Second Primary Tumors and Immune Checkpoint Inhibitors: What Do We Know?

Therapeutic innovations over the past decade have led to effective new options for the management of advanced melanoma. However, the short-term benefit of immune checkpoint inhibitors (ICI) in melanoma management may have long-term implications for patient surveillance and management. Specifically, a new analysis shows that patients who survive a first primary melanoma in the era of ICIs have a 98 percent increased risk of developing a second primary cancer (SPC), compared to the general population. This is up from a 68 percent increased risk in the pre-ICI era. The basis for the increased risk is not immediately clear.

Data At-a-Glance

The various agents approved for the treatment of advanced melanoma have been shown to provide benefit in pivotal clinical trials, and data suggest that the availability of these drugs has had a positive impact on overall survival. One study has found that age-standardized, one-year net survival for advanced melanoma improved during the period from 2001-2013. Improvement was particularly evident from 2010 onward, reaching 58.9 percent in 2013, compared to approximately 43 percent from 2001-2010. Researchers conclude that this improvement in survival may be a consequence of the introduction of ICIs and other targeted treatments for metastatic and unresectable melanomas. Importantly, the study shows that while survival improved in both white and black patients, the benefit was not as robust among black patients, indicating potential disparities in access to treatment.¹

While ICIs are providing benefit in terms of melanoma survival, there may be long-term implications for second primacy cancers. Researchers recently analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database from January 2005 to December 2016.² From a total 5,016 patients diagnosed with metastatic melanoma, they identified two cohorts of patients—one group of those diagnosed from 2005 to 2010 and the other group diagnosed from 2011-2016. Of the entire population, 58 percent of patients were under age 65 and 69 percent were men.

Standardized incidence ratios for select cancers are shown in Table 1. As noted above, compared to the overall cancer incidence rate in the general population, the risk of developing SPCs in individuals who survived the first primary melanoma was 65 percent higher from 2005 to 2011. The overall risk of developing SPCs in this group during the period from 2011-2016 was 98 percent higher, compared to the general population. Interestingly, the five-year cumulative incidence of all-cause mortality among patients with advanced melanoma declined from 0.82 in the pre-ICIs group to 0.76 in the post-ICIs group.

Importantly, the researchers note that the increase in SPCs is not necessarily shown to be related to ICIs. Enhanced overall survival could contribute; longer lifespans provide additional opportunity for development of new cancers. There could also be an effect from enhanced surveillance and improved diagnostics; however, the differences in the types of secondary tumors suggests a potential effect of ICIs.

Implications

While the nature of the risk remains unclear, the data suggest that patients treated with ICIs for advanced melanoma may be at risk to develop second primary cancers. Of course, dermatologists are already vigilant for melanoma recurrence or secondary tumors in patients with a history of advanced melanoma. Now, dermatologists should also keep in mind the potential risk of secondary tumors in patents with a history of advanced melanoma and ICI use.

1. Di Carlo V, Estève J, Johnson C, et al. Trends in short-term survival from distant-stage cutaneous melanoma in the United States, 2001-2013 (CONCORD-3). JNCI Cancer Spectr. 2020 Sep 14;4(6):pkaa078.

2. Deng W, Wang Y, Liu X, et al. Assessment of Trends in Second Primary Cancers in Patients With Metastatic Melanoma From 2005 to 2016. JAMA Netw Open. 2020 Dec 1;3(12):e2028627.