Commentary: Another win for immunotherapy

Abstract

Central MessageImmunotherapy likely contributes to improvements in the survival of patients with postresection recurrence of non–small cell lung cancer, especially in those without driver mutations.See Article page XXX.In this issue of the Journal, authors Hashimoto and colleagues1Hashimoto K. Ariyasu R. Ichinose J. Matsuura Y. Nakao M. Yoshiaki A. et al.Advances in the treatment of postoperative recurrence of non–small cell lung cancer and their impact on survival in Asian patients.J Thorac Cardiovasc Surg. August 24, 2022; ([Epub ahead of print])Abstract Full Text Full Text PDF Scopus (1) Google Scholar from the Japanese Cancer Institute Hospital group report their experience in postresection recurrence in non–small cell lung cancer (NSCLC), with data encompassing the pretargeted and immunotherapy era as well as the current era, including tyrosine kinase inhibitors (TKIs) against epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) fusions, and immunotherapy targeting the programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) pathways. The authors included 2254 patients at their institution with NSCLC who underwent R0 resection via lobectomy or pneumonectomy between 2008 and 2018. Of these greater than 2000 patients, 19.7% of patients had a postresection recurrence. Postresection recurrence is an issue faced by thoracic surgeons and medical oncologists in their daily practice, and yet there is no standard accepted treatment. Treatment being offered is often extrapolated from the treatment of stage IV lung cancer, which does not necessarily represent the same entity as a postresection recurrence.During the study, TKIs against EGFR were available at the beginning of the time course, with ALK-TKIs becoming commercially available in 2012 and then the first immunotherapy drug (nivolumab, a PD-1 inhibitor) for NSCLC becoming available in 2015. The authors conducted regular surveillance of their postresection patients with routine imaging, including at least annual computed tomography scans. The average time to recurrence was just over a year. Both the initial resection specimens and the postresection recurrence specimens were tested for EGFR and ALK mutation status. EGFR mutations (EGFR+ group) and ALK rearrangements (ALK+ group) were detected in (43.1%) and (2.9%) of patients with recurrence. In the rest of the 239 patients with recurrence (54.0%), mutations were not detected or unknown. Patients who were discovered to have postresection recurrence received a variety of therapies, including resection of the recurrence, radiation, chemoradiation, and systemic therapy. Throughout the postrecurrence course, 36% of patients received EGFR-TKIs, 2.9% received ALK-TKIs, and 15.3% received immunotherapy.Overall, patients with EGFR and ALK mutations had significantly improved postrecurrence survival as compared with those without targetable mutations in these pathways, with a median survival of 4.7 years in the EGFR+/ALK+ group and 2.1 years in patients without driver mutations, respectively. When the study data were analyzed including all patients regardless of mutation status, the 2-year survival after recurrence improved significantly over the study period. However, when broken down by mutation status, the EGFR+ and ALK+ patients had stable 2-year survival postrecurrence over the decade whereas the nonmutant group made significant gains in 2-year postrecurrence survival over time; this was also associated with the utilization of immunotherapy in the same group of patients. Thus, the authors posit that improvement in postrecurrence survival in patients with NSCLC, especially those without targetable mutations in EGFR or ALK, was positively influenced by the adoption of immunotherapy in the treatment of postresection patients experiencing recurrence.PD-1/PD-L1–based regimens have shown a survival benefit in patients with metastatic NSCLC.2Borghaei H. Gettinger S. Vokes E.E. Chow L.Q. Burgio M.A. de Castro Carpeno J. et al.Five-year outcomes from the randomized, phase III trials CheckMate 017 and 057: nivolumab versus docetaxel in previously treated non-small-cell lung cancer.J Clin Oncol. 