A paradigm shift in the treatment of resectable stage III melanoma is expected, given the superior results of neoadjuvant (neoadj) immune checkpoint inhibition (ICI) in the SWOG S1801 trial and with the 1st phase III trial (NCT04949113) on its way. In this rapidly evolving field, long-term outcomes of neoadj ICI are scarce. Here we report the 4- and 6-yr survival update of the OpACIN and OpACIN-neo. In the randomized OpACIN trial, 20 patients (pts) with resectable stage III melanoma were treated with ipilimumab (IPI) 3mg/kg + nivolumab (NIVO) 1mg/kg; in the adjuvant (adj) arm 4 cycles after therapeutic lymph node dissection (TLND) and in the neoadj arm 2 cycles before and 2 after TLND. In the OpACIN-neo trial, 86 pts were randomized between neoadj IPI 3mg/kg + NIVO 1mg/kg (2x; arm A), IPI 1mg/kg + NIVO 3 mg/kg (2x; arm B) and IPI 3mg/kg (2x) > NIVO 3mg/kg (2x; arm C), followed by TLND without adj therapy. Event-free survival (EFS) was defined as time from randomization to progression, recurrence or death. Median follow-up (FU) for OpACIN was 84.0 mo. Estimated 6-yr EFS was 60% for both the adj and neoadj arm, while OS was 70% and 90% respectively. Only 1 recurrence has been observed after the 3-yr landmark. Median FU for OpACIN-neo was 60.7 mo. Estimated 4-yr EFS was 80% (see table for EFS/OS). After the 3-yr landmark, 1 new recurrence was observed and 1 non-melanoma related death. Major- and partial pathological responders (MPR/pPR) had 4-yr EFS rates of 96% and 92%, versus 33% in non-responders (pNR). Combining data from both trials, the median time to recurrence was 6.2 mo for the 16 pts that relapsed after pNR, while this was 37.7 mo for the 3 pts that relapsed after MPR/pPR.Table: 1096P6-year EFS (95% CI)6-year OS (95% CI)OpACIN – adjuvant60% (36-100)70% (47-100)OpACIN - neoadjuvant60% (36-100)90% (73-100)4-year EFS (95% CI)4-year OS (95% CI)OpACIN-neo80% (43-89)92% (86-98)Arm A87% (75-100)90% (80-100)Arm B77% (63-93)93% (85-100)Arm C77% (62-95)92% (83-100) Open table in a new tab Although the EFS rates are similar for the neoadj and adj arms after 6 yrs in the OpACIN trial, the favorable EFS and OS rates observed in the larger OpACIN-neo support the durability of response to neoadj IPI plus NIVO. The pathological response may serve as predictor for long-term outcome.

IMPemBra was the first trial testing intermittent, short-term, dabrafenib and trametinib (DT) plus pembrolizumab (PEM) in patients with stage IV melanoma, with the concept of inducing stronger immune infiltration in the tumor, translating in better long-term outcome. The adverse event (AE) rate of intermittent DT was lower than for continuous triple therapy. While addition of DT only slightly increased the best overall response from 75% to 88%, the 3-year progression free survival (PFS) and overall survival (OS) was higher for the DT+PEM cohorts as compared to PEM only (53% vs 25%, and 64% vs 33%, respectively), no statistically significant differences were found probably due to small patient cohorts. Here we present the updated 5-year PFS and OS data from patients enrolled in the IMPemBra trial. 32 treatment-naïve patients with stage IV melanoma harboring a BRAFV600E/K mutated melanoma were enrolled. All patients started with 2 cycles of PEM 200mg (Q3W), followed by randomization to either PEM monotherapy (cohort 1); PEM in combination with either dabrafenib (D) 150 mg BID + trametinib (T) 2mg QD intermittent for 2x1 week (cohort 2), 2x2 weeks (cohort 3) or continuously for 6 weeks (cohort 4). From week 12 and onwards, all cohorts continued PEM for a maximum of in total 2 years. With a median follow-up of 59.6 months, the estimated 5-year RFS and OS rates were 25% and 50% in cohort 1, 63% and 63% in cohort 2, 38% and 75% in cohort 3, and 60% and 75% in cohort 4, respectively, as shown in the table. We observed no differences in the quantity and type of subsequential therapies between the cohorts. No new safety signals were identified.Table: 1112P5-year clinical outcomes5-year PFS (95% CI)5-year OS (95% CI)All patients (n=32)46% (32.5-67.3)66% (51.1-84.3)Cohort 1 (n=8)25% (7.5-83.0)50% (25.0-100)Cohort 2 (n=8)63% (36.5-100.0)63% (36.5-100)Cohort 3 (n=8)38% (15.3-91.7)75% (50.3-100)Cohort 4 (n=8)60% (33.1-100)75% (50.3-100)Subsequential therapiesSubsequential treatmentAnti-PD1Anti-CTLA-4Anti-CTLA-4 + anti-PD1Targeted therapySurgeryOtherAll patients18 (56%)6 (33%)2 (11%)7 (39%)14 (78%)2 (11%)1 (6%)Cohort 16 (75%)1 (13%)1 (13%)3 (38%)5 (63%)1 (13%)Cohort 23 (38%)2 (25%)3 (38%)Cohort 35 (63%)3 (38%)3 (38%)1 (13%)Cohort 44 (50%)2 (25%)1 (13%)2 (25%)3 (38%)1 (13%) Open table in a new tab This update from the IMPemBra trial confirms the previous findings indicating that the addition of short-term DT to PEM can induce long-lasting responses upon PEM that appears to be superior compared to PEM monotherapy. This improved PFS translated also into a promising increase in 5-year OS compared to PEM in first line therapy.

