Adjuvant PD-1 Research Articles

Adjuvant PD-1 blockade with camrelizumab in high-risk locoregionally advanced nasopharyngeal carcinoma (DIPPER): A multicenter, open-label, phase 3, randomized controlled trial.

LBA6000 Background: Patients with high-risk locoregionally advanced nasopharyngeal carcinoma (NPC) often experience disease relapse even after receiving standard-of-care treatment, e.g. induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT). The benefit of PD-1 inhibitor as adjuvant treatment following IC+CCRT in locoregionally advanced NPC remains unclear. Methods: Patients with high-risk locoregionally advanced NPC (T4N1M0 or T1-4N2-3M0) who have received gemcitabine and cisplatin (GP) IC and CCRT were recruited at 11 centers in China. They were randomly assigned (1:1) within 2 weeks after the last radiation dose to receive intravenous camrelizumab (200 mg once every 3 weeks for 12 cycles; Camrelizumab Arm) or observation (Standard-therapy Arm). The primary endpoint was event-free survival (EFS). It is estimated that approximately 442 patients would provide 80% power to detect a hazard ratio (HR) of 0.52 with a log-rank test at a two-sided α level of 0.05. Quality of life (QoL) was assessed by EORTC-C30. Results: A total of 450 patients were randomly assigned to the Camrelizumab Arm (n=226) and the Standard-therapy Arm (n=224). After a median follow-up of 37 months (corresponding to 41 months when calculated from the start of standard therapy), the estimated 3-year EFS was 86.9% in the Camrelizumab Arm and 77.4% in the Standard-therapy Arm (intention-to-treat population; HR 0.61, 95% CI 0.38–0.96; P = 0.03). The incidence of grade 3-4 adverse events (AEs) was 11.2% in the Camrelizumab Arm and 3.2% in the Standard-therapy Arm, including grade 3-4 immune-related AEs in 8 (3.9%) patients in the Camrelizumab Arm. Reactive capillary endothelial proliferation was the most common adverse event related to camrelizumab (RECP, 87.8%, 4 (1.8%) patients had grade 3 RECP). Treatment-related deaths occurred in 1 (<1%) patients in the Camrelizumab group (subarachnoid hemorrhage) and 1 (<1%) patients in the Standard-therapy group (nasopharyngeal necrosis). During treatment, there was no clinically meaningful deterioration of health-related quality of life associated with the use of adjuvant camrelizumab. Conclusions: Adjuvant PD-1 blockade with camrelizumab significantly improved EFS in high-risk locoregionally advanced NPC, with mild toxicity and comparable quality of life. Clinical trial information: NCT03427827 . [Table: see text]

PD-1 inhibitors versus conventional therapies for adjuvant treatment of resected acral melanoma: A systematic review and meta-analysis.

e21555 Background: Acral melanoma (AM) is a rare and aggressive melanoma subtype with unique characteristics in western Caucasian population, but mostly prevalent in Asian population. FDA has approved pembrolizumab and nivolumab for the adjuvant treatment of melanoma. However, its role in AM is still unclear. In US and mainland of China, high-dose interferon alfa was once approved, while in other part of the world, there was no standard treatment for adjuvant therapy of AM. Thus, we performed a meta-analysis to summarize the efficacy of anti-PD-1 monotherapy in patients with AM in adjuvant setting and derive implications for early-stage AM management. Methods: A systematic review of electronic databases was conducted to identify studies that assessed relapse-free survival (RFS) and overall survival (OS) between adjuvant PD-1 and conventional therapy (interferon (IFN) / chemotherapy) or observation alone in patients with AM. RFS was the primary endpoint, OS was the secondary endpoint. We estimated RFS/OS using the fixed-effect model. Statistical analyses in our study were carried out using Stata 12.0 (Stata Corp LP, College Station, TX, USA). Results: Five retrospective studies that totally involving 516 patients with AM were recruited, including 3 China studies and 2 non-China studies. Among them, there were 260 PD-1, 74 IFN, 178 OBS and 4 chemotherapy, respectively. Adjuvant PD-1 inhibitor achieved better efficacy than conventional therapy, showing significant improvement both in RFS (HR 0.76, 95%Cl 0.61-0.95) and OS (HR 0.57 0.37-0.88). This trend of RFS/OS benefit was observed in all subgroups, includes control treatment (OBS/IFN) or study region (China/non-China). Conclusions: Our data supports that patients with resected AM are more likely to derive benefit from adjuvant PD-1 comparing to conventional treatment or observation alone. Perspective studies are warranted to explore the role of adjuvant PD-1 in AM. [Table: see text]

Neoadjuvant pembrolizumab plus lenvatinib in patients with resectable stage III melanoma (NeoPele): Analysis of tumor microenvironment (TME) correlated to pathological response.

