Neoadjuvant immune checkpoint inhibitors for patients with resectable stage III/IV melanoma: A nationwide real-life study in France (NEOMEL).

Chemotherapy + PD-1/PD-L1 Blockade Should Be the Preferred Option in the Neoadjuvant Therapy of NSCLC

9578 Background: Several studies have shown the efficacy of neoadjuvant treatment (NT) with immune checkpoint inhibitors (ICI) for resectable stage III/IV melanoma. However, real-life data are lacking. Methods: NEOMEL is a national multicenter retrospective study assessing the efficacy and tolerability of NT with ICI (NT-ICI) for resectable metastatic melanoma in a real-life setting. Data were obtained in patients (pts) with resectable stage III/IV melanoma who initiated NT-ICI (at least one infusion). Primary endpoint was pathologic complete response (pCR) (i.e no residual tumor) rate. Secondary endpoints were pathologic response (pR) according to INMC, radiologic response (RECIST), safety profile (CTCAE) and survival outcomes. Results: A total of 166 pts with resectable stage III/IV melanoma were included. Median age was 67 years (range, 24-96). Most pts had primary cutaneous melanoma (n=157, 89%), stage IIIB-D disease (n=156, 94%); a BRAF V600-mutant melanoma was observed in 47% (n=78); 8% (n=14) pts had received a previous systemic treatment. The median number of infusions of NT-ICI was 3 (range, 1-5). ICI regimens were anti-PD-1 monotherapy (n=122, 73%) or nivolumab + ipilimumab (NIVO + IPI) (n=44, 27%). Median follow-up was 6.5 months (range, 1-85). Overall, 143 pts (86%) underwent surgery. A pCR was observed in 44% of pts (n=63/143), including 52% (n=51/99) treated with anti-PD-1 monotherapy, and 27% (n=12/44) treated with NIVO + IPI. Of note, 78 pts (54%) were treated with 3 infusions of pembrolizumab (PBZ) (according to SWOG 1801 protocol) and had a pCR in 45% (n=35). A pR was assessed according to INMC criteria in 58% of pts (n=83/143): 51% of pCR (n=42), 8% of near-pCR (n=7) corresponding to a major pR of 59% (n=49/83), 16% of pathologic partial response (n=13) and 25% of pathologic non-response (n=21). Twenty-three pts (14%) did not undergo surgery because of progressive disease (n=10), clinical and radiologic responses (8 complete responses, 1 partial response, 1 stable disease), toxicity (n=2) or patient’s choice (n=1). Radiologic overall response rate according to RECIST (data available after NT in 49% of pts) was 54% (n = 44/82). All grade immune-related adverse events (irAEs) of NT-ICI occurred in 31% (n=51) of pts, including grade 3-4 irAEs in 10% (n=17) and one grade 5 irAE (pneumonitis with PBZ). Severe irAEs (grade 3 or more) were observed in 4% (n=4/99) of pts treated with anti-PD1 monotherapy and 32% (n=14/44) of pts treated with NIVO + IPI. Adjuvant treatment was started for 120 pts (84%). At last follow-up, 26 pts (18%) have had recurrence after surgery, including 3 pts with a pCR and 23 pts with a non-pCR to NT-ICI. Survival data are not yet available. Conclusions: NT-ICI for advanced melanoma demonstrated its efficacy with high rates of pCR in a real-life setting and an acceptable safety profile, particularly NT anti-PD1 monotherapy.

Neoadjuvant treatment with ipilimumab and nivolumab has shown efficacy in melanoma patients with nodal metastases in clinical trials. Real world data on neoadjuvant therapies is lacking. This study investigates the effectiveness of neoadjuvant therapy in a real-world setting and included all melanoma patients who received combined anti-CTLA4/PD1 immunotherapy prior to resection. Pathologic and radiologic responses as well as treatment-related adverse events were assessed, and recurrence-free survival (RFS) was compared between patients with major pathologic response (mPR) and patients without mPR. In total, 24 patients were analyzed, including patients with distant metastases and patients with prior adjuvant treatment. Median follow-up was 21.5months. Upon histologic assessment, mPR was achieved in 50% (12/24) of the patients, including two patients with lung metastases and three patients who progressed after prior adjuvant anti-PD1 therapy. Radiologic response after neoadjuvant treatment correlated with mPR. No patient with mPR relapsed during follow-up (median RFS not reached) compared to six out of 12 patients without mPR (median RFS = 13months, p=0.005). Neoadjuvant treatment with ipilimumab and nivolumab is effective in real-world patients with different melanoma subtypes, different stages of disease and even advanced primary tumor.

