Sebastiano Buti1, Melissa Bersanelli1, Fabiana Perrone1, Sergio Bracarda2, Massimo Di Maio3, Raffaele Giusti4, Olga Nigro5, Diego L Cortinovis6, Joachim G J V Aerts7, Giorgia Guaitoli8, Fausto Barbieri8, Miriam G Ferrara9, Emilio Bria9, Francesco Grossi10, Claudia Bareggi11, Rossana Berardi12, Mariangela Torniai12, Luca Cantini13, Vincenzo Sforza14, Carlo Genova15, Rita Chiari16, Danilo Rocco17, Luigi Della Gravara17, Stefania Gori18, Michele De Tursi19, Pietro Di Marino20, Giovanni Mansueto21, Federica Zoratto22, Marco Filetti4, Fabrizio Citarella23, Marco Russano23, Francesca Mazzoni24, Marina C Garassino25, Alessandro De Toma25, Diego Signorelli26, Alain Gelibter27, Marco Siringo27, Alessandro Follador28, Renato Bisonni29, Alessandro Tuzi5, Gabriele Minuti30, Lorenza Landi30, Serena Ricciardi31, Maria R Migliorino31, Fabrizio Tabbò32, Emanuela Olmetto32, Giulio Metro33, Vincenzo Adamo34, Alessandro Russo34, Gian P Spinelli35, Giuseppe L Banna36, Alfredo Addeo37, Alex Friedlaender37, Katia Cannita38, Giampiero Porzio38, Corrado Ficorella39, Luca Carmisciano40, David J Pinato41, Giulia Mazzaschi1, Marcello Tiseo42, Alessio Cortellini43. 1. Medical Oncology Unit, University Hospital of Parma, Parma, Italy. 2. Struttura Complessa di Oncologia Medica e Traslazionale, Azienda Ospedaliera Santa Maria di Terni, Italy. 3. Department of Oncology, University of Turin and Medical Oncology, AO Ordine Mauriziano, Turin, Italy. 4. Medical Oncolgy, St. Andrea Hospital, Rome, Italy. 5. Medical Oncology, ASST-Sette Laghi, Varese, Italy. 6. Medical Oncology, Ospedale San Gerardo, Monza, Italy. 7. Department of Pulmonary Diseases, Erasmus Medical Center, Rotterdam, the Netherlands. 8. Dipartimeto di Oncologia Ed Ematologia, AOU Policlinico Modena, Modena, Italy. 9. Comprehensive Cancer Center, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy; Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Lazio, Italy. 10. Division of Medical Oncology, University of Insubria, Varese, Italy. 11. Medical Oncology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. 12. Oncology Clinic, Università Politecnica Delle Marche, Ospedali Riuniti Di Ancona, Ancona, Italy. 13. Department of Pulmonary Diseases, Erasmus Medical Center, Rotterdam, the Netherlands; Oncology Clinic, Università Politecnica Delle Marche, Ospedali Riuniti Di Ancona, Ancona, Italy. 14. Thoracic Medical Oncology, Istituto Nazionale Tumori "Fondazione G Pascale", IRCCS, Napoli, Italy. 15. Lung Cancer Unit IRCCS Ospedale Policlinico San Martino, Genova, Italy. 16. Medical Oncology, Ospedali Riuniti Padova Sud "Madre Teresa Di Calcutta", Monselice, Italy. 17. Pneumo-Oncology Unit, Monaldi Hospital, Naples, Italy. 18. Oncology Unit, IRCCS Ospedale Sacro Cuore Don Calabria, Negrar, VR, Italy. 19. Dipartimento di Terapie Innovative in Medicina e Odontoiatria, Università G. D'Annunzio, Chieti-Pescara, Chieti, Italy. 20. Clinical Oncology Unit, S.S. Annunziata Hospital, Chieti, Italy. 21. Medical Oncology, F. Spaziani Hospital, Frosinone, Italy. 22. Medical Oncology, Santa Maria Goretti Hospital, Latina, Italy. 23. Medical Oncology, Campus Bio-Medico University, Rome, Italy. 24. Department of Oncology, Careggi University Hospital, Florence, Italy. 25. Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy. 26. Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy; Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy. 27. Medical Oncology (B), Policlinico Umberto I, "Sapienza" University of Rome, Rome, Italy. 28. Department of Oncology, University Hospital Santa Maria Della Misericordia, Udine, Italy. 29. Medical Oncology, Fermo Area Vasta 4, Fermo, Italy. 30. Department of Oncology and Hematology, AUSL Romagna, Ravenna, Italy. 31. Pneumo-Oncology Unit, St. Camillo-Forlanini Hospital, Rome, Italy. 32. Department of Oncology, University of Turin, San Luigi Hospital, Orbassano, (TO), Italy. 33. Department of Medical Oncology, Santa Maria Della Misericordia Hospital, Azienda Ospedaliera di Perugia, Perugia, Italy. 34. Medical Oncology, A.O. Papardo & Department of Human Pathology, University of Messina, Italy. 35. UOC Territorial Oncology of Aprilia, AUSL Latina, University of Rome Sapienza, Aprilia, Italy. 