9566 Background: The phase II SWOG S1801 study showed an improved event-free survival with anti-PD-1 (PD1) neoadjuvant immunotherapy (neoIT) vs adjuvant PD1. One hypothesis explaining this benefit is the presence of tumor-draining lymph nodes (tdLN; defined as the nearest node to the tumor without direct involvement) as a potential reserve of stem-like (TCF7+) T cells, crucial to a good response to IT. We sought to analyze the immune infiltrate of the tumor-involved LN (ie TME) and tdLN from patients (pts) achieving major pathological response (MPR: complete [pCR] or near-complete [near-pCR] pathological response) vs non-MPR (partial [pPR] or no [pNR] pathological response). Methods: Pts with stage III melanoma treated with 6 weeks of PD1-based neoIT (PD1 + Lenvatinib) were included (NeoPele clinical trial; NCT04207086). Multiplex fluorescent immunohistochemistry of the TME before and after neoIT, and of the tdLN after neoIT was analyzed (T cell panel: CD3, TCF7, CD103, FoxP3, CD39 and Sox10; and B cell panel: CD20, CD21, CXCR5, TCF7, CD3 and SOX10). Lymphoid aggregates, characterized by clusters of CD21+ and CXCR5+ immune cells, were quantified. Results: Of the 20 pts, 11 (55%) had MPR (8 [40%] with pCR and 3 [15%] with near-pCR) and 9 (45%) had a non-MPR (4 [20%] with pPR and 5 [25%] with pNR). At baseline, MPR pts had a higher % of T cells (11% vs 3%, p = 0.0127) and follicular B helper T cells (CXCR5+; 29% vs 9%, p = 0.0293) than non-MPR pts in the TME. NeoIT led to an increase in the % of T cells, mainly in pts with MPR (median +30%; p = 0.0156) vs non-MPR (median +7%; p = 0.0312) pts, including an increase in the % of tumor-reactive (CD39+) T cells (p = 0.0195), but a decrease in % of tissue-resident stem-like (CD103+ TCF7+) T cells (p = 0.0195). Within the B cell compartment, there was an increase in the % of CD21+ B cells and mature (CD21+ CXCR5+) B cells in MPR vs non-MPR pts. At week 6, MPR pts maintained a higher % of T cells (36% vs 11%, p = 0.0172), follicular B helper T cells (20% vs 9%, p = 0.0133), and mature B cells (10% vs 2%, p = 0.0021) in the TME compared with non-MPR. NeoIT led to a significant increase in the number of lymphoid aggregates in the TME from MPR pts (median +42; p = 0,0156), but no difference in non-MPR pts. No differences were observed in the tdLN based on pathological response. Conclusions: MPR pts had a higher density of T cells in the TME at baseline, and a more differentiated and activated immune profile after neoIT compared with non-MPR pts. MPR pts had a significant increase in the number of lymphoid aggregates at week 6 compared to non-MPR pts; however, the role of these lymphoid aggregates, including the follicular B helper T cell subset and mature B cells, promoting a good pathological response to neoIT is yet to be clarified. Clinical trial information: NCT04207086 .

Postoperative lenvatinib + PD-1 blockade reduces early tumor recurrence in hepatocellular carcinoma with microvascular invasion (Barcelona Clinic Liver Cancer stage 0 or A): a propensity score matching analysis

PurposeThis research seeks to determine the effectiveness of post-operative adjuvant lenvatinib plus PD-1 blockade for early-stage HCC patients with microvascular invasion (MVI). Methods393 HCC patients (Barcelona Clinic Liver Cancer stage 0-A) who underwent curative hepatectomy with histopathologically proven MVI were enrolled according to inclusion and exclusion criteria and assigned to two groups: surgery alone (Surgery-alone) and surgery with lenvatinib and PD-1 blockade (Surgery+Len+PD-1) to compare recurrence-free survival (RFS), overall survival (OS), recurrence type, and annual recurrence rate following the application of propensity score matching (PSM). The Cox proportional hazards model was utilized for univariate and multivariate analysis. Results99 matched pairs were selected using PSM. Patients in the Surgery+Len+PD-1 group had significantly higher three-year RFS (76.8%, 65.7%, and 53.5%) compared to patients in the Surgery-alone group (60.6%, 45.5%, and 37.4%) (P=0.012). The two groups showed no significant differences in recurrence types and OS. Surgery-alone, MVI-M2, and AFP≥200ng/mL were independent risk factors for RFS (P<0.05), and history of alcoholism was an independent risk factor for OS (P=0.022). ConclusionsPostoperative lenvatinib plus PD-1 blockade improved the RFS in HCC patients with MVI and was particularly beneficial for specific individuals.