Neoadjuvant use of immune checkpoint inhibitors (ICIs) before liver resection results in pathological tumour regression in patients with hepatocellular carcinoma. We aimed to describe the characteristics of pathological responses after preoperative ICI therapy for hepatocellular carcinoma and to evaluate the association between the depth of tumour regression and relapse-free survival. In this cross-trial, patient-level analysis, we performed a pooled analysis of data from patients with hepatocellular carcinoma receiving ICI therapy before liver resection as part of a global collaborative consortium (NeoHCC) of five phase 1 and 2 clinical trials and standardised observational protocols conducted in 12 tertiary referral centres across the USA, UK, and Taiwan. Eligible patients were adults (aged ≥18 years) diagnosed with hepatocellular carcinoma by tissue core biopsy before treatment initiation, a Liver Imaging Reporting and Data System score of 5 on imaging, or both, with an Eastern Cooperative Oncology Group performance status score of 0-1, and no extrahepatic spread or previous ICI treatment. Pathological response was measured as the percentage of non-viable tumour in the resected surgical specimen, with major pathological response corresponding to at least 70% tumour regression and pathological complete response corresponding to 100% tumour regression. We correlated pathological response with radiological overall response using RECIST criteria (version 1.1) and relapse-free survival, and evaluated the threshold of tumour regression that could be optimally associated with relapse-free survival. At data cutoff on Jan 31, 2024, 111 patients were included in the study, of whom data on pathological response were available for 104 (94%) patients. Patients received treatment from Oct 5, 2017, to Nov 15, 2023, mostly ICI combinations (76 [69%]), for a median of 1·4 months (IQR 0·7-2·9). 87 (78%) patients were men and 24 (22%) were women. Most patients had underlying viral chronic liver disease (73 [66%]) and Barcelona Clinic Liver Cancer stage A hepatocellular carcinoma (61 [55%]), without portal vein thrombosis (87 [78%]). We observed major pathological response in 33 (32%) patients and pathological complete response in 19 (18%) patients. Radiological overall response was associated with major pathological response, with 23 (74%) of 31 patients with radiological response showing major pathological response compared with ten (14%) of 73 patients without radiological response (p<0·0001). However, ten (30%) of 33 major pathological responses were not predicted by radiological response. After a median follow-up of 27·2 months (95% CI 22·3-32·1), median relapse-free survival for the whole cohort was 43·6 months (95% CI 28·3-not evaluable). Relapse-free survival was significantly longer in patients with major pathological response than in those who did not have a major pathological response (not reached [95% CI not evaluable-not evaluable] vs 28·3 months [12·8-43·8]; hazard ratio 0·26 [0·10-0·66]; p=0·0024) and in patients with pathological complete response than in those who did not have a pathological complete response (NR [95% CI not evaluable-not evaluable] vs 32·8 months [15·0-50·5]; 0·19 [0·05-0·78]; p=0·010). Unbiased recursive partitioning of the cohort for the risk of relapse, death, or both identified a threshold of 90% as the optimal cutoff of pathological tumour regression to predict improved relapse-free survival. The extent of tumour regression following neoadjuvant ICI therapy could identify patients with improved relapse-free survival following liver resection. The threshold of at least 90% tumour regression should be validated for its surrogate role for relapse-free survival in phase 3 randomised controlled trials. None.

