Background: Stage IIB/IIC (8th AJCC) melanoma patients are known to have high-risk primary tumors, however they follow the same routine to sentinel lymph node biopsy (SLNB) as more low risk tumors. Guidelines are not conclusive regarding the use of preoperative imaging for these patients. The aim of this pilot study was to assess the value of ultrasound (US) and F-18-FDG PET/CT prior to lymphoscintigraphy (LSG) and SLNB for stage IIB/C melanoma patients. Methods: From 2019-04 till 2020-01, all stage IIB/C melanoma patients underwent US of the regional lymph nodes and whole body F-18-FDG PET/CT before their planned LSG and SLNB. Suspected metastases were confirmed with fine needle aspiration (FNA), prior to surgery. Results: In total 23 patients were screened: six had metastases detected by imaging, two by US, one by F-18-FDG PET/CT and three were detected by both imaging modalities. All metastases were nodal and therefore treatment was altered to lymph node dissection and all but one also received adjuvant therapy. Eight (47%) of the 17 patients without macroscopic disease, still had a positive SN. Sensitivity, specificity and false negative rate for US and F-18-FDG PET/CT were 36%, 89%, 64% and 29%, 100% and 71%, respectively. Conclusion: Preoperative negative imaging does not exclude the presence of SN metastases, therefore SLNB cannot be foregone. However, US detected metastases in 22% of patients, altering their treatment, which suggests it is effective in the work-up of stage IIB/C melanoma. Staging with F-18-FDG PET/CT is not of added value prior to LSG and SLNB and should therefore not be used. (C) 2020 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

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 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.

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: Outcome of high-risk stage III melanoma patients (pts) has been poor, with a 5-year overall survival (OS) rate of< 50%. Adjuvant IPI improved 5-year relapse-free survival (RFS) and OS and adjuvant (adj) anti-PD1 improved RFS further. Neoadjuvant (neoadj) IPI+ NIVO has been shown in 3 investigator-initiated trials to induce high pathologic response rates. While standard dosing regimen of IPI 3mg/kg+ NIVO 1mg/kg has been too toxic for broader application, OpACIN-neo identified 2 courses IPI 1mg/kg+ NIVO 3mg/kg as well tolerated and effective scheme to proceed to phase 3. Pathologic response was a good predictor...

Background: Outcome of high-risk stage III melanoma patients (pts) has been poor, with a 5-year overall survival (OS) rate of < 50%. Adjuvant IPI improved 5-year relapse-free survival (RFS) and OS and adjuvant (adj) anti-PD1 improved RFS further. Neoadjuvant (neoadj) IPI + NIVO has been shown in 3 investigator-initiated trials to induce high pathologic response rates. While standard dosing regimen of IPI 3mg/kg + NIVO 1mg/kg has been too toxic for broader application, OpACIN-neo identified 2 courses IPI 1mg/kg + NIVO 3mg/kg as well tolerated and effective scheme to proceed to phase 3. Pathologic response was a good predictor for early outcome (none of the pts relapsed), but longer follow-up (FU) data are missing so far. Methods: Between August 2015 and October 2016, 20 high risk, stage IIIB/IIIC melanoma pts with palpable nodal disease were included in the phase 1b feasibility OpACIN trial. Pts were randomized to receive IPI 3mg/kg plus NIVO 1mg/kg, either adj 4 courses, or split 2 courses neoadj and 2 adj. Pathological response was reviewed by a blinded pathologist, response was defined as < 50% viable tumor cells. The study was not powered to compare both arms, all efficacy endpoints are descriptive. Results: After a median FU of 31.6 months (minimum 23.5 months FU of pts alive) none of the 7 pts that achieved a pathologic response in the neoadj arm have relapsed. Two non-responding pts in the neoadj arm have relapsed, and 4 pts in the adj arm. 1 pt died in the neoadj arm and 3 in the adj arm. Estimated 30 months RFS rates were 80% for the neoadj arm and 60% for the adj arm and 30 months OS rates were 90% and 67%, respectively. Of the 18 (90%) pts that had developed one or more grade 3-4 adverse events, all recovered to ≤ grade 1, except for grade 2 endocrine toxicities needing hormonal suppletion 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. None of the pts with a pathologic response has relapsed, suggesting that this could become a primary read-out for subsequent neoadj immunotherapy trials and a surrogate marker for RFS and OS. Clinical trial identification: NCT02437279. Legal entity responsible for the study: Netherlands Cancer Institute. Funding: BMS. Disclosure: E.A. Rozeman: Travel support: MSD, NanoString. H.V. van Thienen: Travel support: Roche. D. Peeper: Research support: BMS. J.B.A.G. Haanen: Fees to NKI for advisory roles: BMS, MSD, Roche, Neon Therapeutics, Immunocore, Novartis, AstraZeneca/MedImmune, Pfizer, Ipsen; Grants to NKI: BMS, Merck, Novartis, Neon Therapeutics. A.C.J. van Akkooi: Personal fees for advisory role: Amgen, Bristol-Myers Squibb, Novartis, MSD-Merck, Merck-Pfizer; Grants: Amgen, Novartis, all outside the submitted work. T.N. Schumacher: Consultant: Adaptive Biotechnologies, AIMM Therapeutics, Amgen, Neon Therapeutics, Scenic Biotech; Grant/research support: Merck, BMS, Merck KGaA; Stockholder: AIMM Therapeutics, Neon Therapeutics. C.U. Blank: Personal fees for advisory roles: MSD, BMS, Roche, GSK, Novartis, Pfizer, Lilly; Grants: BMS, Novartis. All other authors have declared no conflicts of interest.