Adjuvant PD-1 Checkpoint Inhibition in Early Cutaneous Melanoma: Immunological Mode of Action and the Role of Ultraviolet Radiation.

Melanoma ranks as the fifth most common solid cancer in adults worldwide and is responsible for a significant proportion of skin-tumor-related deaths. The advent of immune checkpoint inhibition with anti-programmed death protein-1 (PD-1) antibodies has revolutionized the adjuvant treatment of high-risk, completely resected stage III/IV melanoma. However, not all patients benefit equally. Current strategies for improving outcomes involve adjuvant treatment in earlier disease stages (IIB/C) as well as perioperative treatment approaches. Interfering with T-cell exhaustion to counteract cancer immune evasion and the immunogenic nature of melanoma is key for anti-PD-1 effectiveness. Yet, the biological rationale for the efficacy of adjuvant treatment in clinically tumor-free patients remains to be fully elucidated. High-dose intermittent sun exposure (sunburn) is a well-known primary risk factor for melanomagenesis. Also, ultraviolet radiation (UVR)-induced immunosuppression may impair anti-cancer immune surveillance. In this review, we summarize the current knowledge about adjuvant anti-PD-1 blockade, including a characterization of the main cell types most likely responsible for its efficacy. In conclusion, we propose that local and systemic immunosuppression, to some extent UVR-mediated, can be restored by adjuvant anti-PD-1 therapy, consequently boosting anti-melanoma immune surveillance and the elimination of residual melanoma cell clones.

Frequency and characteristics of immune-related thyroid adverse events in patients with resected stage III/IV melanoma treated with adjuvant PD-1 inhibitors: a national cohort study

PurposeImmune-related thyroid adverse events (irTAEs) occur frequently following immune checkpoint inhibitor (ICI) therapy. The purpose of this study is to provide knowledge about the incidence, clinical timeline characteristics, associated factors of irTAEs, and potential impact on treatment efficacy in patients with melanoma receiving adjuvant ICI therapy.MethodsA national multicenter retrospective cohort study of patients with resected stage III/IV melanoma treated with adjuvant PD-1 inhibitors between November 2018 and December 2020. Data were extracted from the Danish Metastatic Melanoma Database. The irTAEs were defined as two consecutive abnormal TSH values and subdivided into transient or persistent.ResultsOf 454 patients, 99 developed an irTAE (21.8%), of these were 46 transient (46.5%) and 53 persistent (53.5%). Median time to transient and persistent irTAE was 55 and 44 days, respectively (p = 0.57). A hyperthyroid phase followed by hypothyroidism was seen in 73.6% of persistent irTAEs, whereas 87% of transient irTAEs developed an isolated hypo- or hyperthyroid phase. Multiple variable analysis demonstrated an association between irTAE and female sex (HR 2.45; 95% CI 1.63–3.70; p < 0.001), but no association with recurrence-free survival (HR 0.86; 95% CI 0.50–1.48; p = 0.587) or overall survival (HR 1.05; 95% CI 0.52–2.12, p = 0.891).ConclusionsIrTAE is a common side effect to PD-1 inhibitors primarily occurring within the first 3 months, with a high risk of persistency. Female sex is a strong predictive factor. IrTAE was not associated with improved clinical outcome.

The Effectiveness of Adjuvant PD-1 Inhibitors in Patients With Surgically Resected Stage III/IV Acral Melanoma.

