Kottschade, Lisa A.

8566 Background: The incidence of malignant melanoma has risen dramatically over the past decades. Prognosis for patients with metastatic melanoma is poor and treatment options are limited. Complete surgical resection is frequently front line therapy for patients with resectable metastases. However this is only an option if relapse is diagnosed early. PET imaging using 2-flourine-18, 2-fluro-2-deoxy-D-glucose (FDG) has been used successfully for staging of metastatic melanoma. However it's usefulness in surveillance for patients at high-risk of relapse (resected stage III and IV disease) has not been well studied. We conducted a retrospective review of our institutional experience using PET scanning as part of regular follow up in patients with resected stage III or IV melanoma for the purpose of detection of early recurrence. Methods: Retrospective review of the medical records of 667 consecutive patients seen at Mayo Clinic from 12/13/1999–1/1/2007, with the diagnosis of malignant melanoma for whom PET imaging was performed or reviewed at our institution. Eligibility criteria included: resected stage III or IV melanoma with at least 2 PET scans (<1 year apart) as part of regular clinical follow-up (surveillance). Frequency of PET scanning was variable and at physician discretion. Results: Of the 667 patients, 110 patients were deemed eligible for review. There were 98 recurrences among 65 patients. Of these 37 recurrences (38%) were found by PET scanning alone (asymptomatic); 61 recurrences (62%) were found by other methods (physical exam, CT, MRI, etc). Of the 37 recurrences found by routine PET scanning 17 (46%) were completely resected; of the other 61 recurrences found by other methods 33 (54%) were completely resected. Conclusions: PET scanning as regular surveillance for patients with high risk melanoma, may be a useful tool in early identification of asymptomatic melanoma relapse amenable to complete surgical resection (additional 1/3 of cases). Considering the potential clinical benefit of completely resected melanoma relapse, and the retrospective nature of this review, these data are hypothesis-generating and warrant further investigation. No significant financial relationships to disclose.

Background: A female survival advantage in cutaneous melanoma has been long recognized. However, whether this extends across all age groups, with risk stratification using the latest prognostic staging system or in the current era of efficacious systemic therapies is unknown. Therefore, we evaluated whether sex-based differences in melanoma survival persisted within a recent population-based patient cohort with consideration of these factors. Materials and Methods: We identified stage II−IV cutaneous melanoma patients from 2010 to 2014 Surveillance, Epidemiology, and End Results cancer registries data. We recalculated stage per American Joint Committee on Cancer 8th edition guidelines. Cancer-specific survival (CSS) was estimated by using the Kaplan–Meier method and multivariable Cox proportional hazards regression. Results: Of 16,807 patients (39.8% female), 8,990 were stage II, 4,826 stage III, and 2,991 stage IV at diagnosis. Unadjusted 3-/5-year CSS estimates for females versus males were 64.2% versus 59.7%, and 53.5% versus 49.9%, respectively, p ≤ 0.0001. Five-year CSS varied within each stage and across age strata of <45, 45 − 59, and ≥60 years. Within each stage, females <45 had better CSS than all other sex/age groups ( p < 0.0001). In multivariable analysis of stage II/III patients, female sex, younger age, and lower mitotic index retained favorable CSS prognostic significance ( p < 0.001). Conclusions: Sex-based differences in melanoma survival persist in a contemporary patient cohort staged with the latest prognostic system. These data may guide decision marking regarding adjuvant therapy, highlight the importance of including sex as a pre-specified clinical trial variable, and suggest that investigation of underlying biologic mechanisms may drive discovery of biomarkers and therapeutic targets to improve patient care.