36. Portsmouth Hospitals University NHS Trust, Portsmouth, UK. 37. Oncology Department, University Hospital of Geneva, Geneva, Switzerland. 38. Medical Oncology, St. Salvatore Hospital, L'Aquila, Italy. 39. Medical Oncology, St. Salvatore Hospital, L'Aquila, Italy; Department of Biotechnology and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy. 40. DISSAL-Biostatistics Unit, University of Genoa, Genova, Italy. 41. Division of Cancer, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK; Department of Translational Medicine, Università del Piemonte Orientale "A. Avogadro", Novara, Italy. 42. Medical Oncology Unit, University Hospital of Parma, Parma, Italy; Department of Medicine and Surgery, University of Parma, Parma, Italy. 43. Department of Biotechnology and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy; Division of Cancer, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK. Electronic address: a.cortellini@imperial.ac.uk.
Abstract
BACKGROUND: We previously demonstrated the cumulative poor prognostic role of concomitant medications on the clinical outcome of patients with advanced cancer treated with immune checkpoint inhibitors, creating and validating a drug-based prognostic score to be calculated before immunotherapy initiation in patients with advanced solid tumours. This 'drug score' was calculated assigning score 1 for each between proton-pump inhibitor and antibiotic administration until a month before cancer therapy initiation and score 2 in case of corticosteroid intake. The good risk group included patients with score 0, intermediate risk with score 1-2 and poor risk with score 3-4. METHODS: Aiming at validating the prognostic and putative predictive ability depending on the anticancer therapy, we performed the present comparative analysis in two cohorts of advanced non-small-cell lung cancer (NSCLC), respectively, receiving first-line pembrolizumab or chemotherapy through a random case-control matching and through a pooled multivariable analysis including the interaction between the computed score and the therapeutic modality (pembrolizumab vs chemotherapy). RESULTS: Nine hundred fifty and 595 patients were included in the pembrolizumab and chemotherapy cohorts, respectively. After the case-control random matching, 589 patients from the pembrolizumab cohort and 589 from the chemotherapy cohort were paired, with no statistically significant differences between the characteristics of the matched subjects. Among the pembrolizumab-treated group, good, intermediate and poor risk evaluable patients achieved an objective response rate (ORR) of 50.0%, 37.7% and 23.4%, respectively, (p < 0.0001), whereas among the chemotherapy-treated group, patients achieved an ORR of 37.0%, 40.0% and 32.4%, respectively (p = 0.4346). The median progression-free survival (PFS) of good, intermediate and poor risk groups was 13.9 months, 6.3 months and 2.8 months, respectively, within the pembrolizumab cohort (p < 0.0001), and 6.2 months, 6.2 months and 4.3 months, respectively, within the chemotherapy cohort (p = 0.0280). Among the pembrolizumab-treated patients, the median overall survival (OS) for good, intermediate and poor risk patients was 31.4 months, 14.5 months and 5.8 months, respectively, (p < 0.0001), whereas among the chemotherapy-treated patients, it was 18.3 months, 16.8 months and 10.6 months, respectively (p = 0.0003). A similar trend was reported considering the two entire populations. At the pooled analysis, the interaction term between the score and the therapeutic modality was statistically significant with respect to ORR (p = 0.0052), PFS (p = 0.0003) and OS (p < 0.0001), confirming the significantly different effect of the score within the two cohorts. CONCLUSION: Our 'drug score' showed a predictive ability with respect to ORR in the immunotherapy cohort only, suggesting it might be a useful tool for identifying patients unlikely to benefit from first-line single-agent pembrolizumab. In addition, the prognostic stratification in terms of PFS and OS was significantly more pronounced among the pembrolizumab-treated patients.