2021; 39: 723-733Crossref PubMed Scopus (135) Google Scholar, 3Reck M. Ciuleanu T.E. Cobo M. Schenker M. Zurawski B. Menezes J. et al.First-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone (four cycles) in advanced non–small-cell lung cancer: CheckMate 9LA 2-year update.ESMO Open. 2021; 6: 100273Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, 4Paz-Ares L.G. Ramalingam S.S. Ciuleanu T.E. Lee J.S. Urban L. Caro R.B. et al.First-line nivolumab plus ipilimumab in advanced NSCLC: 4-year outcomes from the randomized, open-label, phase 3 CheckMate 227 part 1 trial.J Thorac Oncol. 2022; 17: 289-308Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar Recently, the CheckMate 816 trial also demonstrated a benefit of immunotherapy in patients with resectable Stage Ib-IIIa NSCLC.5Forde P.M. Spicer J. Lu S. Provencio M. Mitsudomi T. Awad M.M. et al.CheckMate 816 Investigators. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer.N Engl J Med. 2022; 386: 1973-1985Crossref PubMed Scopus (89) Google Scholar In fact, the addition of neoadjuvant immunotherapy with nivolumab decreased the rate of postresection recurrence, progression, and death in this group. Hashimoto and colleagues1Hashimoto K. Ariyasu R. Ichinose J. Matsuura Y. Nakao M. Yoshiaki A. et al.Advances in the treatment of postoperative recurrence of non–small cell lung cancer and their impact on survival in Asian patients.J Thorac Cardiovasc Surg. August 24, 2022; ([Epub ahead of print])Abstract Full Text Full Text PDF Scopus (1) Google Scholar did not include the PD-L1 status of the tumor in their analysis for this paper, but other studies have shown an increase in the benefit of immunotherapy in tumors with high PD-L1 expression.6Reck M. Rodríguez-Abreu D. Robinson A.G. Hui R. Csőszi T. Fülöp A. et al.KEYNOTE-024 InvestigatorsPembrolizumab versus chemotherapy for PD-L1-positive non–small-cell lung cancer.N Engl J Med. 2016; 375: 1823-1833Crossref PubMed Scopus (5934) Google Scholar Interestingly, CheckMate 816 demonstrated both a benefit with nivolumab plus chemotherapy in all PD-L1 subgroups, with a greater event-free survival benefit in patients with a high tumor PD-L1 expression level of (>/=1%) but yet still an advantage in the group with low PD-L1–expressing tumors.As the authors state within their limitations and also as noted in the title of the article, the results described by this study may be specific to Asian populations, as prevalence of driver mutations differ between different racial and ethnic groups. For example, in this study, 43% of patients had an EGFR mutation, compared with a reported incidence of only 15% in Western populations. However, one could interpret this situation that in Western populations without a prevalence of driver mutations in EGFR/ALK, there is the potential to gain even larger societal benefit from immunotherapy in postresection recurrences.Previously published work on postresection recurrence has shown that the number of lesions and sites at the time of recurrence is an important prognostic factor.7Sonobe M. Yamada T. Sato M. Menju T. Aoyama A. Sato T. et al.Identification of subsets of patients with favorable prognosis after recurrence in completely resected non–small cell lung cancer.Ann Surg Oncol. 2014; 21: 2546-2554Crossref PubMed Scopus (34) Google Scholar This important issue is not explored in this study by Hashimoto and colleagues.1Hashimoto K. Ariyasu R. Ichinose J. Matsuura Y. Nakao M. Yoshiaki A. et al.Advances in the treatment of postoperative recurrence of non–small cell lung cancer and their impact on survival in Asian patients.J Thorac Cardiovasc Surg. August 24, 2022; ([Epub ahead of print])Abstract Full Text Full Text PDF Scopus (1) Google Scholar These authors previously showed that local ablative treatment (surgery or radiation therapy) without systemic treatment may result in favorable survival if the recurrence pattern is that of oligorecurrence.8Sonoda D. Matsuura Y. Kondo Y. Ichinose J. Nakao M. Ninomiya H. et al.Comparison of local therapy in patients with lung oligo-recurrence of non–small-cell lung cancer.J Surg Oncol. 