It’s possible that some patients in the pre-ICIs group received ICIs at a later date or that a portion of the patients in the post-ICIs group did not receive ICIs. of immune checkpoint inhibitors. Meaning In this study, a change in the incidence of second primary cancers was found; screening for these cancers may be warranted in patients treated with immune checkpoint inhibitors for metastatic melanoma. Abstract Importance To date, the risk of developing second primary cancers (SPCs) after the first primary melanoma has not been studied in the era of immune checkpoint inhibitors (ICIs). Objective To assess differences in the risk of SPCs in patients with primary melanoma before (2005-2010) and after (2011-2016) the introduction and approval of ICIs. Design, Setting, and Participants Population-based cohort study using the Surveillance, Epidemiology, and End Results database from January 2005 to December 2016 of patients diagnosed with metastatic melanoma. Data were analyzed from January 4 to June 30, 2020. Exposures Receipt of immunotherapy or other anticancer agents. Main Outcomes and Measures The primary outcome was the development of second primary cancers in patients with melanoma. Standardized incidence ratios (SIRs) were calculated for the development of SPCs before and after the introduction of ICIs. Results Among 5016 patients with diagnosed metastatic melanoma, 2888 (58%) were younger than 65 years at the time of diagnosis, and 3441 (69%) were male. From 2005 to 2010, SIRs were 3.24 (95% CI, 0.08-18.04) for small intestine cancer, 1.93 (95% CI, 1.14-3.05) for lung and bronchus cancer, 2.77 (95% CI, 1.02-6.03) for kidney cancer, and 7.29 (95% CI, 2.93-15.02) for myeloma. From 2011 to 2016, SIRs were 9.23 (95% CI, 1.12-33.35) for small intestine cancer, 1.54 (95% CI, 0.71-2.93) for lung and bronchus cancer, 2.66 (95% CI, 0.73-6.82) for kidney cancer, and 5.90 (95% CI, 1.61-15.10) for myeloma. The overall risk of developing SPCs in Amineptine individuals who survived the first primary melanoma was 65% higher (SIR, 1.65; 95% CI, 1.35-2.00) in the pre-ICIs period and 98% higher (SIR, 1.98; 95% CI, 1.57-2.45) in the post-ICIs period than the overall cancer incidence rate in the general population. Conclusions and Relevance In this study, an increase in the overall risk of second primary cancers after melanoma after the introduction of immune checkpoint inhibitors was observed. The pattern of SPCs has been altered in the era of systemic therapy. Close monitoring and screening for SPCs may be warranted in patients with metastatic melanoma. Introduction Melanoma is one of the most common cancer types and one of the few cancers with increasing incidence in the US.1 Although treatment options for patients with melanoma, Amineptine including chemotherapy, surgery, and radiation, have evolved, achieving optimum treatment outcomes continues to be challenging.2 This evolution is Amineptine especially true for metastatic melanoma because it is usually highly resistant to the standard of care.3 The introduction of immune checkpoint inhibitors (ICIs) has substantially improved clinical outcomes in patients with advanced-stage cancers. For example, the 5-year overall survival rate for metastatic melanoma increased from approximately 9% to 18% with ipilimumab.4 After the approval of ipilimumab in 2011, other ICIs including nivolumab and pembrolizumab were approved by the US Food and Drug Administration (FDA) for treatment of metastatic melanoma. Because patients with advanced-stage cancers are living longer, long-term treatment and disease-related sequelae are becoming increasingly common on follow-up. One of the most life-threatening sequelae, second primary cancers (SPCs), is often overlooked in the era of immunotherapy.5,6 However, to our knowledge, the risk of SPCs among patients with metastatic melanoma has not been assessed after ICIs were introduced. We used the Surveillance, Epidemiology, and End Results (SEER) database to assess differences in the risk of SPCs in patients with primary melanoma before and after the FDA approved ICIs. We also analyzed changes in the incidence of SPCs with the increased adoption of ICIs as part of the standard of.The SEER registry is a database of 18 cancer registries from across the United States that represents approximately 28% of the US population.7 The SEER database is periodically updated with patient information, including