Background The objective of this case cohort study was to describe our experience in the care of patients with immune checkpoint inhibitor–related acute interstitial nephritis (ICI-AIN) including rechallenge. Methods A descriptive case series of patients that received an ICI and had an AKI (defined as a ≥1.5-fold increase in serum creatinine) as an immune-related adverse event (irAE), with biopsy-proven or clinically suspected ICI-AIN from January 1, 2014 to December 1, 2018 at Mayo Clinic, Rochester. We studied details regarding diagnosis, clinical course, management, and outcomes of rechallenge of immunotherapy. Complete response (CR) was defined as return of kidney function back to baseline or <0.3 mg/dl above baseline creatinine; partial response (PR) was defined as creatinine >0.3 mg/dl from baseline, but less than twofold above the baseline by the end of steroid course. Results A total of 14 cases of biopsy-proven (35%) or clinically suspected (65%) ICI-AIN was identified. All patients had their ICI withheld and 12 patients received steroids. Steroid regimens were highly variable. The starting equivalent dose of prednisone was higher in those that had a CR versus a PR (median 0.77 mg/kg versus 0.66 mg/kg). Proton pump inhibitors (PPIs) were used in 11 patients and were stopped in eight (73%) patients at the time of the AKI event. A CR was seen in five (63%) of the eight patients who discontinued PPIs. Rechallenge was attempted in four of the 14 patients: three were successful with no recurrence of AKI, but one patient had recurrent AKI and fatal pneumonitis. Conclusions Careful review, withholding ICI and concomitant known AIN-inducing medications, along with prompt initial steroid management were the key in complete renal kidney recovery. A kidney biopsy should be strongly considered. Rechallenge of immunotherapy after a kidney irAE, although challenging, is possible and would need careful evaluation on an individual basis. Podcast This article contains a podcast at https://www.asn-online.org/media/podcast/K360/2020_01_30_KID0000152019.mp3

Patients diagnosed with stage III melanoma who have undergone curative-intent surgery still remain at relatively high risk of disease recurrence. Recently approved adjuvant therapies with immune checkpoint inhibitors (ICIs) have brought increased relapse-free and overall survival rates. However, they have introduced a new range of side effects that can be difficult to diagnose, are challenging to treat, and may have lifelong consequences for patients. Oncologists and other members of the oncology care team should be aware of these side effects, including atypical presentations, and be prepared to intervene to prevent increased morbidity and mortality. Oncologists also need to have a low threshold for referral to other subspecialists, as many of these immune-related adverse events (irAEs) need to be comanaged using a multidisciplinary approach. Herein, we present a case that illustrates challenging presentations of endocrinopathy and hepatic irAEs in a patient with stage III melanoma receiving ICI therapy in the adjuvant setting.

TPS65 Background: Mucosal melanoma is a rare and, therefore, poorly studied malignancy. Patients with resected primary tumors have a median time to recurrence of 5.5 months. While no one adjuvant therapy is of proven benefit for patients, immunotherapy has shown activity in metastatic mucosal melanoma. Methods: We are performing a single arm, phase II clinical trial through the Midwest Melanoma Partnership/Hoosier Cancer Research Network (6 sites) for resected mucosal melanoma. The primary endpoint is recurrence free survival (RFS), and it will include 36 subjects. Patients must have had an R0 or R1 resection of a mucosal melanoma (sinonasal, anorectal, vulvar, or other), and register within 90 days of surgery. Adjuvant radiation is allowed prior to registration but not required. Therapy consists of ipilimumab (1 mg/kg) and nivolumab (3 mg/kg) IV q3w x 4, then 480 mg nivolumab x 1 year. Statistical power is calculated to be 85% to detect a change in RFS from 5.5 months to 9.5 months, with a one sided alpha of 0.05. Enrollment began Sept 2017, with current participation from 6 large volume centers in the United States, with 17 patients enrolled as of Sept 2019. Full accrual is anticipated to complete by year end 2020. Patients will be followed for RFS and OS. Translational studies will include mutational burden, c-kit, BRAF, NRAS status, and serum markers of immunity -- including soluble PD-L1 and Bim. Clinical trial information: NCT03241186.