Despite the clear potential benefits of neoadjuvant therapy, the optimal neoadjuvant regimen for patients with high-risk resectable melanoma (HRRM) is not known. To compare the safety and efficacy of dual checkpoint inhibitors with anti-programmed cell death protein-1 (anti-PD1) therapy in a neoadjuvant setting among patients with HRRM. In this pooled analysis of clinical trials, studies were selected provided they investigated immune checkpoint inhibitor treatment, were published between January 2018 and March 2023, and were phase 1, 2, or 3 clinical trials. Participant data included in the analysis were derived from trials evaluating the efficacy and safety of anti-PD1 monotherapy and the combination of anti-cytotoxic T lymphocyte-associated protein-4 with anti-PD1 in the neoadjuvant setting, specifically among patients with HRRM. Patients were treated with either anti-PD1 monotherapy; dual checkpoint inhibition (DCPI) with a conventional dose of 3-mg/kg ipilimumab and 1-mg/kg nivolumab; or DCPI with an alternative-dose regimen of 1-mg/kg ipilimumab and 3-mg/kg nivolumab. The main outcomes were radiologic complete response (rCR), radiologic overall objective response (rOOR), and radiologic progressive disease. Also, pathologic complete response (pCR), the proportion of patients undergoing surgical resection, and occurrence of grade 3 or 4 immune-related adverse events (irAEs) were considered. Among 573 patients enrolled in 6 clinical trials, neoadjuvant therapy with DCPI was associated with higher odds of achieving pCR compared with anti-PD1 monotherapy (odds ratio [OR], 3.16; P < .001). DCPI was associated with higher odds of grade 3 or 4 irAEs compared with anti-PD1 monotherapy (OR, 3.75; P < .001). When comparing the alternative-dose ipilimumab and nivolumab (IPI-NIVO) regimen with conventional-dose IPI-NIVO, no statistically significant difference in rCR, rOOR, radiologic progressive disease, or pCR was noted. However, the conventional-dose IPI-NIVO regimen was associated with increased grade 3 or 4 irAEs (OR, 4.76; P < .001). Conventional-dose IPI-NIVO was associated with greater odds of achieving improved rOOR (OR, 1.95; P = .046) and pCR (OR, 2.99; P < .001) compared with anti-PD1 monotherapy. The alternative dose of IPI-NIVO also was associated with higher odds of achieving rCR (OR, 2.55; P = .03) and pCR (OR, 3.87; P < .001) compared with anti-PD1 monotherapy. The risk for grade 3 or 4 irAEs is higher with both the conventional-dose (OR, 9.59; P < .001) and alternative-dose IPI-NIVO regimens (OR, 2.02; P = .02) compared with anti-PD1 monotherapy. In this pooled analysis of 6 clinical trials, although DCPI was associated with increased likelihood of achieving pathological and radiologic responses, the associated risk for grade 3 or 4 irAEs was significantly lower with anti-PD1 monotherapy in the neoadjuvant setting for HRRM. Additionally, compared with alternative-dose IPI-NIVO, the conventional dose of IPI-NIVO was associated with increased risk for grade 3 or 4 irAEs, with no significant distinctions in radiologic or pathologic efficacy.

