week 15, and so were not included in analyses of change from baseline to week 15. PRO compliance was greater than 90% at baseline and approximately 80% at week 15 for both groups. Least-squares mean baseline-to-week-15 change in QLQ-C30 GHS/QOL score was 6·9 (95% CI 3·3 to 10·6) for pembrolizumab and -0·9 (-4·8 to 3·0) for chemotherapy, for a difference of 7·8 (2·9 to 12·8; two-sided nominal p=0·0020). Fewer pembrolizumab-treated patients had deterioration in the QLQ-LC13 composite endpoint than did chemotherapy-treated patients (46 [31%] of 151 patients vs 58 [39%] of 148 patients). Time to deterioration was longer with pembrolizumab than with chemotherapy (median not reached [95% CI 8·5 to not reached] vs 5·0 months [3·6 to not reached]; hazard ratio 0·66, 95% CI 0·44-0·97; two-sided nominal p=0·029). INTERPRETATION Pembrolizumab improves or maintains health-related QOL compared with that for chemotherapy, and might represent a new first-line standard of care for PD-L1-expressing, advanced NSCLC. FUNDING Merck & Co.

Interferon gamma, an important marker of response to immune checkpoint blockade in non-small cell lung cancer and melanoma patients:

Background: Programmed death-ligand 1 (PD-L1) may be induced by oncogenic signals or can be upregulated via interferon gamma (IFN-γ). We have explored whether the expression of IFNG, the gene encoding IFN-γ, is associated with clinical response to the immune checkpoint blockade in non-small cell lung cancer (NSCLC) and melanoma patients. The role of inflammation-associated transcription factors STAT3, IKBKE, STAT1 and other associated genes has also been examined. Methods: Total RNA from 17 NSCLC and 21 melanoma patients was analyzed by quantitative reverse transcription PCR. STAT3 and Rantes, YAP1 and CXCL5, DNMT1, RIG1 and TET1, EOMES, IFNG, PD-L1 and CTLA4, IKBKE and NFATC1 mRNA were examined. PD-L1 protein expression in tumor and immune cells and stromal infiltration of CD8+ T-cells were also evaluated. Progression-free survival and overall survival were estimated. Results: A total of 17 NSCLC patients received nivolumab and 21 melanoma patients received pembrolizumab. Progression-free survival with nivolumab was significantly longer in NSCLC patients with high versus low IFNG expression (5.1 months versus 2 months, p = 0.0124). Progression-free survival with pembrolizumab was significantly longer in melanoma patients with high versus low IFNG expression (5.0 months versus 1.9 months, p = 0.0099). Significantly longer overall survival was observed for melanoma patients with high versus low IFNG expression (not reached versus 10.2 months p = 0.0183). There was a trend for longer overall survival for NSCLC patients with high versus low IFNG expression. Conclusions: IFN-γ is an important marker for prediction of response to immune checkpoint blockade. Further research is warranted in order to validate whether IFNG is more accurate than PD-L1.

PS3 KEYNOTE-024 Update: Pembrolizumab vs Platinum-Based Chemotherapy for Advanced NSCLC with PD-L1 Tumor Proportion Score ≥50%

nivolumab + ipilimumab and chemotherapy, respectively. Grade 3e4 select TRAEs by category with nivolumab + ipilimumab included hepatic (8%), endocrine (4%), and skin (4%), and were consistent with previous reports. Median time to onset of select TRAEs ranged from 2 to 15 weeks, and the majority resolved (median time: 10 weeks). PRO results will be reported in the final presentation. Conclusion: First-line nivolumab + ipilimumab significantly prolonged PFS vs chemotherapy in patients with NSCLC and high TMB 10 mut/Mb regardless of PD-L1 expression. These results validate the role of TMB as a biomarker for the use of nivolumab + ipilimumab in first-line NSCLC. Safety of nivolumab + low-dose ipilimumab was manageable.

PD.1.01 Health-Related Quality of Life with Pembrolizumab or Placebo + Pemetrexed + Platinum in Non-Squamous NSCLC: KEYNOTE-189