Pathologic (path) response (resp) is an excellent surrogate marker for long-term recurrence-free survival after neoadjuvant (neoadj) IPI + NIVO in stage III melanoma. Few resp pts develop recurrence of disease, and their clinical characteristics and mechanisms of tumor immune escape are unknown. In the OpACIN, OpACIN-neo and PRADO trials, pts with recurrence after path resp were identified. All pts received 2x IPI + NIVO neoadj (different dosing regimens) and surgery at week 6. Path resp was classified as major path response (MPR; ≤10% vital tumor) or path partial response (pPR; >10-≤50% vital tumor). Multiplex immunofluorescence staining (CD3, CD8, CD20, CD68, FoxP3, Sox10, DAPI) of paired baseline and recurrent samples was performed. Tumor and stroma regions were classified and % staining-positive cells determined using HALO imaging software. In the three trials, 142 pts obtained path resp, of whom 11 (8%) had a recurrence (n=6/118 [5%] of MPR pts and n=5/24 [21%] of pPR pts). Clinical characteristics were comparable for pts with and without recurrence, except for more frequent BRAF-mutations (73% vs 35%, p=0.044) and less frequent MPR (55% vs 85%, p=0.009) in pts with recurrence. Five pts had a regional recurrence (45%) and 6 pts distant metastases (55%), median 6.7mo and 13.1mo post surgery, respectively. Matched baseline and recurrence multiplex data were available for 6 pts (3 pts had regional and 3 pts distant recurrence): 4 MPR and 2 pPR pts. The percentage of CD3+, CD8+, FoxP3+ and CD68+ cells was increased at recurrence in both pPR patients, while in 3/4 MPR pts tumor immune infiltration was decreased at recurrence. Additional spatial analyses defining the nearest neighbor cell will be presented at ESMO. Obtaining MPR is a surrogate marker for having an excellent clinical outcome. BRAF-mutation and response depth seem associated with recurrence after resp to neoadj IPI + NIVO in stage III melanoma. Regional recurrences were diagnosed earlier than distant metastases. Multiplex staining shows a trend of in- or decrease of immune cell populations according to initial depth of response, although the data presented is based on small numbers.

BACKGROUND:Guidelines for pathological evaluation of neoadjuvant specimens and pathological response categories have been developed by the International Neoadjuvant Melanoma Consortium (INMC). As part of the Optimal Neo-adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo) clinical trial of neoadjuvant combination anti-programmed cell death protein 1/anti-cytotoxic T-lymphocyte-associated protein 4 immunotherapy for stage III melanoma, we sought to determine interobserver reproducibility of INMC histopathological assessment principles, identify specific tumour bed histopathological features of immunotherapeutic response that correlated with recurrence and relapse-free survival (RFS) and evaluate proposed INMC pathological response categories for predicting recurrence and RFS.PATIENTS AND METHODS:Clinicopathological characteristics of lymph node dissection specimens of 83 patients enrolled in the OpACIN-neo clinical trial were evaluated. Two methods of assessing histological features of immunotherapeutic response were evaluated: the previously described immune-related pathologic response (irPR) score and our novel immunotherapeutic response score (ITRS). For a subset of cases (n = 29), cellular composition of the tumour bed was analysed by flow cytometry.RESULTS:There was strong interobserver reproducibility in assessment of pathological response (κ = 0.879) and percentage residual viable melanoma (intraclass correlation coefficient = 0.965). The immunotherapeutic response subtype with high fibrosis had the strongest association with lack of recurrence (P = 0.008) and prolonged RFS (P = 0.019). Amongst patients with criteria for pathological non-response (pNR, >50% viable tumour), all who recurred had ≥70% viable melanoma. Higher ITRS and irPR scores correlated with lack of recurrence in the entire cohort (P = 0.002 and P ≤ 0.0001). The number of B lymphocytes was significantly increased in patients with a high fibrosis subtype of treatment response (P = 0.046).CONCLUSIONS:There is strong reproducibility for assessment of pathological response using INMC criteria. Immunotherapeutic response of fibrosis subtype correlated with improved RFS, and may represent a biomarker. Potential B-cell contribution to fibrosis development warrants further study. Reclassification of pNR to a threshold of ≥70% viable melanoma and incorporating additional criteria of <10% fibrosis subtype of response may identify those at highest risk of recurrence, but requires validation.

