Faculty Bibliography

BACKGROUND:Adjuvant therapy for high-risk resected melanoma with programmed cell-death 1 blockade results in a median relapse-free survival (RFS) of 5 years. The addition of low dose ipilimumab (IPI) to a regimen of adjuvant nivolumab (NIVO) in CheckMate-915 did not result in increased RFS. A pilot phase II adjuvant study of either standard dose or low dose IPI with NIVO was conducted at two centers to evaluate RFS with correlative biomarker studies. METHODS:Patients with resected stages IIIB/IIIC/IV melanoma received either IPI 3 mg/kg and NIVO 1 mg/kg (cohort 4) or IPI 1 mg/kg and NIVO 3 mg/kg (cohorts 5 and 6) induction therapy every 3 weeks for 12 weeks, followed by maintenance NIVO. In an amalgamated subset of patients across cohorts, peripheral T cells at baseline and on-treatment were assessed by flow cytometry and RNA sequencing for exploratory biomarkers. RESULTS:High rates of grade 3-4 adverse events precluded completion of induction therapy in 50%, 35% and 7% of the patients in cohorts 4, 5 and 6, respectively. At a median of 63.9 months of follow-up, 16/56 patients (29%) relapsed. For all patients, at 5 years, RFS was 71% (95% CI: 60 to 84), and overall survival was 94% (95% CI: 88 to 100). Expansion of CD3+CD4+CD38+CD127-GARP- T cells, an on-treatment increase in CD39 expression in CD8+ T cells, and T-cell expression of phosphorylated signal-transducer-and-activator-of-transcription (STAT)2 and STAT5 were associated with relapse. CONCLUSIONS:Adjuvant IPI/NIVO at the induction doses used resulted in promising relapse-free and overall survival, although with a high rate of grade 3-4 adverse events. Biomarker analyses highlight an association of ectoenzyme-expressing T cells and STAT signaling pathways with relapse, warranting future validation. TRIAL REGISTRATION NUMBER:NCT01176474 and NCT02970981.

Background Despite significant improvements in treatment outcomes with ICIs, deeper understanding is needed to improve outcomes for patients with melanoma who experience no clinical benefit from ICI therapy and exhibit early disease progression (primary resistance).1 We analyzed clinical and translational factors using data from 9 BMS-sponsored clinical trials of nivolumab (NIVO), ipilimumab (IPI) and their combination in patients with advanced cutaneous melanoma (Check- Mate 003, 037, 038, 064, 066, 067, 069, 511, 742) to predict resistance to ICIs and explore underlying mechanisms. Methods Analyses of pre-treatment clinical covariates and biomarkers (determined by tumor immunohistochemistry, whole exome DNA sequencing, RNA sequencing, and serum cytokine analysis) were performed in patients with melanoma who received NIVO, IPI or NIVO+IPI and were evaluable for resistance. Several methods were used to develop and test models predicting ICI primary resistance, defined as death due to disease or best overall response of progressive disease (excluding pseudoprogression) before the first radiographic scan (<=13 weeks of treatment). Model performance was assessed using cross-validated area under the receiver operating characteristic curve (AUROC) and bootstrap bias-adjusted calibration metrics. Additionally, we evaluated individual biomarker associations with primary resistance. Results Across 1803 patients from 9 clinical trials, 1638 were evaluable for cutaneous melanoma primary resistance and 585 (36%) met the criteria. A multivariable logistic regression model for predicting primary resistance yielded an AUROC of 0.78 (R2=0.29) and included 17 commonly available clinical factors and PD-L1 (table 1). External validation using data from an independent study yielded an AUROC of 0.70 (R2=0.17). Higher levels of acute phase cytokines and expression of genes associated with suppressive tumor microenvironment or stromal factors, including epithelial-mesenchymal transition, cancer-associated fibroblasts, transforming growth factor beta, and angiogenesis, were associated with increased risk of primary resistance. In contrast, higher levels of tumor mutational burden, PD-L1, CD8, mutations in MAPK-pathway genes, and immune gene signature scores were associated with decreased risk (figure 1, table 2). Conclusions This exploratory analysis of clinical and translational factors in patients with advanced cutaneous melanoma identified associations with primary resistance to NIVO, IPI, or NIVO+IPI, with the best model yielding an AUROC of 0.78. Factors associated with primary resistance included higher levels of prognostic cytokines, gene expression indicating an immune suppressive tumor microenvironment, lower levels of anti-tumor immunity, and lack of MAPK-pathway mutations. These findings are supportive of future clinical trial stratification of patients and mechanistic studies targeting the biology of primary resistance to ICI therapy