Background: The decision to perform cytoreductive nephrectomy (CN) and timing of CN in patients (pts) with metastatic renal cell carcinoma (mRCC) and primary who respond to immune checkpoint therapy (ICT) is a matter of debate. In CheckMate-214, nivolumab plus ipilimumab (N+I) yielded a 35% objective response rate in the primary; however, there is a paucity of pathological data from nephrectomy specimens (Nx) after treatment with N+I. We sought to investigate the radiologic and pathological responses and correlate the findings with outcomes in pts receiving 1L N+I followed by CN. Methods: We reviewed the medical records and Nx of pts with mRCC who received N+I followed by CN at our institution (2016-2021). H&amp;E slides were reviewed to determine the % of residual viable malignant cells. Pathological response was defined as tumor viability ≤20%, and pathological complete response (pCR) defined as absence of residual cancer. Radiologic response was defined as ≥30% reduction in primary size. Progression-free survival (PFS) and overall survival (OS) were determined from date of CN. Results: 22 pts (median age 59) are included: 18 (81.8%) males, 19 (86%) Caucasian, 20 (91%) had clear-cell histology, 20 (91%) had ECOG Performance Status 0-1, 10 (45%) had intermediate-risk disease and 12 (55%) had poor-risk disease by IMDC. Median ICT duration before CN was 6.5 months (mo) (range, 2-19 mo). 17 (77%) completed 4 cycles of N+I, and 16 (73%) received N maintenance before CN. 5 pts (23%) had grade 3/4 immune-related adverse effects; 1 pt did not complete 4 cycles of N+I due to hepatitis. There were no therapy-related deaths. 12 pts (54.5%) had progressive disease (PD); 3 pts (14%) died of RCC. Median PFS was 22 mo, median OS not reached (NR). Pts with pathological response had greater radiologic reduction in primary size compared to pts without pathological response (median reduction 38% vs. 15% p-value 0.01), smaller final primary pathological size (median 5.7 cm vs. 10.65 cm p-value 0.002), and lower pathological yT stage (pT0: 1, pT1: 6, pT2: 2 pT3: 3, pT4: 0 vs. pT0: 0, pT1: 1, pT2: 0, pT3: 8, pT4: 1 p-value 0.045); ICT duration was similar between groups (median 5.5 mo vs. 7 mo p-value 0.733). 6 pts achieved low viability within 5 mo of ICT. In 9 pts with optimal radiopathological response [viability ≤20% and ≥30% primary size reduction], PFS was longer compared to PFS in pts with suboptimal radiopathological response: median PFS NR vs. 17 months (HR 0.23, 95% CI 0.076 - 0.741; p-value 0.041). In 13 pts with suboptimal response, 10 (77%) had PD, the most common sites of PD were lymph nodes [6 pts (60%)] and brain [3 pts (30%)]. Conclusions: In this small cohort, N+I yielded a low pCR in Nx of pts with mRCC. Radiologic response but not ICT duration was associated with low tumor viability. Citation Format: Leticia Campos Clemente, Omar Alhalabi, Matthew T. Campbell, Guillermo Corredor Alonso, Kieko Hara, Pavlos Msaouel, Andrew C. Johns, Chad Tang, Jose A. Karam, Priya Rao, Nizar M. Tannir. An integrated analysis of radiologic and pathological responses in patients with metastatic renal cell carcinoma who presented with primary renal tumor in situ and received first-line nivolumab plus ipilimumab followed by cytoreductive nephrectomy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7523.

TPS9605 Background: Adjuvant treatment with anti-PD1 therapy improves the recurrence free survival (RFS) in resectable stage III melanoma. The Checkmate-238 and KEYNOTE-054 trials respectively reported a 4-year RFS of 52.5% for adjuvant nivolumab and a 3-year RFS of 63.7% for adjuvant pembrolizumab. Despite these improved outcomes, a considerable proportion of patients have a relapse in the years after therapeutic lymph node dissection (TLND). The OpACIN trial showed that neoadjuvant treatment with nivolumab (NIVO) plus ipilimumab (IPI) is feasible and induces a stronger and broader T-cell response. The subsequent OpACIN-neo trial identified 2 cycles of NIVO 3mg/kg + IPI 1mg/kg as a neoadjuvant dosing scheme with decreased toxicity and preserved high pathologic response rates (77%), which was confirmed in the PRADO trial. A favorable 2-year RFS (83,6%) was achieved in the overall OpACIN-neo population, although patients with a pathological partial or non-response have a worse prognosis and may therefore benefit from additional adjuvant therapy. The efficacy of neoadjuvant checkpoint inhibition versus the current standard of adjuvant therapy needs to be confirmed in a phase III trial, before neoadjuvant therapy can be considered as a standard option for this patient population. Methods: This international, randomized phase 3 trial aims to compare the efficacy of neoadjuvant IPI + NIVO with adjuvant NIVO in macroscopic stage III melanoma. In total 420 patients diagnosed with recurrent or de novo melanoma, with at least one pathologically proven, clinically detectable lymph node (up to 3 in-transit metastases (ITMs) allowed), will be randomized to neoadjuvant or adjuvant treatment. The population will be stratified by BRAF mutation, continent and the presence of ITMs. Patients in arm A will receive 2 cycles of IPI 80mg + NIVO 240mg and will undergo TLND at week 6. In the case of pathological partial response or non-response, surgery will be followed by adjuvant NIVO (11 cycles) or adjuvant dabrafenib + trametinib (46 weeks) if BRAFV600-mutation is present. Patients in arm B will undergo upfront TLND followed by 12 cycles of NIVO 480mg. The primary endpoint will be the event free survival (EFS) defined as the time from randomization until progression to unresectable stage III or stage IV melanoma, recurrent melanoma, a new primary melanoma or death due to melanoma or treatment. Final analysis will be performed after 132 events have been observed, or at latest 2 years after the last patient is included. Baseline biopsies and blood samples (screening, week 0, 3, 6, 9 and 12) will be collected for translational research. Quality of Life questionnaires and electronic Patient Reported Outcomes will be collected using the Kaiku application. The first patient was enrolled on the 23rd of July 2021. Clinical trial information: NCT04949113.