Neoadjuvant ipilimumab plus nivolumab showed high pathologic response rates (pRRs) in patients with macroscopic stage III melanoma in the phase 1b OpACIN ( NCT02437279 ) and phase 2 OpACIN-neo ( NCT02977052 ) studies1,2. While the results are promising, data on the durability of these pathologic responses and baseline biomarkers for response and survival were lacking. After a median follow-up of 4 years, none of the patients with a pathologic response (n = 7/9 patients) in the OpACIN study had relapsed. In OpACIN-neo (n = 86), the 2-year estimated relapse-free survival was 84% for all patients, 97% for patients achieving a pathologic response and 36% for nonresponders (P < 0.001). High tumor mutational burden (TMB) and high interferon-gamma-related gene expression signature score (IFN-γ score) were associated with pathologic response and low risk of relapse; pRR was 100% in patients with high IFN-γ score/high TMB; patients with high IFN-γ score/low TMB or low IFN-γ score/high TMB had pRRs of 91% and 88%; while patients with low IFN-γ score/low TMB had a pRR of only 39%. These data demonstrate long-term benefit in patients with a pathologic response and show the predictive potential of TMB and IFN-γ score. Our findings provide a strong rationale for a randomized phase 3 study comparing neoadjuvant ipilimumab plus nivolumab versus standard adjuvant therapy with antibodies against the programmed cell death protein-1 (anti-PD-1) in macroscopic stage III melanoma. Long-term outcomes and biomarker analyses of two neoadjuvant immunotherapy clinical trials in melanoma patients support the clinical benefit of this treatment approach and uncover prognostic correlates of response.

Background Before adjuvant checkpoint inhibition the 5-year overall survival (OS) rate was poor (<50%) in high-risk stage III melanoma patients. Adjuvant CTLA-4 (ipilimumab, IPI) and PD-1 (nivolumab, NIVO, or pembrolizumab) blockade have been shown to improve relapse-free survival (RFS) and OS (latter only for IPI so far). Due to a broader immune activation neoadjuvant therapy with checkpoint inhibitors might be more effective than adjuvant, as suggested in preclinical experiments. The OpACIN trial compared neoadjuvant versus adjuvant IPI plus NIVO, while the subsequent OpACIN-neo trial tested three different dosing schedules of neoadjuvant IPI plus NIVO without adjuvant therapy. High pathologic response rates of 74–78% were induced by neoadjuvant IPI plus NIVO. Here, we present the 36- and 24-months RFS of the OpACIN and OpACIN-neo trial, respectively. Materials and Methods The phase 1b OpACIN trial included 20 stage IIIB/IIIC melanoma patients, which were randomized to receive IPI 3 mg/kg plus NIVO 1 mg/kg either adjuvant 4 cycles or split 2 cycles neoadjuvant and 2 adjuvant. In the phase 2 OpACIN-neo trial, 86 patients were randomized to 2 cycles neoadjuvant treatment, either in arm A: 2x IPI 3 mg/kg plus NIVO 1 mg/kg q3w (n=30), arm B: 2x IPI 1 mg/kg plus NIVO 3 mg/kg q3w (n=30), or arm C: 2x IPI 3 mg/kg q3w followed immediately by 2x NIVO 3 mg/kg q3w (n=26). Pathologic response was defined as <50% viable tumor cells and in both trials centrally reviewed by a blinded pathologist. RFS rates were estimated using the Kaplan-Meier method. Results Only 1 of 71 (1.4%) patients with a pathologic response on neoadjuvant therapy had relapsed, versus 16 of 23 patients (69.6%) without a pathologic response, after a median follow-up of 36 months for the OpACIN and 24 months for the OpACIN-neo trial. In the OpACIN trial, the estimated 3-year RFS rate for the neoadjuvant arm was 80% (95% CI: 59%-100%) versus 60% (95% CI: 36%-100%) for the adjuvant arm. Median RFS was not reached for any of the arms within the OpACIN-neo trial. Estimated 24-months RFS rate was 84% for all patients (95% CI: 76%-92%); 90% for arm A (95% CI: 80%-100%), 78% for arm B (95% CI: 63%-96%) and 83% for arm C (95% CI: 70%-100%). Baseline interferon-γ gene expression score and tumor mutational burden predict response. Conclusions OpACIN for the first time showed a potential benefit of neoadjuvant IPI plus NIVO versus adjuvant immunotherapy, whereas the OpACIN-neo trial confirmed the high pathologic response rates that can be achieved by neoadjuvant IPI plus NIVO. Both trials show that pathologic response can function as a surrogate markers for RFS. Clinical trial information NCT02437279, NCT02977052 Disclosure Information J.M. Versluis: None. E.A. Rozeman: None. A.M. Menzies: F. Consultant/Advisory Board; Modest; BMS, MSD, Novartis, Roche, Pierre-Fabre. I.L.M. Reijers: None. O. Krijgsman: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; BMS. E.P. Hoefsmit: None. B.A. van de Wiel: None. K. Sikorska: None. C. Bierman: None. P. Dimitriadis: None. M. Gonzalez: None. A. Broeks: None. R.M. Kerkhoven: None. A.J. Spillane: None. J.B.A.G. Haanen: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; BMS, MSD, Neon Therapeutics, Novartis. F. Consultant/Advisory Board; Modest; BMS, MSD, Novartis, Pfizer, AZ/MedImmune, Rocher/Genentech, Ipsen, Bayer, Immunocore, SeattleGenetics, Neon Therapeutics, Celsius Therapeutics, Gadet, GSK. W.J. van Houdt: None. R.P.M. Saw: None. H. Eriksson: None. A.C.J. van Akkooi: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; Amgen, BMS, Novartis. F. Consultant/Advisory Board; Modest; Amgen, BMS, Novartis, MSD Merck, Merck-Pfizer, 4SC. R.A. Scolyer: F. Consultant/Advisory Board; Modest; MSD, Neracare, Myriad, Novartis. T.N. Schumacher: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; MSD, BMS, Merck. E. Ownership Interest (stock, stock options, patent or other intellectual property); Modest; AIMM Therapeutics, Allogene Therapeutics, Amgen, Merus, Neogene Therapeutics, Neon Therapeutics. F. Consultant/Advisory Board; Modest; Adaptive Biotechnologies, AIMM Therapeutics, Allogene Therapeutics, Amgen, Merus, Neon Therapeutics, Scenic Biotech. Other; Modest; Third Rock Ventures. G.V. Long: F. Consultant/Advisory Board; Modest; Aduro, Amgen, BMS, Mass-Array, Pierre-Fabre, Novartis, Merck MSD, Roche. C.U. Blank: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; BMS, Novartis, NanoString. E. Ownership Interest (stock, stock options, patent or other intellectual property); Modest; Uniti Cars, Neon Therapeutics, Forty Seven. F. Consultant/Advisory Board; Modest; BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre-Fabre.

