Checkpoint blockade and BRAF/MEK therapy in the therapeutic setting improved the overall survival after sentinel node biopsy: A retrospective study comparing patients with primary care between 1998‐2009 and 2010‐2017

Immunotherapies using checkpoint blockade and BRAF/MEK therapies have improved overall survival (OS) in patients with unresectable melanoma metastases. In this retrospective study, we aimed to demonstrate the resulting increase in melanoma‐specific survival (MSS) and OS after the excision of primary melanomas (≥1 mm thick) and sentinel lymph node (SN) biopsy (SNB). Using Kaplan‐Meier estimates and Cox models, we compared two consecutive cohorts. Patients in cohort 1 (N = 518) underwent SNB between 1998 and 2009, and patients in cohort 2 (N = 460) between 2010 and 2017, when checkpoint blockade and BRAF/(MEK) inhibition became available for the treatment of unresectable relapses. The median follow‐up times were 120 and 73 months, respectively. While recurrence‐free and distant metastasis‐free survival rates remained very similar, MSS and OS increased in favor of cohort 2. The estimated 5‐year OS rate of SN‐positive patients increased by 14.3% (78.5% vs 64.2%, logrank test: P = .005). The MSS benefit was significant even with low SN tumor burden (metastasis diameter < 1 mm). On multivariate analyses, the risk‐reduction in favor of cohort 2 was significant in the total population and in the SN‐negative and SN‐positive subgroups. In SN‐positive patients, besides the availability of modern therapies, SN metastasis diameter and ulceration were independent factors of MSS and OS. Treatment of unresectable melanoma recurrences with modern drug therapies results in significantly higher survival rates in a population with SNB. The survival benefit measured from primary melanoma affects both the SN‐positive and SN‐negative subpopulations.

significantly in a population with SNB. In multivariate analysis adjusting for Breslow thickness, ulceration and SN status, the relative risk of death nearly halved after the introduction of modern recurrence therapies. Significantly higher OS rates were observed in both SN-negative and SN-positive subpopulations. On multivariate analysis of SN-positive patients, the availability of effective recurrence therapies, SN tumor burden and ulceration were significant for OS. Our study exemplifies that the assumption of proportionality of DMFS and OS can become invalid when effective therapies are used in the later course of the disease.

| INTRODUCTION
Until about 2010, chemotherapy was the mainstay of therapy for unresectable metastatic melanoma, with very few complete or long-lasting remissions. 1 The subsequent successful introduction of antibodies targeting immune checkpoint regulators and small molecule BRAF/MEK inhibitors improved this situation quite substantially. Checkpoint-directed inhibition of cytotoxic T-lymphocyte antigen 4 (CTLA-4) 2 or programmed death receptor 1 (PD-1) 3,4 may show delayed onset of action. However, remissions produced are often long lasting and there is a real prospect of cure. For patients whose melanomas harbor BRAF V600 mutations, targeted therapies with BRAF and MEK inhibitors have produced high response rates, improved recurrence-free survival (RFS) and overall survival (OS). [5][6][7] Advantages of BRAF/MEK therapies include rapid onset of action and high response rates, even with high tumor burden. 8 Thus, it was obvious to investigate the modern BRAF/MEK and immunotherapies for the adjuvant indication. In patients with complete lymph node dissection (CLND) in stage III melanoma, [9][10][11] the early use of nivolumab, pembrolizumab and dabrafenib/trametinib has resulted in improved RFS and distant metastasis-free survival (DMFS).
The recent approval of adjuvant pembrolizumab in stage IIB and C melanoma was based exclusively on improved RFS. 12 RFS is a popular surrogate endpoint for OS in studies because fewer patients are needed; data become available at an earlier time point, and are not affected by subsequent therapies. However, the relationship between RFS and OS is not always straightforward. While there is a strong correlation between the two endpoints in some diseases, such as colon and ovarian cancer, the relationship appears less clear for tumors such as sarcoma, advanced breast cancer, prostate cancer and non-smallcell lung cancer. 13 An association between DMFS and OS has also been described in melanoma, but the underlying data predate the introduction of highly effective drugs for recurrence therapy. 14 Decisions regarding adjuvant therapy should take into account, that checkpoint blockade and BRAF/MEK can cause significant toxicity. 9,10,[15][16][17][18] In a real-world population of patients treated with adjuvant BRAF/MEK inhibition, adverse effects occurred in 90% of patients, leading to treatment discontinuation in 65%. 19 A multicenter study showed that chronic immune-mediated adverse events occurred in 43.2% of patients after adjuvant therapy with anti-PD-1 or anti-PD-L1 antibodies for melanoma. 18 This is much more frequent than previously thought. It should be kept in mind that significant improvement in OS with adjuvant administration of BRAF/MEK inhibition or anti-PD-1 immunotherapies has not been demonstrated to date. 9,20 Adjuvant therapy decisions are often based on historical OS outcomes that are possibly not representative of the era since the introduction of modern systemic therapies for metastatic disease.
Moreover, in SN-positive patients prognosis-relevant aspects of the extent of the SN metastasis has been insufficiently considered.
In the present study, we aimed to demonstrate the extent to which melanoma-specific survival (MSS) and OS after SNB have improved with the introduction of modern targeted and immunologic therapies for the treatment of unresectable recurrences. Such data may be useful for future studies and may also facilitate decisionmaking in adjuvant therapy education.