9572 Background: OpACIN was the first trial testing neoadjuvant ipilimumab (IPI) + nivolumab (NIVO) versus the same combination given adjuvant. An unexpected high pathologic responses of 78% was observed in the neoadjuvant arm with a 2-year relapse-free survival (RFS) rate of 80%. The subsequent OpACIN-neo trial tested 3 different dosing schedules of neoadjuvant IPI + NIVO and identified 2 cycles IPI 1 mg/kg + NIVO 3 mg/kg q3w as most favorable schedule with a pathologic response rate of 77% and 20% grade 3-4 immune-related adverse events. Long-term data on the durability of the pathologic (path) responses upon neoadjuvant checkpoint inhibition are lacking so far. Therefore, we present here the updated RFS and overall survival (OS) data of both trials. Methods: In OpACIN 20 macroscopic stage III melanoma pts were randomized to receive either IPI 3 mg/kg + NIVO 1 mg/kg q3w 4 cycles adjuvant after lymph node dissection or split 2 cycles neoadjuvant and 2 adjuvant. In OpACIN-neo 86 macroscopic stage III melanoma pts were randomized to arm A (2x IPI 3 mg/kg + NIVO 1 mg/kg q3w, n=30), arm B (2x IPI 1 mg/kg + NIVO 3 mg/kg q3w, n=30), or arm C (2x IPI 3 mg/kg q3w followed by 2x NIVO 3 mg/kg q2w, n=26) followed by lymph node dissection in week 6. RFS and OS were estimated using Kaplan Meier method. All comparative efficacy endpoints are descriptive for OpACIN, since the trial was not powered for comparison of the arms. Results: After a median follow-up (FU) of 68.6 months for OpACIN (minimum FU of 59.8 months), median RFS and OS were not reached. Only 1/7 patients (pts) with a pathologic response on neoadjuvant therapy has relapsed. Estimated 5-year RFS and OS rates for the neoadjuvant arm were 70.0% (95%CI: 46.7-100.0) and 90.0% (95%CI: 73.2-100.0) versus 60.0% (95%CI 36.2-99.5) and 70.0% (95%CI: 46.7-100.0) for the adjuvant arm. After a median FU of 46.8 months for OpACIN-neo (minimum FU of 38.2 months), median RFS and OS were not reached. Of pts with path response on neoadjuvant therapy, 3/64 (4.7%) had an event (2 pts relapsed, 1 pt died due to toxicity), versus 14/21 (66.7%) without path response. This resulted in a 3-year RFS rate of 95.3% (95%CI: 90.3-100.0) for responding versus 36.8% (95%CI: 20.4-66.4) for non-responding pts (p&lt;0.001). Of the pts who relapsed after response, 1 had major path response (&lt;10% vital tumor) and 1 a partial response (10-15% vital tumor). Estimated 3-year RFS and OS rates are presented in the Table. Conclusions: Updated data from OpACIN and OpaCIN-neo trials confirm the durability of responses upon neoadjuvant combination checkpoint inhibition in high risk stage III melanoma. Pathologic response remains a reliable surrogate marker for RFS and OS. Clinical trial information: NCT02437279, NCT02977052. [Table: see text]