Helper (CD4⁺) T cells perform direct therapeutic functions and augment responses of cells such as cytotoxic (CD8⁺) T cells against a wide variety of diseases and pathogens. Nevertheless, inefficient synthetic technologies for expansion of antigen-specific CD4⁺ T cells hinders consistency and scalability of CD4⁺ T cell-based therapies, and complicates mechanistic studies. Here we describe a nanoparticle platform for ex vivo CD4⁺ T cell culture that mimics antigen presenting cells (APC) through display of major histocompatibility class II (MHC II) molecules. When combined with soluble co-stimulation signals, MHC II artificial APCs (aAPCs) expand cognate murine CD4⁺ T cells, including rare endogenous subsets, to induce potent effector functions in vitro and in vivo. Moreover, MHC II aAPCs provide help signals that enhance antitumor function of aAPC-activated CD8⁺ T cells in a mouse tumor model. Lastly, human leukocyte antigen class II-based aAPCs expand rare subsets of functional, antigen-specific human CD4⁺ T cells. Overall, MHC II aAPCs provide a promising approach for harnessing targeted CD4⁺ T cell responses.

Checkpoint immunotherapies (CPIs) have improved outcomes for metastatic melanoma patients, with objective response rates to combination ipilimumab and nivolumab of ~58%. Preclinical data suggest that histone deacetylase (HDAC) inhibition enhances antitumor immune activity and may augment CPI. In a phase Ib open-label pilot trial (NCT03565406), patients with therapy-naive metastatic melanoma were treated with the class I/IV HDAC inhibitor mocetinostat orally three times a week in combination with nivolumab and ipilimumab every 3 weeks for 12 weeks followed by 12-week maintenance cycles of nivolumab every 2 weeks and mocetinostat at the same dose and schedule as induction. The endpoints of the trial were safety, definition of a recommended phase 2 dose, preliminary assessment of response, and correlative marker determination. Patient PBMC and serum samples collected at baseline and on-treatment were assessed by flow cytometry and Luminex assays for immune correlates. Ten patients were treated: nine with 70-mg and one with 50-mg mocetinostat. In the 70-mg cohort, eight patients had objective responses. The patient in the 50-mg cohort had an early progression of disease. All patients had grade 2 or higher toxicities, and six had grades 3 and 4 toxicities. Patient PBMC showed significant decreases in myeloid-derived suppressor cells and trends towards reduced anti-inflammatory monocyte phenotypes. Patient serum showed significant upregulation of granzyme A and TNF and trends towards increased granzyme B and IFNγ. Collectively, combining CPI and mocetinostat had favorable response rates but with high levels of toxicity. Assessment of immune correlates supports a shift away from immunosuppressive phenotypes towards enhanced immune responses.

BACKGROUND:Recent data suggest that patients with stage III melanoma are at high risk for developing central nervous system (CNS) metastases. Because a subset of patients with stage II melanoma experiences worse survival outcomes than some patients with stage III disease, the authors investigated the risk of CNS metastasis in stage II melanoma to inform surveillance guidelines for this population. METHODS:test, the cumulative incidence, and Cox multivariable regression analyses were performed to evaluate the association between baseline characteristics and the development of CNS metastases. RESULTS:Patients with stage III melanoma had a higher rate of developing brain metastases than those with stage II melanoma (100 of 468 patients [21.4%] vs. 82 of 586 patients [14.0%], respectively; p = .002). However, patients who had stage IIC melanoma had a significantly higher rate of isolated first recurrences in the CNS compared with those who had stage III disease (12.1% vs. 3.6%; p = .002). The risk of ever developing brain metastases was similarly elevated for patients who had stage IIC disease (hazard ratio [HR], 3.16; 95% CI, 1.77-5.66), stage IIIB disease (HR, 2.83; 95% CI, 1.63-4.91), and stage IIIC disease (HR, 2.93; 95% CI, 1.81-4.74), and the risk was highest in patients who had stage IIID disease (HR, 8.59; 95% CI: 4.11-17.97). CONCLUSIONS:Patients with stage IIC melanoma are at elevated risk for first recurrence in the CNS. Surveillance strategies that incorporate serial neuroimaging should be considered for these individuals until more accurate predictive markers can be identified.