2021; 123: 1828-1835Crossref PubMed Scopus (1) Google Scholar Further research into the merits of immunotherapy in combination with local ablative therapies for recurrent NSCLC is needed. Given the overwhelming positive trials with the inclusion of immunotherapy in nearly every phase of lung cancer treatment,2Borghaei H. Gettinger S. Vokes E.E. Chow L.Q. Burgio M.A. de Castro Carpeno J. et al.Five-year outcomes from the randomized, phase III trials CheckMate 017 and 057: nivolumab versus docetaxel in previously treated non-small-cell lung cancer.J Clin Oncol. 2021; 39: 723-733Crossref PubMed Scopus (135) Google Scholar, 3Reck M. Ciuleanu T.E. Cobo M. Schenker M. Zurawski B. Menezes J. et al.First-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone (four cycles) in advanced non–small-cell lung cancer: CheckMate 9LA 2-year update.ESMO Open. 2021; 6: 100273Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, 4Paz-Ares L.G. Ramalingam S.S. Ciuleanu T.E. Lee J.S. Urban L. Caro R.B. et al.First-line nivolumab plus ipilimumab in advanced NSCLC: 4-year outcomes from the randomized, open-label, phase 3 CheckMate 227 part 1 trial.J Thorac Oncol. 2022; 17: 289-308Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 5Forde P.M. Spicer J. Lu S. Provencio M. Mitsudomi T. Awad M.M. et al.CheckMate 816 Investigators. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer.N Engl J Med. 2022; 386: 1973-1985Crossref PubMed Scopus (89) Google Scholar, 6Reck M. Rodríguez-Abreu D. Robinson A.G. Hui R. Csőszi T. Fülöp A. et al.KEYNOTE-024 InvestigatorsPembrolizumab versus chemotherapy for PD-L1-positive non–small-cell lung cancer.N Engl J Med. 2016; 375: 1823-1833Crossref PubMed Scopus (5934) Google Scholar it seems likely to be beneficial. Overall, immunotherapy clearly has changed the way we treat NSCLC. It likely provides a benefit to patients with postresection recurrence. It's an incredible tool in our armamentarium for treating advanced-stage or recurrent lung cancer, as evidenced by this study. Immunotherapy likely contributes to improvements in the survival of patients with postresection recurrence of non–small cell lung cancer, especially in those without driver mutations. Immunotherapy likely contributes to improvements in the survival of patients with postresection recurrence of non–small cell lung cancer, especially in those without driver mutations. See Article page XXX. See Article page XXX. In this issue of the Journal, authors Hashimoto and colleagues1Hashimoto K. Ariyasu R. Ichinose J. Matsuura Y. Nakao M. Yoshiaki A. et al.Advances in the treatment of postoperative recurrence of non–small cell lung cancer and their impact on survival in Asian patients.J Thorac Cardiovasc Surg. August 24, 2022; ([Epub ahead of print])Abstract Full Text Full Text PDF Scopus (1) Google Scholar from the Japanese Cancer Institute Hospital group report their experience in postresection recurrence in non–small cell lung cancer (NSCLC), with data encompassing the pretargeted and immunotherapy era as well as the current era, including tyrosine kinase inhibitors (TKIs) against epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) fusions, and immunotherapy targeting the programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) pathways. The authors included 2254 patients at their institution with NSCLC who underwent R0 resection via lobectomy or pneumonectomy between 2008 and 2018. Of these greater than 2000 patients, 19.7% of patients had a postresection recurrence. Postresection recurrence is an issue faced by thoracic surgeons and medical oncologists in their daily practice, and yet there is no standard accepted treatment. Treatment being offered is often extrapolated from the treatment of stage IV lung cancer, which does not necessarily represent the same entity as a postresection recurrence. During the study, TKIs against EGFR were available at the beginning of the time course, with ALK-TKIs becoming commercially available in 2012 and then the first immunotherapy drug (nivolumab, a PD-1 inhibitor) for NSCLC becoming available in 2015. The authors conducted regular surveillance of their postresection patients with routine imaging, including at least annual computed tomography scans. The average time to recurrence was just over a year. Both the initial resection specimens and the postresection recurrence specimens were tested for EGFR