10064 Background: Neoadjuvant ipilimumab and nivolumab induces high pathologic response rates of 74-78% (OpACIN and OpACIN-neo trial), thus the role of Therapeutic Lymph Node Dissections (TLND) in patients with major pathologic responses (MPR: pathological (near) complete response) is now unclear. In the PRADO trial, TLND was omitted in patients with MPR in their index lymph node ((ILN), the largest LN marked prior to neoadjuvant therapy). We sought to determine if less extensive surgery is associated with better Health Related Quality of Life (HRQoL). These are the first results of the comparison of HRQoL between patients undergoing a TLND or less extensive ILN excision. Methods: HRQoL was assessed with the European Organisation for Research and Treatment of Cancer QoL questionnaire-C30 (QLQ-C30). A generalized estimation equation was used to assess the difference in HRQoL outcomes between patients who underwent TLND (pathological non- and partial-responders, pNR/pPR) versus those who did not (pathological (near)complete responders, pNCR/pCR). Differences were adjusted for age, gender and follow-up (FU, in weeks), but not for pathological responses (pNR, pPR, pNCR & pCR). Differences in QLQ-C30 scores were classified as clinically important according to published guidelines. Results: A total of 49 patients from the PRADO study had reached at least 24 weeks FU, and were included in the first explorative analysis. The median age of this study population was 58 years (range, 22-84). Questionnaire completion rates were high: 94% at baseline, 100%, 90%, 88% at week 6, 12 and 24, respectively. Sixteen (33%) patients underwent TLND versus 33 (67%) who had ILN excision only. Over a FU period of 24 weeks, patients who underwent TLND scored significantly lower on global (68 vs 78, adjusted difference (diff) = -9.53, p = .005), physical (84 vs 94 diff = -11.1, p = < .001), emotional (69 vs 83, diff = -11.7, p = .001), role (70 vs 85, diff = -13, p = .004), and social functioning (81 vs 91, diff = -8.9, p = .016) and had a higher symptom burden of fatigue (35 vs 23, diff = 11.1, p = .004), insomnia (38 vs 18, diff = 16.6, p = .002) and financial impact (12 vs 4, diff = 7.9, p = .027) than patients undergoing ILN excision only. These differences were indicated as clinically relevant. Conclusions: First results from PRADO suggest that reducing the extent of surgery following neoadjuvant immunotherapy might result in better HRQoL of high-risk stage III melanoma patients. Clinical trial information: NCT02977052.

Neoadjuvant (neoadj) IPI + NIVO showed in different trials in almost 200 patients (pts) a pathologic response rate of 71-78%. The investigator-initiated OpACIN trial was the first trial testing neoadj IPI + NIVO and therefore has the longest follow-up (FU). Pathologic responses were observed in 7/9 pts (78%) in the neoadj arm, 1 pt was non-evaluable. The question remains how durable these responses are. Here we present the 4-year safety and survival data from this trial. Twenty macroscopic stage IIIB-C melanoma pts were included in the phase 1b feasibility OpACIN trial between Augustus 2015 and October 2016. Pts were randomized to receive either IPI 3 mg/kg + NIVO 1 mg/kg 4 cycles adjuvant (adj) after lymph node dissection or split 2 cycles neoadj and 2 adj. The 4-year RFS and OS rates were estimated using the Kaplan Meier method. All comparative efficacy endpoints are descriptive since the trial was not powered for comparison of the arms. None of the 7 pts with a pathologic response in the neoadj arm have relapsed after a median FU of 48.0 months (minimum 38.1 months FU of pts alive). Within the neoadj arm only the two non-responding pts and the one non-evaluable pt have relapsed, 4 pts have relapsed in the adj arm. Estimated 4-year RFS rate was 60% for the neoadj arm and 60% for the adj arm, the 4-year OS rates were 90% and 70%, respectively. All grade 3-4 immune-related adverse events, initially for both arms reported in 90% of pts, have recovered to grade 1 or less, except for the grade 2 endocrinopathies requiring hormonal replacement therapy that are ongoing within 8 (50%) of the 16 pts alive. The 4-year survival data of OpACIN indicate that pathologic response upon neoadj IPI + NIVO in macroscopic stage III melanoma is an excellent surrogate marker for long-term outcome (RFS and OS), as none of the responders has relapsed. In combination with data from other neoadj trials, these data suggest that pathologic response could be a valuable outcome parameter in neoadj immune checkpoint inhibitor trials.