PURPOSE/OBJECTIVE:Ipilimumab and nivolumab have each shown treatment benefit for high-risk resected melanoma. The phase III CheckMate 915 trial evaluated adjuvant nivolumab plus ipilimumab versus nivolumab alone in patients with resected stage IIIB-D or IV melanoma. PATIENTS AND METHODS/METHODS:In this randomized, double-blind, phase III trial, 1,833 patients received nivolumab 240 mg once every 2 weeks plus ipilimumab 1 mg/kg once every 6 weeks (916 patients) or nivolumab 480 mg once every 4 weeks (917 patients) for ≤ 1 year. After random assignment, patients were stratified by tumor programmed death ligand 1 (PD-L1) expression and stage. Dual primary end points were recurrence-free survival (RFS) in randomly assigned patients and in the tumor PD-L1 expression-level < 1% subgroup. RESULTS:= .269) or in patients with PD-L1 expression < 1% (hazard ratio, 0.91; 95% CI, 0.73 to 1.14). In all patients, 24-month RFS rates were 64.6% (combination) and 63.2% (nivolumab). Treatment-related grade 3 or 4 adverse events were reported in 32.6% of patients in the combination group and 12.8% in the nivolumab group. Treatment-related deaths were reported in 0.4% of patients in the combination group and in no nivolumab-treated patients. CONCLUSION/CONCLUSIONS:Nivolumab 240 mg once every 2 weeks plus ipilimumab 1 mg/kg once every 6 weeks did not improve RFS versus nivolumab 480 mg once every 4 weeks in patients with stage IIIB-D or stage IV melanoma. Nivolumab showed efficacy consistent with previous adjuvant studies in a population resembling current practice using American Joint Committee on Cancer eighth edition, reaffirming nivolumab as a standard of care for melanoma adjuvant treatment.

PURPOSE:Adjuvant immunotherapy produces durable benefit for patients with resected melanoma, but many develop recurrence and/or immune-related adverse events (irAE). We investigated whether baseline serum autoantibody (autoAb) signatures predicted recurrence and severe toxicity in patients treated with adjuvant nivolumab, ipilimumab, or ipilimumab plus nivolumab. EXPERIMENTAL DESIGN:This study included 950 patients: 565 from CheckMate 238 (408 ipilimumab versus 157 nivolumab) and 385 from CheckMate 915 (190 nivolumab versus 195 ipilimumab plus nivolumab). Serum autoAbs were profiled using the HuProt Human Proteome Microarray v4.0 (CDI Laboratories, Mayaguez, PR). Analysis of baseline differentially expressed autoAbs was followed by recurrence and severe toxicity signature building for each regimen, testing of the signatures, and additional independent validation for nivolumab using patients from CheckMate 915. RESULTS:In the nivolumab independent validation cohort, high recurrence score predicted significantly worse recurrence-free survival [RFS; adjusted HR (aHR), 3.60; 95% confidence interval (CI), 1.98-6.55], and outperformed a model composed of clinical variables including PD-L1 expression (P < 0.001). Severe toxicity score was a significant predictor of severe irAEs (aHR, 13.53; 95% CI, 2.59-86.65). In the ipilimumab test cohort, high recurrence score was associated with significantly worse RFS (aHR, 3.21; 95% CI, 1.38-7.45) and severe toxicity score significantly predicted severe irAEs (aHR, 11.04; 95% CI, 3.84-37.25). In the ipilimumab plus nivolumab test cohort, high autoAb recurrence score was associated with significantly worse RFS (aHR, 6.45; 95% CI, 1.48-28.02), and high severe toxicity score was significantly associated with severe irAEs (aHR, 23.44; 95% CI, 4.10-212.50). CONCLUSIONS:Baseline serum autoAb signatures predicted recurrence and severe toxicity in patients treated with adjuvant immunotherapy. Prospective testing of the signatures that include datasets with longer follow-up and rare but more severe toxicities will help determine their generalizability and potential clinical utility. See related commentary by Hassel and Luke, p. 3914.