and ALK mutation status. EGFR mutations (EGFR+ group) and ALK rearrangements (ALK+ group) were detected in (43.1%) and (2.9%) of patients with recurrence. In the rest of the 239 patients with recurrence (54.0%), mutations were not detected or unknown. Patients who were discovered to have postresection recurrence received a variety of therapies, including resection of the recurrence, radiation, chemoradiation, and systemic therapy. Throughout the postrecurrence course, 36% of patients received EGFR-TKIs, 2.9% received ALK-TKIs, and 15.3% received immunotherapy. Overall, patients with EGFR and ALK mutations had significantly improved postrecurrence survival as compared with those without targetable mutations in these pathways, with a median survival of 4.7 years in the EGFR+/ALK+ group and 2.1 years in patients without driver mutations, respectively. When the study data were analyzed including all patients regardless of mutation status, the 2-year survival after recurrence improved significantly over the study period. However, when broken down by mutation status, the EGFR+ and ALK+ patients had stable 2-year survival postrecurrence over the decade whereas the nonmutant group made significant gains in 2-year postrecurrence survival over time; this was also associated with the utilization of immunotherapy in the same group of patients. Thus, the authors posit that improvement in postrecurrence survival in patients with NSCLC, especially those without targetable mutations in EGFR or ALK, was positively influenced by the adoption of immunotherapy in the treatment of postresection patients experiencing recurrence. PD-1/PD-L1–based regimens have shown a survival benefit in patients with metastatic NSCLC.2Borghaei H. Gettinger S. Vokes E.E. Chow L.Q. Burgio M.A. de Castro Carpeno J. et al.Five-year outcomes from the randomized, phase III trials CheckMate 017 and 057: nivolumab versus docetaxel in previously treated non-small-cell lung cancer.J Clin Oncol. 2021; 39: 723-733Crossref PubMed Scopus (135) Google Scholar, 3Reck M. Ciuleanu T.E. Cobo M. Schenker M. Zurawski B. Menezes J. et al.First-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone (four cycles) in advanced non–small-cell lung cancer: CheckMate 9LA 2-year update.ESMO Open. 2021; 6: 100273Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, 4Paz-Ares L.G. Ramalingam S.S. Ciuleanu T.E. Lee J.S. Urban L. Caro R.B. et al.First-line nivolumab plus ipilimumab in advanced NSCLC: 4-year outcomes from the randomized, open-label, phase 3 CheckMate 227 part 1 trial.J Thorac Oncol. 2022; 17: 289-308Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar Recently, the CheckMate 816 trial also demonstrated a benefit of immunotherapy in patients with resectable Stage Ib-IIIa NSCLC.5Forde P.M. Spicer J. Lu S. Provencio M. Mitsudomi T. Awad M.M. et al.CheckMate 816 Investigators. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer.N Engl J Med. 2022; 386: 1973-1985Crossref PubMed Scopus (89) Google Scholar In fact, the addition of neoadjuvant immunotherapy with nivolumab decreased the rate of postresection recurrence, progression, and death in this group. Hashimoto and colleagues1Hashimoto K. Ariyasu R. Ichinose J. Matsuura Y. Nakao M. Yoshiaki A. et al.Advances in the treatment of postoperative recurrence of non–small cell lung cancer and their impact on survival in Asian patients.J Thorac Cardiovasc Surg. August 24, 2022; ([Epub ahead of print])Abstract Full Text Full Text PDF Scopus (1) Google Scholar did not include the PD-L1 status of the tumor in their analysis for this paper, but other studies have shown an increase in the benefit of immunotherapy in tumors with high PD-L1 expression.6Reck M. Rodríguez-Abreu D. Robinson A.G. Hui R. Csőszi T. Fülöp A. et al.KEYNOTE-024 InvestigatorsPembrolizumab versus chemotherapy for PD-L1-positive non–small-cell lung cancer.N Engl J Med. 2016; 375: 1823-1833Crossref PubMed Scopus (5934) Google Scholar Interestingly, CheckMate 816 demonstrated both a benefit with nivolumab plus chemotherapy in all PD-L1 subgroups, with a greater event-free survival benefit in patients with a high tumor PD-L1 expression level of (>/=1%) but yet still an advantage in the group with low PD-L1–expressing