Background: Thyroid immune-related adverse events (IRAEs) have been reported more frequently with programmed cell death protein-1 (PD-1) inhibitors than cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors, but there is limited data describing endocrinopathies from programmed cell death protein–ligand 1 (PD-L1) inhibitors. This study characterizes thyroid IRAEs in cancer patients treated with PD-L1 inhibitors and examines the impact on overall survival. Methods: This is a retrospective cohort study of cancer patients treated with atezolizumab and avelumab at the Mayo Clinic, Rochester, Minnesota, from June 1, 2016 to January 30, 2018, and followed for a median of 10.1 months. Thyroid IRAEs were characterized as new onset hypothyroidism, thyrotoxicosis, and worsening of pre-existing hypothyroidism. Results: Of 91 patients treated with a PD-L1 inhibitor, 19 (21%) developed new onset thyroid dysfunction, of whom 14 presented with hypothyroidism and 5 with thyrotoxicosis (3 progressed to hypothyroidism and 2 returned to euthyroidism), and 4 (4%) had worsening of pre-existing hypothyroidism. Thyroid IRAEs occurred after a median of two doses (6 weeks), 48% required thyroid hormone replacement, and none required steroids or discontinuation of immunotherapy. Two out of four patients with thyroid peroxidase (TPO) antibody >9 IU/mL at baseline developed thyroid IRAEs. Median TPO antibody titer was not different between those with and without thyroid IRAEs but was higher in those with overt than those with subclinical hypothyroidism (5 vs. 0.3 IU/mL, p = 0.003) and those prescribed thyroid hormone replacement as compared with observation (5.5 vs. 0.3, p = 0.008). Diffusely increased thyroid 18-fluorodeoxyglucose ( 18 FDG) uptake on positron emission tomography (PET) scan occurred in 71% with thyroid IRAE as compared with 6% without thyroid IRAEs ( p = 0.001). Patients who developed thyroid IRAEs had longer overall survival ( p = 0.027) and lower mortality (hazard ratio 0.49 [95% CI 0.25–0.99], p = 0.034) after adjusting for potential confounders. Conclusions: PD-L1 inhibitors lead to immune-mediated thyroiditis, the most frequent endocrine IRAE. In most cases, management is supportive without requiring steroids or discontinuation of immunotherapy. Diffusely increased thyroid 18 FDG uptake on PET scan may predict the occurrence of thyroiditis, whereas TPO antibodies may help identify its severity. Thyroiditis may be a biomarker for antitumor immune response, highlighting the need to further characterize its underlying mechanism.

4 Background: Membrane expression of PD-L1 on tumor cells is associated with poor survival in patients with advanced malignancies including metastatic melanoma (MM). In addition, tumor-associated PD-L1 has been proposed as a predictor of response to anti-PD-1 therapy, although responses are observed in some cases of PD-L1 negative MM. We hypothesize that tumor-derived PD-L1 has additional systemic effects through the release of biologically active soluble forms of PD-L1 (sPD-L1) into the circulation, which further impedes the anti-tumor immune response and contributes to poor clinical outcomes in MM. Methods: We developed a sPD-L1 ELISA and biochemically confirmed the identity of the detected protein. We measured the levels of sPD-L1 in 276 patients with MM enrolled on 3 clinical trials who had stored pre-treatment plasma samples and 37 healthy volunteers (HV) undergoing blood donation at Mayo Clinic. We also measured sPD-L1 in baseline samples from 38 MM patients treated with anti-PD1 (pembrolizumab) 2 mg/kg every 3 weeks. ROC analysis was used to compute sPD-L1 concentration cut-off value and Wald test was used to asses the difference of overall survival (OS) in patients with low versus high sPD-L1 concentration. Results: We found that sPD-L1 levels were significantly elevated in MM patients compared with HV (p=0.0011). Mean sPD-L1 level in MM was 1.73 ng/mL (range: 0.13-18.29) compared with 0.77 ng/mL (range: 0.11–6.02) for HV. Patients with higher levels (>0.293 ng/mL) had a median OS of 11.3 months compared to 14.8 months for patients with sPD-L1 level ≤ 0.293 ng/mL (p=0.040). Similarly to tumor-related PD-L1 findings, patients who had clinical benefit (OR/PR/SD) after 4 cycles of anti-PD1 had higher sPD-L1 levels at baseline (2.1 vs. 1.1 ng/mL). Conclusions: To our knowledge, our study is the first to report a correlation of sPD-L1 with MM patient outcome, although a larger study is needed to establish the utility of sPD-L1 as an independent prognostic and possibly predictive biomarker.