Background: Lifileucel showed durable responses in patients (pts) with advanced (unresectable/metastatic) melanoma in the post anti-PD-1 setting, with an ORR of 36% (Sarnaik JCO 2021). The recent approval of relatlimab (anti-LAG3 antibody) + nivolumab provides a new option for first-line (1L) treatment of advanced melanoma; however, ORR after exposure to this novel combination has been reported only for anti-CTLA-4-based therapies (11%; Menzies NEJM 2022).
Method(s): In the phase 2, C-144-01 study (NCT02360579), pts with advanced melanoma were previously treated with immune checkpoint inhibitor(s) (ICI) and BRAF +/- MEK inhibitors (if BRAF V600 mutation-positive). We performed a retrospective exploratory analysis to assess efficacy and safety of lifileucel in pts enrolled in C-144-01 who progressed on/after anti-LAG3-containing therapy. ORR was assessed by investigators per RECIST v1.1.
Result(s): Thirteen pts received prior anti-LAG3 (12 with anti-PD-1; 1 with anti-PD-1 + anti-CTLA-4), with a median of 3 prior therapies. Anti-LAG3 was the last therapy prior to TIL therapy in 7 pts; 6 pts had other therapies after anti-LAG3 (eg, chemotherapy, ICI, targeted therapy). Anti-LAG3 was used in 1L in 4 pts; 9 pts received it post-progression. Median duration of anti-LAG3 therapy was 3.3 mo (range, 0.03-9.2 mo). ORR for lifileucel was 38.5% (5 partial responses); 3 responders had primary and 2 acquired resistance to anti-LAG3 + anti-PD-1. Responses were durable, with 60% of responses extending beyond 12 mo. Safety profile was consistent with prior reports; most common (>=30%) grade 3/4 treatment-emergent adverse events were anemia (85%), thrombocytopenia (85%), febrile neutropenia (39%), leukopenia (31%), neutropenia (31%), and lymphopenia (31%).
Conclusion(s): Lifileucel showed an encouraging 38.5% ORR in pts with advanced melanoma refractory to prior anti-LAG3 + anti-PD-1 +/- anti-CTLA-4. Similar to prior observations in pts after anti-PD-1 therapy, both primary and acquired anti-LAG3-resistant pts responded to lifileucel, suggesting that lifileucel outcomes may not be affected by prior anti-LAG3 therapy. Clinical trial identification: NCT02360579. Editorial acknowledgement: Medical writing support was provided by Second City Science (Vaniam Group, LLC) and funded by Iovance Biotheraputics, Inc. Legal entity responsible for the study: Iovance Biotherapeutics, Inc.
Funding(s): Iovance Biotherapeutics, Inc. Disclosure: J. Larkin: Financial Interests, Personal, Other, Honoraria: Eisai, Novartis, Incyte, Merck, touchIME, touchEXPERTS, Pfizer, Royal College of Physicians, Cambridge Healthcare Research, RGCP, VJOncology, Agence Unik, BMS, Pierre Fabre, Ipsen, Roche, EUSA Pharma, Aptitude, AstraZeneca, GSK, Calithera, Ultimovacs, Seagen, eCancer, Inselgruppe, Goldman Sachs, MSD; Financial Interests, Personal, Advisory Role, Consulting: iOnctura, Apple Tree, Merck, BMS, Eisai, Debipharm, Incyte; Financial Interests, Institutional, Research Grant: Achilles, BMS, MSD, Nektar, Novartis, Pfizer, Roche, Immunocore, Aveo, Pharmacyclics. S. Dalle: Financial Interests, Institutional, Research Grant: BMS, MSD; Financial Interests, Personal, Other, Travel expenses: BMS; Financial Interests, Institutional, Advisory Board: MSD. M.F. Sanmamed: Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Personal, Advisory Role, Consulting: Numab, BMS; Financial Interests, Personal, Other, Honoraria: MSD; Financial Interests, Personal, Advisory Board: Numab. J.C. Hassel: Financial Interests, Institutional, Research Grant: Clinical Trial Agreement. H. Kluger: Financial Interests, Institutional, Research Grant: Apexigen, BMS, Merck; Non-Financial