tumors. As the authors state within their limitations and also as noted in the title of the article, the results described by this study may be specific to Asian populations, as prevalence of driver mutations differ between different racial and ethnic groups. For example, in this study, 43% of patients had an EGFR mutation, compared with a reported incidence of only 15% in Western populations. However, one could interpret this situation that in Western populations without a prevalence of driver mutations in EGFR/ALK, there is the potential to gain even larger societal benefit from immunotherapy in postresection recurrences. Previously published work on postresection recurrence has shown that the number of lesions and sites at the time of recurrence is an important prognostic factor.7Sonobe M. Yamada T. Sato M. Menju T. Aoyama A. Sato T. et al.Identification of subsets of patients with favorable prognosis after recurrence in completely resected non–small cell lung cancer.Ann Surg Oncol. 2014; 21: 2546-2554Crossref PubMed Scopus (34) Google Scholar This important issue is not explored in this study by Hashimoto and colleagues.1Hashimoto K. Ariyasu R. Ichinose J. Matsuura Y. Nakao M. Yoshiaki A. et al.Advances in the treatment of postoperative recurrence of non–small cell lung cancer and their impact on survival in Asian patients.J Thorac Cardiovasc Surg. August 24, 2022; ([Epub ahead of print])Abstract Full Text Full Text PDF Scopus (1) Google Scholar These authors previously showed that local ablative treatment (surgery or radiation therapy) without systemic treatment may result in favorable survival if the recurrence pattern is that of oligorecurrence.8Sonoda D. Matsuura Y. Kondo Y. Ichinose J. Nakao M. Ninomiya H. et al.Comparison of local therapy in patients with lung oligo-recurrence of non–small-cell lung cancer.J Surg Oncol. 2021; 123: 1828-1835Crossref PubMed Scopus (1) Google Scholar Further research into the merits of immunotherapy in combination with local ablative therapies for recurrent NSCLC is needed. Given the overwhelming positive trials with the inclusion of immunotherapy in nearly every phase of lung cancer treatment,2Borghaei H. Gettinger S. Vokes E.E. Chow L.Q. Burgio M.A. de Castro Carpeno J. et al.Five-year outcomes from the randomized, phase III trials CheckMate 017 and 057: nivolumab versus docetaxel in previously treated non-small-cell lung cancer.J Clin Oncol. 2021; 39: 723-733Crossref PubMed Scopus (135) Google Scholar, 3Reck M. Ciuleanu T.E. Cobo M. Schenker M. Zurawski B. Menezes J. et al.First-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone (four cycles) in advanced non–small-cell lung cancer: CheckMate 9LA 2-year update.ESMO Open. 2021; 6: 100273Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, 4Paz-Ares L.G. Ramalingam S.S. Ciuleanu T.E. Lee J.S. Urban L. Caro R.B. et al.First-line nivolumab plus ipilimumab in advanced NSCLC: 4-year outcomes from the randomized, open-label, phase 3 CheckMate 227 part 1 trial.J Thorac Oncol. 2022; 17: 289-308Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 5Forde P.M. Spicer J. Lu S. Provencio M. Mitsudomi T. Awad M.M. et al.CheckMate 816 Investigators. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer.N Engl J Med. 2022; 386: 1973-1985Crossref PubMed Scopus (89) Google Scholar, 6Reck M. Rodríguez-Abreu D. Robinson A.G. Hui R. Csőszi T. Fülöp A. et al.KEYNOTE-024 InvestigatorsPembrolizumab versus chemotherapy for PD-L1-positive non–small-cell lung cancer.N Engl J Med. 2016; 375: 1823-1833Crossref PubMed Scopus (5934) Google Scholar it seems likely to be beneficial. Overall, immunotherapy clearly has changed the way we treat NSCLC. It likely provides a benefit to patients with postresection recurrence. It's an incredible tool in our armamentarium for treating advanced-stage or recurrent lung cancer, as evidenced by this study. Advances in the treatment of postoperative recurrence of non–small cell lung cancer and their impact on survival in Asian patientsThe Journal of Thoracic and Cardiovascular SurgeryPreviewWe investigated the effect of tyrosine kinase inhibitors (TKIs) and immunotherapy on survival after postoperative recurrence of non–small cell lung cancer (NSCLC). Full-Text PDF