Our aim was to assess the efficacy of adjuvant programmed cell death protein-1 (PD-1) inhibitors and compare the other adjuvant treatments in patients with surgically resected stage III or IV acral melanoma. This study is a multicenter, retrospective analysis. We included 114 patients with stage III or IV acral malignant melanoma who underwent surgery within the past 10 years. We analyzed the effect of adjuvant programmed cell death protein-1 inhibitors on disease-free survival (DFS). The mean follow-up was 40 months, during which 69 (59.5%) patients experienced recurrence. Among the participants, 64 (56.1%) received systemic adjuvant therapy. Specifically, 48.4% received anti-PD-1 therapy, 29.7% received interferon, 14.1% received tezozolomide, and 7.8% received B-Raf proto-oncogene/mitogen-activated protein kinase inhibitors. Patients who received adjuvant therapy had a median DFS of 24 (10.9-37.2) months, whereas those who did not receive adjuvant therapy had a median DFS of 15 (9.8-20.2) months. Multivariate analysis for DFS revealed that the receipt of adjuvant therapy and lymph node metastasis stage were independent significant parameters ( P = 0.021, P = 0.018, respectively). No statistically significant difference was observed for DFS between programmed cell death protein-1 inhibitor treatment and other adjuvant treatments. Regarding overall survival (OS), patients who received adjuvant treatment had a median OS of 71 (30.4-111.7) months, whereas those who did not receive adjuvant treatment had a median OS of 38 (16.7-59.3; P = 0.023) months. In addition, there were no significant differences in OS observed between various adjuvant treatment agents ( P = 0.122). In our study, we have shown that adjuvant therapy had a positive effect on both DFS and OS in patients with stages III-IV acral melanoma who underwent curative intent surgery. Notably, we found no significant differences between anti-PD-1 therapy and other adjuvant therapies.

Outcomes of patients with resected stage III/IV acral or mucosal melanoma, treated with adjuvant anti-PD-1 based therapy

ImportanceAcral (AM) and mucosal melanomas (MM) are rare subtypes with a poor prognosis. In those with advanced disease, anti-PD-1 (PD1) therapy has reduced activity compared to that seen in non-acral cutaneous melanoma. ObjectiveTo determine the efficacy of adjuvant PD1 in resected AM or MM. DesignAn international, retrospective cohort study SettingData up to November 2021 collected from 20 centres across 10 countries. ParticipantsOne hundred and ninety four patients with resected stage III or IV1 AM or MM who received adjuvant PD1 were included and compared to matched patients from the Melanoma Institute Australia (MIA) database using a propensity score matching analysis. Main outcomes and measuresRecurrence-free survival (RFS), distant metastasis-free survival (DMFS) and overall survival (OS) were investigated. ResultsForty five of 139 (32%) AM and 9 of 55 (16%) MM patients completed adjuvant therapy. The main reason for early treatment cessation in both groups was disease recurrence: 51 (37%) and 30 (55%) in the AM and MM groups, respectively. In the AM group adjuvant PD1 was associated with a longer RFS [HR-0.69 (0.52–0.92, p = 0.0127)], DMFS [HR0.58 (0.38–0.89, p = 0.0134)] and OS [HR of 0.59 (0.38–0.92, p-value 0.0196)] when compared to the historical cohort. In the MM group there was no statistical difference in RFS [HR1.36 (0.69–2.68,p-value 0.3799], DMFS or OS. Conclusion and relevanceAfter adjuvant PD1, both AM and MM have a high risk of recurrence. Our data suggests a benefit to using adjuvant PD1 therapy in resected AM but not in resected MM. Additional studies to investigate the efficacy of adjuvant PD1 for MM are needed.

Efficacy and safety of ‘Second Adjuvant’ therapy with BRAF/MEK inhibitors after local therapy for recurrent melanoma following adjuvant PD-1 based immunotherapy

BackgroundAnti-PD-1 antibodies and BRAK/MEK inhibitors (BRAF/MEKi) reduce the risk of recurrence for patients with resected stage III melanoma. BRAFV600-mutated (BRAFmut) melanoma patients who recur with isolated disease following adjuvant therapy may be suitable for ‘second adjuvant' treatment after local therapy. We sought to examine the efficacy and safety of ‘second adjuvant’ BRAF/MEKi. Patients and methodsPatients with BRAFmut melanoma treated with adjuvant PD-1 based immunotherapy who recurred, underwent definitive local therapy and were then treated with adjuvant BRAF/MEKi were identified retrospectively from 13 centres (second adjuvant group). Demographics, disease and treatment characteristics and outcome data were examined. Outcomes were compared to BRAFmut patients who did not receive ‘second adjuvant’ therapy (no second adjuvant group). Results73 patients were included; 61 who received ‘second adjuvant’ therapy and 12 who did not. Most initially recurred on PD-1 therapy (66%). There were no differences in characteristics between groups. 92% of second adjuvant group received dabrafenib and trametinib and median duration of therapy was 11.8 months (0.4, 34.5). 72% required dose adjustments, 23% had grade 3 + toxicity and 38% permanently discontinued drug due to toxicity. After median 26.1 months (1.9, 56.3) follow-up, recurrence-free survival (RFS) was improved in second adjuvant group versus no second adjuvant group (median 30.8 vs 4 months, HR 0.35; p = 0.014), largely driven by a delay in early recurrence, with no difference in overall survival (p = 0.59). ConclusionThis is the first study examining outcomes of ‘second adjuvant’ targeted therapy for melanoma, after failure of adjuvant PD-1 based immunotherapy. Data suggest a short-term improvement in RFS, but at the cost of toxicity. Alternative strategies and more data on sequencing adjuvant therapies are required to improve outcomes.