Interests, Personal, Other, Unpaid relationship: Celldex. M. Orloff: Financial Interests, Personal, Advisory Role, Consulting: Trisalus, Ideaya, Immunocore; Financial Interests, Personal, Advisory Board: Trisalus, Ideaya, Immunocore. J.S. Weber: Financial Interests, Personal, Funding, supports an IIT: BMS; Financial Interests, Personal, Stocks/Shares: Biond, Evaxion, Neximmune, Instil Bio, OncoC4; Financial Interests, Personal, Other, Honoraria: BMS, Merck, Pfizer, AstraZeneca, Regeneron, Incyte, Genentech, Iovance, OncoC4, Sellas, Biond, Instil Bio, Evaxion; Financial Interests, Personal, Advisory Role: BMS, Merck, Pfizer, AstraZeneca, Regeneron, Incyte, Genentech, Iovance, OncoC4, Sellas, Biond, Instil Bio, Evaxion; Financial Interests, Personal, Royalties, named on a CTLA4 biomarker and a TIL growth patent: Moffitt; Financial Interests, Personal, Royalties, named on a PD-1 biomarker patent: Biodesix; Financial Interests, Personal, Other, Travel: BMS. F. Graf Finckenstein: Financial Interests, Personal, Full or part-time Employment: Iovance Biotherapeutics, Inc.; Financial Interests, Personal, Stocks/Shares: Iovance Biotherapeutics, Inc. P. Hari: Financial Interests, Personal, Full or part-time Employment: Iovance Biotherapeutics, Inc.; Financial Interests, Personal, Stocks/Shares: Iovance Biotherapeutics, Inc. M. Jagasia: Financial Interests, Personal, Full or part-time Employment: Iovance Biotherapeutics, Inc.; Financial Interests, Personal, Stocks/Shares: Iovance Biotherapeutics, Inc. H. Yin: Financial Interests, Personal, Full or part-time Employment: Iovance Biotherapeutics, Inc.; Financial Interests, Personal, Stocks/Shares: Iovance Biotherapeutics, Inc. W. Shi: Financial Interests, Personal, Full or part-time Employment: Iovance Biotherapeutics, Inc.; Financial Interests, Personal, Stocks/Shares: Iovance Biotherapeutics, Inc. G. Sulur: Financial Interests, Personal, Full or part-time Employment: Iovance Biotherapeutics, Inc.; Financial Interests, Personal, Stocks/Shares: Iovance Biotherapeutics, Inc. X. Wu: Financial Interests, Personal, Full or part-time Employment: Iovance Biotherapeutics, Inc.; Financial Interests, Personal, Stocks/Shares: Iovance Biotherapeutics, Inc. V. Gontcharova: Financial Interests, Personal, Full or part-time Employment: Iovance Biotherapeutics, Inc.; Financial Interests, Personal, Stocks/Shares: Iovance Biotherapeutics, Inc. K. Lewis: Financial Interests, Personal, Advisory Role: Array BioPhar, Merck, Roche, Regeneron, Sanofi, Iovance Biotherapeutics, nektar, Merck; Financial Interests, Personal, Other, Travel: Roche/Genentech, Regeneron, Neon Therapeutics, alkermes; Financial Interests, Personal, Other, Honoraria: Array BioPharma, Iovance Biotherapeutics; Financial Interests, Institutional, Funding: Roche/Genentech, Merck, Array BioPharma, Incyte, Nektar, Iovance Biotherapeutics, Bristol Myers Squibb, Kartos Therapeutics, OncoSec, Regeneron, alkermes, Neon Therapeutics, Ultimovacs, Senhwa Biosciences, Replimune, Amgen, Seattle Genetics; Non-Financial Interests, Personal, Other, Uncompensated Relationships: Roche/Genentech, Regeneron. All other authors have declared no conflicts of interest.
Copyright

Background/Purpose: Treatment with a combination of immune checkpoint inhibitors (ICI) has promising outcomes in many tumor types but carries higher adverse event risk than ICI monotherapy. Also, patients with pre-existing autoimmune disease (AID) have largely been excluded from ICI clinical trials due to concern for pre-existing AID flare or immune-related adverse events (irAEs). This is the first study to analyze safety and effectiveness of ICI combination versus monotherapy for this at-risk population.