Neoadjuvant-adjuvant therapy for locally advanced or potentially resectable metastatic melanoma was expected to improve operability and clinical outcomes over upfront surgery and adjuvant treatment only. Forty-seven consecutive patients were treated with neoadjuvant-adjuvant BRAF inhibitors (BRAFi)/MEK inhibitors (MEKi) and surgery. Twelve (26%) patients achieved a pathological complete response and 10 (21%) patients achieved a near-complete response. In the whole group, median recurrence-free survival was 19.4 months and median distant metastasis-free survival (mDMFS) was 21.9 months. In patients with a pathological complete response (pCR)/near-pCR median recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) were significantly longer than in patients with minor pathological response with hazard ratio (HR)=0.37 (p=.005) for RFS and HR=0.33 (p=.002) for DMFS. After median follow-up of 52.5 months, median progression-free survival since BRAFi/MEKi therapy initiation was 25.1 months. The median time-to-treatment-failure since initiation of neoadjuvant therapy was 22.2 months and was significantly longer in patients with pCR/near-pCR (HR=0.45; p=.022). Neoadjuvant therapy did not result in any new specific complications of surgery. After 48 months, RFS and overall survival were 36.3% and 64.8% or 20% and 37.4% in patients with pCR/near-pCR and pathological partial response/pathological nonresponse, respectively. The authors confirmed that BRAFi/MEKi combination is an effective and safe regimen in the perioperative treatment of stage III/IV melanoma. Major pathological response to neoadjuvant treatment is a surrogate marker of recurrence including DMFS in these patients. Our study presents a large comprehensive analysis of neoadjuvant-adjuvant systemic therapy in patients diagnosed with marginally resectable stage III or IV melanoma. Neoadjuvant therapy effectively reduced the volume of the disease, which facilitated subsequent surgical resection. After median follow-up of 52.5 months, median progression-free survival since therapy initiation was 25.1 months. Twelve patients had complete pathological response and 10 patients had a near-complete pathological response-and together they had median recurrence-free survival and distant metastasis-free survival significantly longer than in patients with pathological partial response or nonresponse. Complete/near-complete pathological response to neoadjuvant treatment is a surrogate marker of recurrence-free, including distant metastasis-free, survival in these patients.

9576 Background: In the last years, the treatment of locally advanced and/or metastatic cutaneous squamous cell carcinoma (CSCC) has been revolutionized by the introduction of cemiplimab, an anti-PD-1 antibody, which showed a 50% overall response rate and long term benefit (1). Recently, a phase II trial of neoadjuvant cemiplimab in resectable CSCC patients (2), showed a major pathological response (MPR) rate of 63.3%. In the current multicenter, phase II trial we evaluated the efficacy of neoadjuvant plus adjuvant immune checkpoint inhibitor in patients with surgically resectable, high-risk stage III/IV (M0) CSCC. Methods: Patients with surgically resectable high-risk stage III/IV (M0) CSCC received cemiplimab at a dosage of 350 mg every 3 weeks for two cycles prior surgery and for one year after surgery. The study primary endpoint was MPR [pathological complete response (pCR) or near pCR ( &lt; 10% remaining viable tumour cells in the surgical pathology sample)] per independent central pathology review. Key secondary endpoints included recurrence-free survival (RFS), overall survival (OS), safety and the analysis of predictive biomarkers. Results: From May 2021 to October 2022 twenty-three patients were enrolled in 6 centers. pCR was observed in 9 (39%) patients and near pCR in 2 (8%) patients, while pathological partial response (10-50% remaining viable tumour cells) and no pathologic response was observed in 1 patient and 11 patients, respectively. At data lock of 31st January 2023, only one patient was discontinued due to clinical progression. Furthermore, it was observed n = 60 (57%) any adverse events (AE) and n = 29 (30%) treatment-related AE. No any G3/G4 AE were observed. Conclusions: Neoadjuvant cemiplimab induced a pathological response in 52% of stage III/IV (M0) CSCC patients with a MPR in 48%. The study is still ongoing to evaluate the impact of combined neoadjvuant and adjuvant immunotherapy on RFS and biomarkers analysis. Clinical trial information: NCT04632433 .