Background Continuous combination of MAPK pathway inhibition (MAPKi) and anti-programmed death-(ligand) 1 (PD-(L)1) showed high response rates, but only limited improvement in progression-free survival (PFS) at the cost of a high frequency of treatment-related adverse events (TRAE) in patients with BRAF V600 -mutated melanoma. Short‐term MAPKi induces T-cell infiltration in patients and is synergistic with anti-programmed death-1 (PD‐1) in a preclinical melanoma mouse model. The aim of this phase 2b trial was to identify an optimal regimen of short-term MAPKi with dabrafenib plus trametinib in combination with pembrolizumab. Methods Patients with treatment-naïve BRAF V600E/K -mutant advanced melanoma started pembrolizumab 200 mg every 3 weeks. In week 6, patients were randomized to continue pembrolizumab only (cohort 1), or to receive, in addition, intermittent dabrafenib 150 mg two times per day plus trametinib 2 mg one time per day for two cycles of 1 week (cohort 2), two cycles of 2 weeks (cohort 3), or continuously for 6 weeks (cohort 4). All cohorts continued pembrolizumab for up to 2 years. Primary endpoints were safety and treatment-adherence. Secondary endpoints were objective response rate (ORR) at week 6, 12, 18 and PFS. Results Between June 2016 and August 2018, 33 patients with advanced melanoma have been included and 32 were randomized. Grade 3–4 TRAE were observed in 12%, 12%, 50%, and 63% of patients in cohort 1, 2, 3, and 4, respectively. All planned targeted therapy was given in 88%, 63%, and 38% of patients in cohort 2, 3, and 4. ORR at week 6, 12, and 18 were 38%, 63%, and 63% in cohort 1; 25%, 63%, and 75% in cohort 2; 25%, 50%, and 75% in cohort 3; and 0%, 63%, and 50% in cohort 4. After a median follow-up of 43.5 months, median PFS was 10.6 months for pembrolizumab monotherapy and not reached for patients treated with pembrolizumab and intermittent dabrafenib and trametinib (p=0.17). The 2-year and 3-year landmark PFS were both 25% for cohort 1, both 63% for cohort 2, 50% and 38% for cohort 3 and 75% and 60% for cohort 4. Conclusions The combination of pembrolizumab plus intermittent dabrafenib and trametinib seems more feasible and tolerable than continuous triple therapy. The efficacy is promising and appears to be favorable over pembrolizumab monotherapy. Trial registration number NCT02625337 .

Background Outcome of high-risk stage III melanoma patients (pts) was poor with a 5-year OS rate of < 50%. Adjuvant (adj) IPI improved 5-year RFS and OS and adjuvant anti-PD-1 improved RFS further. Preclinical data suggested that neoadjuvant (neoadj) treatment might be more favorable due to broader immune activation. The investigator-initiated OpACIN trial compared neoadj with adj IPI + NIVO. Neoadj IPI + NIVO induced a pathologic (path) response in a high percentage of pts (7/9 evaluable pts, 78%). None of the reponders relapsed during the first 2 years, but long-term outcome is pending. Here we present the 3-year landmark safety and survival data. Methods Between Augustus 2015 and October 2016, 20 stage IIIB/IIIC melanoma pts with palpable nodal disease were included in the phase Ib feasibility OpACIN trial. Pts were randomized to receive IPI 3 mg/kg …

Background Outcome of high-risk stage III melanoma patients (pts) was poor with a 5-year OS rate of Methods Between Augustus 2015 and October 2016, 20 stage IIIB/IIIC melanoma pts with palpable nodal disease were included in the phase Ib feasibility OpACIN trial. Pts were randomized to receive IPI 3 mg/kg + NIVO 1 mg/kg, either adj 4 courses or split 2 courses neoadj and 2 adj. Path response, as reviewed by a blinded pathologist, was defined as Results After a median FU of 36.7 months (minimum 28.3 months FU of pts alive) none of the 7 pts with a path response in the neoadj arm have relapsed. Both non-responding pts in the neoadj have relapsed versus 4 pts in the adj arm. One pt has died in the neoadj arm and 3 in the adj arm. The estimated 3-year RFS rate was 80% for the neoadj arm and 60% for the adj arm. The 3-year OS rates were 90% and 67%, respectively. Of the 18 (90%) pts that had developed 1 or more grade 3-4 adverse events all have recovered to ≤ grade 1, except for grade 2 endocrine toxicities needing hormonal supplementation therapy that are ongoing in 8 (50%) of 16 pts alive. Conclusions OpACIN was the first trial investigating neoadj IPI + NIVO in pts with macroscopic stage III melanoma, thus having the longest FU. At 3 years FU, no new safety events occurred and none of the pts with a path response have relapsed, suggesting that path response could be considered as surrogate marker for RFS and OS in neoadjuvant checkpoint inhibitor trials. Clinical trial identification NCT02437279. Legal entity responsible for the study Netherlands Cancer Institute. Funding BMS. Disclosure C.U. Blank: Advisory / Consultancy: MSD; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: Roche; Advisory / Consultancy: GSK; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: GenMab; Advisory / Consultancy: Lilly; Research grant / Funding (institution): NanoString; Advisory / Consultancy: Pierre Fabre. J.V. van Thienen: Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis. J.B.A.G. Haanen: Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Pfizer; Advisory / Consultancy: AZ/MedImmune; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Bayer; Advisory / Consultancy: Immunocore; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy, Research grant / Funding (institution): Neon Therapeutics; Advisory / Consultancy: Celsius Therapautics; Advisory / Consultancy: Gadet; Advisory / Consultancy: GSK. A.C.J. van Akkooi: Advisory / Consultancy, Research grant / Funding (institution): Amgen; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: MSD Merck; Advisory / Consultancy: Merck-Pfizer; Advisory / Consultancy: 4SC. T.N. Schumacher: Advisory / Consultancy: Adaptive Biotechnologies; Advisory / Consultancy, Shareholder / Stockholder / Stock options: AIMM Therapeutics; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Allogene Therapeutics; Advisory / Consultancy: Amgen; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Merus; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Neon Therapeutics; Advisory / Consultancy: Scenic Biotech; Research grant / Funding (institution): MSD; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Merck KGaA; Shareholder / Stockholder / Stock options: Neogene Therapeutics; Shareholder / Stockholder / Stock options, Venture partner: Third Rock Venture. E.A. Rozeman: Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: NanoString. All other authors have declared no conflicts of interest.