| PATIENTS AND METHODS
The present retrospective cohort study DRKS00023405 (survival rates of melanoma patients with sentinel node biopsy before and after  Patients with microsatellites in the vicinity of primary melanoma were eligible. Adjuvant therapy with low-dose interferon was permitted.

| Exclusion criteria
Study participants from the verum groups of adjuvant therapy trials dealing with ipilimumab or pembrolizumab (EORTC 18071, 16 EORTC 1325 10 ) were excluded. Patients with primary tumor thickness of <1 mm and patients with spitzoid primary melanomas were also excluded due to their excellent prognosis (numbers shown in Figure 1).

| Outcome variables
RFS was defined as time interval between primary tumor excision and first melanoma recurrence, regardless of recurrence type. DMFS was defined as time interval between primary tumor excision and first distant metastasis of melanoma. MSS was defined as duration from excision of the primary melanoma to last follow-up or death due to melanoma. OS was defined as duration from primary melanoma excision to death or last follow-up, with no restriction on the cause of death.

| Objectives
Primary objectives were to compare the MSS and OS rates for both cohorts, with respect to SN status and nodal tumor burden. Secondary objectives were to compare RFS and DMFS rates.

| Control of possible biases
The primary care modalities mentioned below were very similar in the two comparison periods. The same individuals throughout the study period maintained surgical and pathologic standards. Clinical and histologic data were prospectively entered into an electronic database of the Göttingen Department of Dermatology. To control for confounding, we used stratification according to SN tumor burden and adjustment by multivariate Cox models. To avoid shrinkage and reporting errors in our database, data clearing took place in 2021. With the help of the Göttingen Comprehensive Cancer Center, residents' registration offices, internet search focusing on possible death notifications, and telephone calls to outpatient physicians, we were able to update missing follow-up data of 578 patients.

| Primary care
Standard treatment for a primary melanoma was wide local excision with adequate safety margins and SNB, as previously described. 21 F I G U R E 1 Study population, exclusion criteria and cohorts building. SNB, sentinel lymph node biopsy.

| Pathological SN assessment
We used standardized multiple slices protocols for pathologic workup of SNs and a standardized sheet for pathologic reporting. 22

| Follow-up
Follow-up care was provided in accordance with the applicable guidelines. The aim was to follow the individual patients until 10 years after the last melanoma manifestation.

| Recurrence-free survival
The RFS rates were virtually identical for the two periods compared

| Overall survival
On univariate analysis, the OS survival significantly improved in favor of cohort 2 ( Figure 3A-C). In the SN-positive subpopulation, the percent differences by 5 and 10 years were 14.3% and 10.0%, respectively ( Figure 3B).

| DISCUSSION
This retrospective study compared two consecutive cohorts of patients with primary melanomas ≥1 mm in thickness from a population of 1250 Primary tumor-and SN-related risk factors were very similar in the two cohorts compared. Consequently, the RFS and DMFS curves were also very similar. Our study may be the first to demonstrate that the introduction of modern targeted and immunologic therapies in the treatment of unresectable metastases produced an OS benefit that was clearly measurable even up to the total SNB population. The F I G U R E 3 (A-C) Compared with cohort 1 (lower curves), patients within the later cohort 2 (upper curves) had increased overall survival when the entire study population (A) was considered. The overall survival benefit was greatest in the sentinel node-positive subpopulation (B). The sentinel node-negative subpopulation (C) also showed improved outcome for cohort 2, when modern antitumor therapies were available.
avoidance of early-onset resistance and, from an economic perspective, significant potential savings.
We here show with multivariate analysis that metastasis diameter in the SN is an independent factor of OS, besides relapse therapy with modern drugs and ulceration. Therefore, the risk factors of the pri- Improvements in other areas of medicine may have contributed to the improved OS rates over time. This seems unlikely, as we did not

FUNDING INFORMATION
Open Access funding enabled and organized by Project DEAL.