POSTER DISCUSSION SESSION 1 AUGUST 18, 2018 — 08:00 e 09:15 PD.1.01 Health-Related Quality of Life with Pembrolizumab or Placebo + Pemetrexed + Platinum in Non-Squamous NSCLC: KEYNOTE-189 M. Garassino, D. Rodríguez-Abreu, S. Gadgeel, E. Esteban, E. Felip, G. Speranza, M. Domine, M. Hochmair, S. Powell, S. Cheng, H. Bischoff, N. Peled, M. Reck, R. Hui, E. Garon, M. Boyer, J. Yang, T. Burke, M.C. Pietanza, L. Gandhi Fondazione IRCCS Istituto Nazionale dei Tumori, Milan/IT, Hospital Universitario Insular de Gran Canaria, Las Palmas de Gran Canaria/ES, University of Michigan, Ann Arbor/MI/US, Hospital Universitario Central de Asturias, Oviedo/ES, Vall d’Hebron University, Vall d’Hebron Institute of Oncology (VHIO), Barcelona/ES, Centre Integré de Cancérologie de la Montérégie, Hôpital Charles Le Moyne, Greenfield Park, QC/CA, Fundación Jiménez Díaz, Madrid/ES, Otto Wagner Hospital, Vienna/AT, Sanford Health, Sioux Falls, SD/US, Sunnybrook Health Sciences Centre, Toronto, ON/CA, Thoraxklinik, Heidelberg/DE, Clalit Health Services, Soroka Medical Center, Beer-Sheeva/IL, LungenClinic, Airway Research Center North, German Center for Lung Research, Grosshansdorf/DE, Westmead Hospital and the University of Sydney, Sydney, NSW/AU, David Geffen School of Medicine at UCLA, Los Angeles, CA/US, Chris O’Brien Lifehouse, Camperdown, NSW/AU, Merck & Co., Inc., Kenilworth, NJ/US, NYU Perlmutter Cancer Center, New York, NY/US Background: In the double-blind, phase 3 KEYNOTE-189 study (NCT02578680), pembrolizumab+pemetrexed/platinum significantly improved OS and PFS over placebo+pemetrexed/platinum as first-line therapy for nonsquamous NSCLC. Overall, the incidence and severity of AEs with pembrolizumab+pemetrexed/platinum was similar to those with placebo+pemetrexed/platinum. We report the prespecified patient-reported outcome (PRO) analyses from KEYNOTE-189.Method: 616 patients were randomized to pembrolizumab 200 mg Q3W or placebo for 2 years; all patients received pemetrexed plus 4 cycles of carboplatin/cisplatin. EORTC QLQ-C30 and QLQ-LC13 were administered at cycles 1-5, then every 3 cycles during year 1, and every 4 cycles during years 2/3. Key PROs were change from baseline to weeks 12 and 21 in the QLQ-C30 global health status (GHS)/quality of life (QoL) score and time to deterioration in composite of cough/chest pain/ dyspnea. PROs were analyzed in all treated patients who completed 1 PRO instrument (n 1⁄4 602). P values are nominal and 2-sided. Results: QLQ-C30 compliance was w90% at baseline and week 12 in both arms and was w76% with pembrolizumab and w64% with placebo at week 21. Mean baseline scores were 61.98 and 60.56 in the pembrolizumab and placebo arms, respectively. At weeks 12 and 21, GHS/QoL scores were stable with pembrolizumab and decreased with placebo, with significantly greater decrement with placebo at week 21 (Table). The proportion of improved GHS/QoL was similar at week 12 (28.9% with pembrolizumab vs 26.5% with placebo) but was greater with pembrolizumab at week 21 (30.1% vs 22.5%). Median time to deterioration in composite of cough/chest pain/dyspnea was not reached (NR) with pembrolizumab (95% CI, 10.2 months-NR) vs 7.0 months (95% CI, 4.8-NR) with placebo (HR, 0.81; 95% CI, 0.60-1.09; P1⁄40.161). Conclusion: In KEYNOTE-189, pembrolizumab+pemetrexed/platinum maintained or improved health-related QoL over placebo+pemetrexed/ platinum. These data support use of pembrolizumab+pemetrexed/ platinum as first-line therapy for metastatic nonsquamous NSCLC.

30 Immunotherapy in advanced NSCLC—from the ‘tsunami’ of therapeutic knowledge to a clinical practice algorithm: results from an international expert panel meeting of the Italian Association of Thoracic Oncology (AIOT)

Although lung cancer remains the leading cause of death from cancer worldwide, the advent of immunotherapy is changing the survival of patients affected by non-small cell lung cancer (NSCLC). A multitude of clinical trials are evaluating different immune checkpoints inhibitors in this new field of thoracic oncology. At the beginning of the immunotherapy era, nivolumab, pembrolizumab and atezolizumab showed high efficacy in patients with advanced NSCLC in second-line setting, receiving approvals for clinical practice. Nivolumab and atezolizumab are approved independently from programmed death lig and 1 (PD-L1) expression, while pembrolizumab is currently approved only for patients with PD-L1 expression ≥1%. The role of PD-L1 expression acquired more interest considering first-line clinical trials, in which the role of immunotherapy as monotherapy was confirmed only for pembrolizumab in patients with PD-L1 expression ≥50%. These data were analysed in this paper, focusing on the implications in clinical practice and how to use them to an accurate clinical benefit of patients with advanced NSCLC. We report a review based on a MEDLINE/PubMed, searched for randomised phase 2/3 trials evaluating immune checkpoint inhibitors and NSCLC, that moved to an approval from Food and Drug Administration (FDA) and European Medicine Agency (EMA). The evidence discussed in this manuscript and the final therapeutic algorithm, coming out from an International Experts Panel Meeting of the Italian Association of Thoracic Oncology.