Benefit, recurrence pattern, and toxicity to adjuvant anti-PD-1 monotherapy varies by ethnicity and melanoma subtype: An international multicenter cohort study

Anti-Program-Death-1 (PD-1) is a standard adjuvant therapy for patients with resected melanoma. We hypothesized that there are discrepancies in survival, recurrence pattern and toxicity to adjuvant PD-1 between different ethnicities and melanoma subtypes. We performed a multicenter cohort study incorporating 6 independent institutions in Australia, China, Japan, and the United States. The primary outcomes were recurrence free survival (RFS) and overall survival (OS). Secondary outcomes were disease recurrence patterns and toxicities. In total 534 patients were included. East-Asian/Hispanic/African reported significantly poorer RFS/OS. Nonacral cutaneous or melanoma of unknown primary reported the best RFS/OS, followed by acral, and mucosal was the poorest. Within the nonacral cutaneous or melanoma of unknown primary subtypes, East-Asian/Hispanic/African reported significantly poorer RFS/OS than Caucasian. In the multivariate analysis incorporating ethnicity/melanoma-subtype/age/sex/stage/lactate dehydrogenase/BRAF (v-Raf murine sarcoma viral oncogene homolog B)-mutation/adjuvant radiotherapy, East-Asian/Hispanic/African had independently significantly poorer outcomes (RFS: HR, 1.71; 95% CI, 1.19-2.44 and OS: HR, 2.34; 95% CI, 1.39-3.95), as was mucosal subtype (RFS: HR, 3.25; 95% CI, 2.04-5.17 and OS: HR, 3.20; 95% CI, 1.68-6.08). Mucosal melanoma was an independent risk factor for distant metastasis, especially liver metastasis. East-Asian/Hispanic/African had significantly lower incidence of gastrointestinal/musculoskeletal/respiratory/other-rare-type-toxicities; but higher incidences of liver toxicities. A retrospective study. Ethnicity and melanoma subtype are associated with survival and recurrence pattern in melanoma patients treated with adjuvant anti-PD-1. Toxicity profile differs by ethnicity and may require a precision toxicity surveillance strategy.

Adjuvant treatment and outcome of stage III melanoma patients: Results of a multicenter real-world German Dermatologic Cooperative Oncology Group (DeCOG) study

PurposeClinical trials demonstrated significantly improved recurrence-free survival (RFS) of melanoma patients receiving adjuvant treatment. As data from controlled trials are based on selected populations, we investigated adjuvantly treated stage III melanoma patients under real-world conditions. Patients and methodsIn a prior multicenter cohort study, stage III-IV melanoma patients were analysed for their choice of adjuvant therapy. In this follow-up study, we examined RFS, overall and melanoma-specific survival (MSS) and response to the subsequent treatment of 589 stage III patients (232 BRAF-mutated) receiving adjuvant PD-1 inhibitors (PD1; n = 479) or targeted therapy (TT; n = 110). ResultsThe median follow-up of the total cohort was 25.7 months. The main reason for premature discontinuation of adjuvant therapy was disease progression in PD1- (28.8%, n = 138/479) and adverse events in TT-treated patients (28.2%, n = 31/110).Among BRAF-mutated patients, RFS at 24 months was 49% (95% CI 40.6–59.0%) for PD1- and 67% (95% CI 58–77%) for TT-treated patients. The risk of recurrence was higher for BRAF-mutated PD1 than TT (hazard ratio 1.99; 95% CI 1.34–2.96; hazard ratio adjusted for age, sex and tumour stage, 2.21; 95% CI 1.48–3.30). Twenty-four months MSS was 87% (95% CI 81.0–94.1) for PD1 and 92% (95% CI 86.6–97.0) for TT.Response to subsequent systemic treatment for unresectable disease was 22% for all PD1- and 16% for TT-treated patients. ConclusionsPD1-treated patients had more and earlier recurrences than TT patients. In BRAF-mutated patients, adjuvant TT might prevent early recurrences more effectively than PD1 treatment. Management of recurrence despite adjuvant treatment is challenging, with low response to current therapeutic options.