BACKGROUND:Neoadjuvant/induction chemotherapy (NAIC) improves survival in patients with muscle-invasive bladder carcinoma (MIBC). On-treatment response assessment may aid in decisions to continue or cease NAIC. OBJECTIVE:We investigated whether 18F-fluoro-2-deoxy-D-glucose-Positron Emission Tomography/Computed Tomography (FDG-PET/CT) could predict response to NAIC and compared to contrast-enhanced Computed Tomography (CECT). METHODS:We prospectively included 83 patients treated for MIBC (i.e. high-risk cT2-4N0M0 or cT1-4N+M0-1a) between 2014 and 2018. Response to NAIC was assessed after 2-3 cycles with FDG-PET/CT (Peter-Mac and EORTC criteria) and CECT (RECIST1.1 criteria). We assessed prediction of complete pathological response (pCR; ypT0N0), complete pathological down-staging (pCD;≤ypT1N0), any down-staging from baseline (ypTN < cTN) and progression (inoperable tumor/ypN+/M+). The reference standard was histopathological assessment or clinical follow-up. Sensitivity, specificity, and accuracy were calculated. RESULTS:Pathological response rates were 21% for pCR, 29% for pCD, and 10% progressed. All patients underwent FDG-PET/CT and 61 patients also underwent CECT (73%). Accuracy of FDG-PET/CT for prediction of pCR, pCD, and progression were 73%, 48%, and 73%, respectively. Accuracy of CECT for prediction of pCR, pCD, and progression were 78%, 65%, and 67%, respectively. Specificity of CECT was significantly higher than FDG-PET/CT for prediction of pCD and any down-staging (p = 0.007 and p = 0.022). In all other analyses, no significant differences between FDG-PET/CT and CECT were found. CONCLUSIONS:Routine FDG-PET/CT has insufficient predictive power to aid in response assessment compared to CECT.

Background: Changing the neoadjuvant chemotherapy regimen in insufficiently responding breast cancer is not a standard policy. We analysed a series of patients with 'luminal'-type breast cancer in whom the second half of neoadjuvant chemotherapy was selected based on the response to the first half.Methods: Patients with oestrogen receptor-positive (ER+) human epidermal growth factor receptor 2-negative (HER2-) breast cancer received three courses of neoadjuvant dose-dense doxorubicin and cyclophosphamide (ddAC). Three further courses of ddAC were administered in case of a 'favourable response' on the interim magnetic resonance imaging (MRI) and a switch to docetaxel and capecitabine (DC) was made in case of an ` unfavourable response', using previously published response criteria. The efficacy of this approach was evaluated by tumour size reductions on serial contrast-enhanced MRI, pathologic response and relapse-free survival.Results: Two hundred and forty-six patients received three courses of ddAC. One hundred and sixty-four patients (67%) had a favourable response at the interim MRI, with a mean tumour size reduction of 31% after the first three courses and 34% after the second three courses. Patients with unfavourable responsive tumours had a mean tumour size reduction of 12% after three courses and received three courses of DC rather than ddAC. This led to a mean shrinkage of 27%.Conclusion: The tumour size reduction of initially less responsive tumours after treatment adaptation adds further evidence that a response-adapted strategy may enhance the efficacy of neoadjuvant chemotherapy.