The combination of locoregional and systemic therapy may achieve remarkable tumor response for unresectable hepatocellular carcinoma (HCC). We aimed to investigate the correlation between radiologic and pathologic responses following combination therapy, evaluate their prognostic values, and to establish a non-invasive prediction system for pathologic response. This single-center retrospective study included 112 consecutive patients with HCC who underwent locoregional and systemic combination therapy followed by liver resection or transplantation. Radiologic response was assessed with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and modified RECIST (mRECIST). Pathologic necrosis percentage was assessed to determine major pathologic response (MPR, ≥90% tumor necrosis) and pathologic complete response (100% tumor necrosis). Performance of the response criteria in predicting pathologic response was assessed with the area under the receiver operator characteristic curve (AUC). Among all radiologic and pathologic response criteria, MPR was the only independent predictor of post-resection recurrence-free survival (RFS) (adjusted hazard ratio 0.34, 95% CI 0.16-0.72, p=0.004). In addition, mRECIST showed stronger correlation with pathologic response than RECIST 1.1 (spearman r values: 0.76 vs 0.42, p<0.001). A prediction system for MPR was developed that included a combination of mRECIST response (ie, >70% decrease of viable target lesions) with either >90% decrease in AFP (for AFP-positive group, n=75) or >80% decrease in PIVKA-II (for AFP-negative group, n=37), which yielded a respective AUC of 0.905 and 0.887. Furthermore, the system-defined dual-positive responders showed improved median RFS (not reached) than non-responders (7.1 months for AFP-positive group [p=0.043] and 13.3 months for AFP-negative group [p=0.099]). mRECIST was more indicative of pathologic response after combination therapy than RECIST 1.1. Integration of mRECIST with AFP or PIVKA-II responses allowed for accurate prediction of MPR and could support decision-making on subsequent curative-intent treatment.

BackgroundTrials investigating neoadjuvant treatment with immune checkpoint inhibitors (ICI) in patients with melanoma have shown high clinical and pathologic response rates. Treatment with talimogene laherparepvec (T-VEC), a modified herpes simplex virus type-1 (HSV-1), is approved for patients with unresectable stage IIIB-IVM1a melanoma and has the potential to make tumors more susceptible for ICI. Combination ICI and intralesional T-VEC has already been investigated in patients with unresectable stage IIIB-IV disease, however, no data is available yet on the potential benefit of this combination therapy in neoadjuvant setting.MethodsThis single center, single arm, phase II study aims to show an improved major pathologic complete response (pCR) rate, either pCR or near-pCR, up to 45% in 24 patients with resectable stage IIIB-IVM1a melanoma upon neoadjuvant combination treatment with intralesional T-VEC and systemic nivolumab (anti-PD-1 antibody). Patients will receive four courses of T-VEC up to 4 mL (first dose as seroconversion dose) and three doses of nivolumab (240 mg flatdose) every 2 weeks, followed by surgical resection in week nine. The primary endpoint of this trial is pathologic response rate. Secondary endpoints are safety, the rate of delay of surgery and event-free survival. Additionally, prognostic and predictive biomarker research and health-related quality of life evaluation will be performed.DiscussionIntralesional T-VEC has the capacity to heighten the immune response and to elicit an abscopal effect in melanoma in combination with ICI. However, the potential clinical benefit of T-VEC plus ICI in the neoadjuvant setting remains unknown. This is the first trial investigating the efficacy and safety of neoadjuvant treatment of T-VEC and nivolumab followed by surgical resection in patients with stage IIIB-IVM1a melanoma, with the potential of high pathologic response rates and acceptable toxicity.Trial registrationThis trial was registered in the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT- number: 2019–001911-22) and the Central Committee on Research Involving Human Subjects (NL71866.000.19) on 4th June 2020.Secondary identifying number: NCT04330430.

BackgroundNeoadjuvant immunotherapy has become the new standard of care for stage III melanoma. This study sought to describe the metabolic changes seen with fludeoxyglucose-18-positron emission tomography (FDG-PET) following neoadjuvant immunotherapy...

Immune-Related Adverse Events and Outcomes in Patients with Advanced Non–Small Cell Lung Cancer: A Predictive Marker of Efficacy?

BackgroundICIs (PD-1 inhibitors, PDL-1 inhibitors, CTLA-4 inhibitors) are increasingly used to treat various malignancies. The percentage of cancer patients in the US who may benefit from ICIs has increased from...