Background: Cutaneous squamous cell carcinoma (CSCC) harbors a high tumor mutation burden (TMB) due to ultraviolet light-mediated DNA damage, and are highly immune-responsive.Cemiplimab, a monoclonal antibody directed against programmed death 1 (PD-1), is approved by the FDA and EMA as treatment for advanced CSCC patients who are not candidates for curative surgery.Here we explore the efficacy of neoadjuvant cemiplimab in CSCC-head and neck (HN) patients for whom surgery and radiation was planned.Methods: Patients with stage III/IV (M0) (AJCC 8 th Ed) CSCC-HN were treated with 2 doses of cemiplimab 350 mg intravenously every 3 weeks prior to surgery.The primary endpoint was overall response rate (ORR) per RECIST v1.1.Secondary endpoints included pathologic response rate, safety and tolerability, and analysis of candidate biomarkers from pre-and post-treatment blood and tumor specimens.Results: Twenty patients (18M, 2F) enrolled with median age 69 years (range: 42-88) and stage III (n ¼ 8) or IV (n ¼ 12) disease.Seven (35%) patients experienced grade 1 or 2 adverse events (AEs); 6 (30%) grade 1 rash/pruritis, 1 (5%) grade 2 myalgia, and 1 (5%) grade 2 fatigue.There were no grade 3 AEs and no surgical delays.ORR by RECIST was 30% (6 partial response, 12 stable disease, 2 progressive disease).Pathologic complete response (pCR) was observed in 11 (55%) patients and major pathology response (MPR, 10% viable tumor) in an additional 3 (15%) patients.TMB and PD-L1 expression analyses in pre-treatment samples are in process.Eleven (55%) patients did not receive planned radiotherapy after surgery based on the pathologic responses.No recurrences have been observed with a median follow up of 3.8 months (range: 1.5-11.2).Conclusions: Neoadjuvant cemiplimab was well-tolerated and induced a pCR or MPR in 70% of stage III/IV (M0) CSCC patients.A multicenter phase II study is planned to confirm these results and to describe the ability of neoadjuvant cemiplimab to allow less extensive treatment.Clinical trial identification: NCT03565783.

BACKGROUND:The outcome of patients with macroscopic stage III melanoma is poor. Neoadjuvant treatment with ipilimumab plus nivolumab at the standard dosing schedule induced pathological responses in a high proportion of patients in two small independent early-phase trials, and no patients with a pathological response have relapsed after a median follow up of 32 months. However, toxicity of the standard ipilimumab plus nivolumab dosing schedule was high, preventing its broader clinical use. The aim of the OpACIN-neo trial was to identify a dosing schedule of ipilimumab plus nivolumab that is less toxic but equally effective.METHODS:OpACIN-neo is a multicentre, open-label, phase 2, randomised, controlled trial. Eligible patients were aged at least 18 years, had a WHO performance status of 0-1, had resectable stage III melanoma involving lymph nodes only, and measurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1. Patients were enrolled from three medical centres in Australia, Sweden, and the Netherlands, and were randomly assigned (1:1:1), stratified by site, to one of three neoadjuvant dosing schedules: group A, two cycles of ipilimumab 3 mg/kg plus nivolumab 1 mg/kg once every 3 weeks intravenously; group B, two cycles of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg once every 3 weeks intravenously; or group C, two cycles of ipilimumab 3 mg/kg once every 3 weeks directly followed by two cycles of nivolumab 3 mg/kg once every 2 weeks intravenously. The investigators, site staff, and patients were aware of the treatment assignment during the study participation. Pathologists were masked to treatment allocation and all other data. The primary endpoints were the proportion of patients with grade 3-4 immune-related toxicity within the first 12 weeks and the proportion of patients achieving a radiological objective response and pathological response at 6 weeks. Analyses were done in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02977052, and is ongoing with an additional extension cohort and to complete survival analysis.FINDINGS:Between Nov 24, 2016 and June 28, 2018, 105 patients were screened for eligibility, of whom 89 (85%) eligible patients were enrolled and randomly assigned to one of the three groups. Three patients were excluded after randomisation because they were found to be ineligible, and 86 received at least one dose of study drug; 30 patients in group A, 30 in group B, and 26 in group C (accrual to this group was closed early upon advice of the Data Safety Monitoring Board on June 4, 2018 because of severe adverse events). Within the first 12 weeks, grade 3-4 immune-related adverse events were observed in 12 (40%) of 30 patients in group A, six (20%) of 30 in group B, and 13 (50%) of 26 in group C. The difference in grade 3-4 toxicity between group B and A was -20% (95% CI -46 to 6; p=0·158) and between group C and group A was 10% (-20 to 40; p=0·591). The most common grade 3-4 adverse events were elevated liver enzymes in group A (six [20%)]) and colitis in group C (five [19%]); in group B, none of the grade 3-4 adverse events were seen in more than one patient. One patient (in group A) died 9·5 months after the start of treatment due to the consequences of late-onset immune-related encephalitis, which was possibly treatment-related. 19 (63% [95% CI 44-80]) of 30 patients in group A, 17 (57% [37-75]) of 30 in group B, and nine (35% [17-56]) of 26 in group C achieved a radiological objective response, while pathological responses occurred in 24 (80% [61-92]) patients in group A, 23 (77% [58-90]) in group B, and 17 (65% [44-83]) in group C.INTERPRETATION:OpACIN-neo identified a tolerable neoadjuvant dosing schedule (group B: two cycles of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg) that induces a pathological response in a high proportion of patients and might be suitable for broader clinical use. When more mature data confirm these early observations, this schedule should be tested in randomised phase 3 studies versus adjuvant therapies, which are the current standard-of-care systemic therapy for patients with stage III melanoma.FUNDING:Bristol-Myers Squibb.