patient demographic characteristics, tumor characteristics, initial treatment modality, diagnosis date, and death date. before the era of immune checkpoint inhibitors. Meaning In this study, a change in the incidence of second primary cancers was found; screening for these cancers may be warranted in patients treated with immune checkpoint inhibitors for metastatic melanoma. Abstract Importance To date, the risk of developing second primary cancers (SPCs) after the first primary melanoma has not been studied in the era of immune checkpoint inhibitors (ICIs). Objective To assess differences in the risk of SPCs in patients with primary melanoma before (2005-2010) and after (2011-2016) the introduction and approval of ICIs. Design, Setting, and Participants Population-based cohort study using the Surveillance, Epidemiology, and End Results database from January 2005 to December 2016 of patients diagnosed with metastatic melanoma. Data were analyzed from January 4 to June 30, 2020. Exposures Receipt of immunotherapy or other anticancer agents. Main Outcomes and Measures The primary outcome was the development of second primary cancers in patients with melanoma. Standardized incidence ratios (SIRs) were calculated for the development of SPCs before and after the introduction of ICIs. Results Among 5016 patients with diagnosed metastatic melanoma, 2888 (58%) were younger than 65 years at the time of diagnosis, and 3441 (69%) were male. From 2005 to 2010, SIRs were 3.24 (95% CI, 0.08-18.04) for small intestine cancer, 1.93 (95% CI, 1.14-3.05) for lung and bronchus cancer, 2.77 (95% CI, 1.02-6.03) for kidney cancer, and 7.29 (95% CI, 2.93-15.02) for myeloma. From 2011 to 2016, SIRs were 9.23 (95% CI, 1.12-33.35) for small intestine cancer, 1.54 (95% CI, 0.71-2.93) for lung and bronchus cancer, 2.66 (95% CI, 0.73-6.82) for kidney cancer, and 5.90 (95% CI, 1.61-15.10) for myeloma. The overall risk of developing SPCs in individuals who survived the first primary melanoma was 65% higher (SIR, 1.65; 95% CI, 1.35-2.00) in the pre-ICIs period and 98% higher (SIR, 1.98; 95% CI, 1.57-2.45) in the post-ICIs period than the overall cancer incidence rate in the general population. Conclusions and Relevance In this study, an increase in the overall risk of second primary cancers after melanoma after the introduction of immune checkpoint inhibitors was observed. The pattern of SPCs has been altered in the era of systemic therapy. Close monitoring and screening for SPCs may be warranted in patients with metastatic melanoma. Introduction Melanoma is one of the most common cancer types and one of the few cancers with increasing incidence in the US.1 Although treatment options for patients with melanoma, including chemotherapy, surgery, and radiation, have evolved, achieving optimum treatment outcomes continues to be challenging.2 This evolution is especially true for metastatic melanoma because it is usually highly resistant to the standard of care.3 The introduction of immune checkpoint inhibitors (ICIs) has substantially improved clinical outcomes in patients with advanced-stage cancers. For example, the 5-year overall survival rate for metastatic melanoma increased from approximately 9% to 18% with ipilimumab.4 After the approval of ipilimumab in 2011, other ICIs including nivolumab and pembrolizumab were approved by the US Food and Amineptine Drug Administration (FDA) for treatment of metastatic melanoma. Because patients with advanced-stage cancers are living longer, long-term treatment and disease-related sequelae are becoming increasingly common on follow-up. One of the most life-threatening sequelae, second primary cancers (SPCs), is often overlooked in the era of immunotherapy.5,6 However, to our knowledge, the risk of SPCs among patients with metastatic melanoma has not been assessed after ICIs were introduced. We used the Surveillance, Epidemiology, and End Results (SEER) database to assess differences in the risk of SPCs in patients with primary melanoma before and after the FDA approved ICIs. We also analyzed changes in the incidence of SPCs with the increased adoption of ICIs as part of the standard of care. Our study hypothesis is that the pattern of SPCs that develop in patients with melanoma has altered in recent years. Methods Data Source and Case Definition Our hypothesis is based on the CENPA assumption that patients who have been diagnosed with metastatic melanoma.