Abstract Background: Standard treatment for stage III melanoma is surgery followed by consideration of adjuvant therapy. This strategy is inadequate for high-risk stage III patients who have a substantial risk of subsequent relapse and distant metastasis. The goals of this trial are to improve oncologic outcomes, assess treatment response and spare patients with poorly responsive, rapidly metastatic disease from a futile operation. This protocol based on the hypothesis that treatment before surgery will immunize patients against his or her own unique tumor. While new drugs are now FDA-approved for adjuvant treatment of stage III melanoma, outcomes are still suboptimal in high-risk patients. The neoadjuvant approach is largely untested and preclinical data suggest neoadjuvant therapy is more effective than adjuvant immunotherapy. While targeted therapies can be rapidly effective, immunotherapy responses, when they occur, tend to be much more durable, prompting this study. Our specific strategy is based on the fact that BRAFm melanoma patients benefit both from BRAF/MEK inhibition (vemurafenib/cobimetinib) and PD-1 axis inhibition (atezolizumab) while patients with BRAFwt melanoma benefit from PD-1 axis inhibition (atezolizumab) and intermittent MEKi (cobimetinib) may increase effector function in tumor-infiltrating T cells. A second component of the study is robust evaluation of biomarkers of response, toxicity and outcome. Specific correlatives include assessment of the predictive value of Bim levels in tumor-related T cells, correlation of sPD-L1 with efficacy and toxicity, correlation of PD-L1 expression with efficacy, and determination of key relationships between tumor and immune cells via mIHC spatial analysis, gene expression profiles and microbiome associations with clinical response. Methods: The NeoACTIVATE trial enrolls melanoma patients with resectable clinically detectable nodal metastases (by physical examination or imaging), dual nodal basin disease or nodal recurrence of melanoma. Neoadjuvant systemic therapy is based on BRAF mutation status; participants receive either vemurafenib, cobimetinib and atezolizumab (vem/cobi/atezo), or cobimetinib and atezolizumab (cobi/atezo) before surgery. Following surgery, all patients receive atezo immunotherapy. The primary aim of the study is RFS estimates for each cohort. Secondary aims are safety/toxicity, pathologic complete response rate and prospective evaluation of biomarkers of treatment response and toxicity. This study is significant in that it is the first to test 1) combined of targeted and immunotherapy in the neoadjuvant setting for patients with resectable Stage III melanoma and 2) the novel combination of MEK-inhibition with immunotherapy in the neoadjuvant setting for resectable Stage III melanoma. As of January 1, 2019, 10% of planned patients have been enrolled and enrollment continues. Citation Format: Tina J. Hieken, Vera J. Suman, Shernan G. Holtan, Thomas J. Flotte, Lisa A. Kottschade, Matthew S. Block. Neoadjuvant combination targeted and immunotherapy for high-risk resectable stage III melanoma (NeoACTIVATE), NCT03554083 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT121.

138 Background: Clinical management of metastatic melanoma (MM) after PD-1 blockade failure remains challenging and lacks a standard of care. Chemo-immunotherapy (CIT) combinations have demonstrated favorable efficacy and safety profiles in lung cancer patients. In this study, we compared the clinical outcomes of CIT with immunotherapy or chemotherapy alone after PD-1 blockade failure. Methods: We reviewed MM patients seen at Mayo Clinic between Jan, 2012 and Jun, 2018 who failed anti-PD1 therapy and received subsequent CIT, or immune checkpoint inhibitors (ICI) or chemotherapy alone. A total of 60 patients were analyzed, the CIT cohort [n=33 (55%)] treatment consisted of carboplatin/paclitaxel (n=29), nab-paclitaxel (n=2), paclitaxel (n=1), and temozolomide (n=1). In the ICI (n=9) or chemotherapy alone cohort (n=18) [n=27 (45%)], treatment consisted of carboplatin/paclitaxel (n=11), temozolomide (n=4), nab-paclitaxel (n=3), ipilimumab/nivolumab (n=4), pembrolizumab (n=4), or nivolumab (n=1). Results: Patients in the CIT cohort had a median OS of 3.5 years (95% CI: 1.7-NR) compared to 1.8 years (95% CI: 0.9-2) in the ICI or chemotherapy alone cohort, p=0.02. The median EFS following CIT was 7.6 months (95% CI: 6-10) compared to 3.4 months (95% CI: 2.8-4.1) following either ICI or chemotherapy alone, p=0.0005. A trend towards longer median EFS with use of CIT was seen in patients with BRAF wild-type [median 9 months (95% CI: 6-12)] compared to those harboring a BRAF mutation [median 6.5 months (95% CI: 1.8-9.1), p=0.29]. Side effects were similar among both groups. Conclusions: In MM patients who have failed anti-PD-1 therapy, the CIT combination showed favorable clinical outcomes and acceptable safety profile. This regimen should be considered for MM pts in this setting who have limited treatment options. [Table: see text]