This pilot study explored the value of localized index node removal after neoadjuvant immunotherapy in patients with stage III melanoma, for use as a response indicator to guide the extent of completion lymph node dissection. Promising technology.

Background Programmed cell death protein 1 (PD-1) blocking monoclonal antibodies improve the overall survival of patients with advanced melanoma but the optimal duration of treatment has not been established. Patients and Methods This academic real-world cohort study investigated the outcome of 185 advanced melanoma patients who electively discontinued anti-PD-1 therapy with pembrolizumab (N=167) or nivolumab (N=18) in the absence of disease progression (PD) or treatment limiting toxicity (TLT) at 14 medical centres across Europe and Australia. Results Median time on treatment was 12months (range 0.7-43). The best objective tumour response at the time of treatment discontinuation was complete response (CR) in 117 (63%) patients, partial response (PR) in 44 (24%) patients and stable disease (SD) in 16 (9%) patients; 8 (4%) patients had no evaluable disease (NE). After a median follow-up of 18months (range 0.7-48) after treatment discontinuation, 78% of patients remained free of progression. Median time to progression was 12months (range 2-23). PD was less frequent in patients with CR (14%) compared with patients with PR (32%) and SD (50%). Six out of 19 (32%) patients who were retreated with an anti-PD-1 at the time of PD obtained a new antitumour response. Conclusions In this real-world cohort of advanced melanoma patients discontinuing anti-PD-1 therapy in the absence of TLT or PD, the duration of anti-PD-1 therapy was shorter when compared with clinical trials. In patients obtaining a CR, and being treated for >6months, the risk of relapse after treatment discontinuation was low. Patients achieving a PR or SD as best tumour response were at higher risk for progression after discontinuing therapy, and defining optimal treatment duration in such patients deserves further study. Retreatment with an anti-PD-1 at the time of progression may lead to renewed antitumour activity in some patients. Clinical trial registration NCT02673970 (https://clinicaltrials.gov/ct2/show/NCT02673970?cond=melanoma&cntry=BE&city=Jette&rank=3)

IntroductionImmunotherapy is regarded as one of the major breakthroughs in cancer treatment. Despite its success, only a subset of patients responds—urging the quest for predictive biomarkers. We hypothesize that artificial intelligence (AI) algorithms can automatically quantify radiographic characteristics that are related to and may therefore act as noninvasive radiomic biomarkers for immunotherapy response.Patients and methodsIn this study, we analyzed 1055 primary and metastatic lesions from 203 patients with advanced melanoma and non-small-cell lung cancer (NSCLC) undergoing anti-PD1 therapy. We carried out an AI-based characterization of each lesion on the pretreatment contrast-enhanced CT imaging data to develop and validate a noninvasive machine learning biomarker capable of distinguishing between immunotherapy responding and nonresponding. To define the biological basis of the radiographic biomarker, we carried out gene set enrichment analysis in an independent dataset of 262 NSCLC patients.ResultsThe biomarker reached significant performance on NSCLC lesions (up to 0.83 AUC, P < 0.001) and borderline significant for melanoma lymph nodes (0.64 AUC, P = 0.05). Combining these lesion-wide predictions on a patient level, immunotherapy response could be predicted with an AUC of up to 0.76 for both cancer types (P< 0.001), resulting in a 1-year survival difference of 24% (P = 0.02). We found highly significant associations with pathways involved in mitosis, indicating a relationship between increased proliferative potential and preferential response to immunotherapy.ConclusionsThese results indicate that radiographic characteristics of lesions on standard-of-care imaging may function as noninvasive biomarkers for response to immunotherapy, and may show utility for improved patient stratification in both neoadjuvant and palliative settings.