Method(s): We conducted a multi-center retrospective study in patients with pre-existing AIDs receiving ICIs (i.e., antiprogrammed cell death protein 1 (PD-1) single-agent (monotherapy) or ICI combination). Primary endpoints included the time to occurrence of any-type ICI AE (irAE or AID flare), time to irAEs and time to AID flares in the presence of the competing risk of death with progression free survival (PFS, time to progression or death) and overall survival (OS) as secondary endpoints. We used Fine-Gray models and Cox regression models to investigate the factors associated with these endpoints.
Result(s): 133 patients with pre-existing AID who received ICIs were identified: 69 (52%) monotherapy and 64 (48%) combination (Table 1). About half the patients had melanoma (44%) and 25% had lung cancer. Rheumatic (34%) or dermatologic (22%) pre-existing AIDs were the most common. Most patients (95%) had controlled autoimmune disease at ICI start. Six of 7 patients with active AID at baseline experienced some AE. Patients receiving baseline DMARD(s) were more likely to experience an AE (95%CI 1.079-2.996, p=0.024). The cumulative incidence of irAEs was higher for ICI combination compared to monotherapy (subdistribution hazard ratio (sHR) 2.28, 95%CI 1.36-3.84), adjusting for age at malignancy, but there was no significant difference between rate of high-grade toxicity for patients treated with ICI combination versus monotherapy (See Figure 1). On subgroup analysis for patients with melanoma or lung cancer, the cumulative incidence of irAEs or AID flares were not statistically different between treatment groups. PFS was longer (but not statistically significant) for combination therapy for any tumor type compared to single agent (median 12.3mo, 95%CI 5.0-23.2 versus 7.3mo, 95%CI 5.2-11.3, p=0.116). Similar trend was noted for PFS for melanoma (median 23.2mo combination vs. 14.0mo monotherapy, p=0.4237), while the opposite relation was noted for lung cancer subgroup (4.4mo combination vs. 7.1mo monotherapy, p=0.2933).
Conclusion(s): Efficacy of ICI combination versus monotherapy was not statistically significant and so still remains unclear in this patient population, but there was no significant difference in rates of high-grade toxicity between the two cohorts. Our data supports the notion that patients with pre-existing AIDs should not be indiscriminately precluded from getting ICI combination. Our results provide guidance for future prospective clinical trials studying combination therapy for subgroups of this at-risk population. No statistically significant difference appreciated in high grade adverse events between patients with pre-existing autoimmune disease treated with ICI combination versus monotherapy. Grading determined by the Common Terminology Criteria for Adverse Events rubric with grade 3 or higher considered "high grade."

PURPOSE/OBJECTIVE:Nivolumab was approved as adjuvant therapy for melanoma based on data from CheckMate 238, which enrolled patients per American Joint Committee on Cancer version 7 (AJCC-7) criteria. Here, we analyse long-term outcomes per AJCC-8 staging criteria compared with AJCC-7 results to inform clinical decisions for patients diagnosed per AJCC-8. PATIENTS AND METHODS/METHODS:In a double-blind, phase 3 trial (NCT02388906), patients aged ≥15 years with resected, histologically confirmed AJCC-7 stage IIIB, IIIC, or IV melanoma were randomised to receive nivolumab 3 mg/kg every 2 weeks or ipilimumab 10 mg/kg every 3 weeks for 4 doses and then every 12 weeks, both intravenously ≤1 year. Recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) were assessed in patients with stage III disease, per AJCC-7 and AJCC-8. RESULTS:Per AJCC-7 staging, 42.4% and 57.3% of patients were in substage IIIB and IIIC, respectively; per AJCC-8, 1.1%, 30.4%, 62.8%, and 5.0% were in IIIA, IIIB, IIIC, and IIID. After 4 years' minimum follow-up, the AJCC-7 superior efficacy of nivolumab over ipilimumab in patients with resected stage III melanoma was preserved per AJCC-8 analysis. No statistically significant difference in RFS between stage III substage hazard ratios was observed per AJCC-7 or -8 staging criteria (interaction test: AJCC-7, P = 0.8115; AJCC-8, P = 0.1051; P = 0.8392 ((AJCC-7) and P = 0.8678 (AJCC-8) for DMFS). CONCLUSIONS:CheckMate 238 4-year RFS and DMFS outcomes are consistent per AJCC-7 and AJCC-8 staging criteria. Outcome benefits can therefore be translated for patients diagnosed per AJCC-8.