BACKGROUND: We previously demonstrated the cumulative poor prognostic role of concomitant medications on the clinical outcome of patients with advanced cancer treated with immune checkpoint inhibitors, creating and validating a drug-based prognostic score to be calculated before immunotherapy initiation in patients with advanced solid tumours. This 'drug score' was calculated assigning score 1 for each between proton-pump inhibitor and antibiotic administration until a month before cancer therapy initiation and score 2 in case of corticosteroid intake. The good risk group included patients with score 0, intermediate risk with score 1-2 and poor risk with score 3-4. METHODS: Aiming at validating the prognostic and putative predictive ability depending on the anticancer therapy, we performed the present comparative analysis in two cohorts of advanced non-small-cell lung cancer (NSCLC), respectively, receiving first-line pembrolizumab or chemotherapy through a random case-control matching and through a pooled multivariable analysis including the interaction between the computed score and the therapeutic modality (pembrolizumab vs chemotherapy). RESULTS: Nine hundred fifty and 595 patients were included in the pembrolizumab and chemotherapy cohorts, respectively. After the case-control random matching, 589 patients from the pembrolizumab cohort and 589 from the chemotherapy cohort were paired, with no statistically significant differences between the characteristics of the matched subjects. Among the pembrolizumab-treated group, good, intermediate and poor risk evaluable patients achieved an objective response rate (ORR) of 50.0%, 37.7% and 23.4%, respectively, (p < 0.0001), whereas among the chemotherapy-treated group, patients achieved an ORR of 37.0%, 40.0% and 32.4%, respectively (p = 0.4346). The median progression-free survival (PFS) of good, intermediate and poor risk groups was 13.9 months, 6.3 months and 2.8 months, respectively, within the pembrolizumab cohort (p < 0.0001), and 6.2 months, 6.2 months and 4.3 months, respectively, within the chemotherapy cohort (p = 0.0280). Among the pembrolizumab-treated patients, the median overall survival (OS) for good, intermediate and poor risk patients was 31.4 months, 14.5 months and 5.8 months, respectively, (p < 0.0001), whereas among the chemotherapy-treated patients, it was 18.3 months, 16.8 months and 10.6 months, respectively (p = 0.0003). A similar trend was reported considering the two entire populations. At the pooled analysis, the interaction term between the score and the therapeutic modality was statistically significant with respect to ORR (p = 0.0052), PFS (p = 0.0003) and OS (p < 0.0001), confirming the significantly different effect of the score within the two cohorts. CONCLUSION: Our 'drug score' showed a predictive ability with respect to ORR in the immunotherapy cohort only, suggesting it might be a useful tool for identifying patients unlikely to benefit from first-line single-agent pembrolizumab. In addition, the prognostic stratification in terms of PFS and OS was significantly more pronounced among the pembrolizumab-treated patients.