Background: Checkpoint inhibitors have changed overall survival for patients with advanced melanoma. However, there is a lack of data on health-related quality of life (HRQoL) of long-term advanced melanoma survivors, years after treatment. Therefore, we evaluated HRQoL in long-term advanced melanoma survivors and compared the study outcomes with matched controls without cancer. Material and methods: Ipilimumab-treated advanced melanoma survivors without evidence of disease and without subsequent systemic therapy for a minimum of two years following last administration of ipilimumab were eligible for this study. The European Organization for Research and Treatment of Cancer quality of life questionnaire Core 30 (EORTC QLQ-C30), the Multidimensional Fatigue Inventory (MFI), the Hospital Anxiety and Depression Scale (HADS), and the Functional Assessment of Cancer Therapy-Melanoma questionnaire (FACT-M) were administered. Controls were individually matched for age, gender, and educational status. Outcomes of survivors and controls were compared using generalized estimating equations, and differences were interpreted as clinically relevant according to published guidelines. Results: A total of 89 survivors and 265 controls were analyzed in this study. After a median follow-up of 39 (range, 17-121) months, survivors scored significantly lower on physical (83.7vs. 89.8, difference (diff) = -5.80,p=.005), role (83.5vs.90, diff = -5.97,p=.02), cognitive (83.7vs.91.9, diff = -8.05,p=.001), and social functioning (86.5vs.95.1, diff = -8.49,p= <.001) and had a higher symptom burden of fatigue (23.0vs.15.5, diff = 7.48,p=.004), dyspnea (13.3vs.6.7, diff = 6.47p=.02), diarrhea (7.9vs.4.0, diff = 3.78,p=.04), and financial impact (10.5vs.2.5, diff = 8.07,p=.001) than matched controls. Group differences were indicated as clinically relevant. Discussion: Compared to matched controls, long-term advanced melanoma survivors had overall worse functioning scores, more physical symptoms, and financial difficulties. These data may contribute to the development of appropriate survivorship care.

Background In the multi-center investigator-initiated OpACIN-neo trial, patients (pts) with macroscopic stage III melanoma were randomized (stratified by center) to 3 different dosing schemes of neoadjuvant (neoadj) IPI+NIVO. Two cycles IPI 1mg/kg + NIVO3mg/kg was identified as the most favorable regimen with 20% grade 3-4 adverse events and a pathological response rate (pRR) of 77%. After a median follow-up (FU) of 8.3 months (mo) none (0/86) of the pts with a pathologic (path) response had relapsed, while 9/21 (43%) without a path response relapsed. Post-hoc analyses were conducted to investigate potential differences between pts treated in Europe (EU) and in Australia (AUS). Methods Baseline patient characteristics, safety and efficacy in terms of path response were evaluated in pts treated in EU (n=48) and AUS (n=38). Multivariate analyses were performed using logistic regression method. Median FU was 9.3mo for EU pts and 6.9mo for AUS pts. Results Baseline characteristics (AUS vs EU) differed in age (median 60 vs 53 year [yr], p=0.017) and AUS pts were more likely to be male (65.8 vs 50.0%, p=0.142) and have an unknown primary melanoma (36.8 vs 20.8%, p=0.100); no difference in PD-L1 expression was observed. There was a trend to a higher pRR for AUS pts than for EU pts (84.2% vs 68.1%, OR 2.50, p=0.092). pRR was also higher for pts >60yr compared to £60yr (91.2% vs 64.7%, OR 5.64, p=0.010) and males vs females (83.7% vs 63.9%, OR 2.90, p=0.041). Multivariate analysis including continent, age and gender showed an adjusted OR for path response of 1.85 (p=0.289) for AUS vs EU pts, an OR of 4.89 (p=0.021) for pts >60yrs vs £60yrs and an OR of 2.50 (p=0.095) for males vs females. The frequency of high grade toxicity was the same in pts 60yr (42.3% vs 32.4%, p=0.353). Conclusions The continental difference in path response appears mostly driven by differences in age and gender. It remains to be elucidated whether the higher pRRs in elderly pts and pts from AUS can be explained by differences in mutational burden (analysis in progress and will be presented). Our data also indicate that neoadj IPI+NIVO is safe and highly effective in the elderly. Clinical trial identification NCT02977052. Legal entity responsible for the study Netherlands Cancer Institute. Funding BMS. Disclosure E.A. Rozeman: Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: NanoString. A.M. Menzies: Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pierre Fabre. R.A. Scolyer: Advisory / Consultancy: MSD; Advisory / Consultancy: Neracare; Advisory / Consultancy: Novartis. A.C.J. van Akkooi: Advisory / Consultancy, Research grant / Funding (institution): Amgen; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Merck MSD; Advisory / Consultancy: Merck-Pfizer; Advisory / Consultancy: 4SC. J. Hansson: Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Novartis. G.V. Long: Advisory / Consultancy: Aduro; Advisory / Consultancy: Amgen; Advisory / Consultancy: BMS; Advisory / Consultancy: Merck MSD; Advisory / Consultancy: Mass-Array; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Roche. C.U. Blank: Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Roche; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Lilly; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Pfizer; Advisory / Consultancy: GSK; Advisory / Consultancy: GenMab; Research grant / Funding (institution): NanoString. All other authors have declared no conflicts of interest.