Survival impact of immediate complete lymph node dissection for Chinese acral and cutaneous melanoma with micrometastasis in sentinel nodes: a retrospective study

Sentinel node biopsy (SNB) has become a critical part of standard surgical treatment for melanoma with no clinical metastatic evidence. However, for patients with a positive sentinel node, the MSLT-II and DeCOG-SLT trials have shown that immediate complete lymph node dissection (CLND) does not bring further survival benefits. There is still an argument among the Chinese population dominated by acral subtypes on whether CLND can be omitted. Thus, this study aims to investigate the impact of immediate CLND on relapse-free survival (RFS) in Chinese melanoma patients with a positive sentinel node. Patients with acral or cutaneous melanoma of clinical Stages I–II who received SNB procedure and were detected with nodal micrometastasis were retrospectively collected at Fudan University Cancer Center (FUSCC) from January 2017 to December 2021. The clinicopathologic features and prognostic factors for RFS were analyzed. Out of 381 patients who received SNB in the past 5 years, 130 (34%) cases with SN micrometastasis detected were included in this study. Ninety-nine patients underwent immediate CLND while the other 31 patients received observation alone. Among patients who received CLND, the non-SN(NSN)-positive rate was 22.2%. Most of the clinicopathologic factors were balanced well between the CLND and non-CLND groups. However, more patients in the CLND group were detected with BRAF and NRAS mutation (P = 0.006) and received adjuvant PD-1 monotherapy (P = 0.042) as well. There were slightly fewer N1 patients in the CLND group, although the difference did not reach statistical significance (P = 0.075). The study found no significant difference in RFS between the two groups (P = 0.184). Even for patients with the acral subtype (P = 0.925), primary T4 lesion (P = 0.769), or presence of ulceration (P = 0.249), immediate CLND did not bring more survival benefits. Immediate CLND did not bring further RFS benefit for Chinese melanoma patients with SN micrometastasis in real-world clinical practice, even for patients with acral subtype or more tumor burden such as thick Breslow invasion and ulceration.

Efficacy of adjuvant therapy in patients (pts) with AJCC v8 stage IIIA cutaneous melanoma.

9518 Background: Pts with resected AJCC v8 stage IIIA melanoma have been under-represented in clinical trials of adjuvant drug therapy. The benefit of adjuvant targeted and immunotherapy in this population is unclear. Methods: In this multicenter, retrospective study, pts with stage IIIA melanoma (AJCC v8) who received adjuvant pembrolizumab or nivolumab (PD1), BRAF/MEK-targeted therapy dabrafenib + trametinib (TT), or no adjuvant treatment (OBS) were included. Recurrence free survival (RFS), distant metastasis free survival (DMFS), and toxicity rates were examined. Results: 613 pts from 34 centers across Australia, Europe and USA were included. The median follow-up was 2.6 yrs (IQR, 1.6-3.4 yrs). Pt characteristics and follow-up were similar across the cohorts (Table). Completion rates of 12-month PD1 and TT therapy were 57.0% and 69.2% respectively. 1-yr RFS was 93.3% (95% CI, 90.3-96.4) in PD1, 100% in TT and 91.3% (95% CI, 88.1-94.7) in OBS cohorts. 2-yr RFS was 79.3% (95% CI, 74.1-84.8) for PD1, 100% for TT and 84.3% (95% CI, 79.9-89.0) in OBS cohorts. 2-yr DMFS was 88.4% (95% CI, 84.3-92.8) in PD1, 100% in TT and 91.1% (95% CI, 87.7-94.7) in OBS cohorts. Risk of recurrence was associated with higher breslow thickness (HR 1.73, 95% CI 1.36-2.20), higher mitotic rate (HR 1.07, 95% CI 1.02-1.12) and neck as the site of nodal metastases (HR 2.71, 95% CI 1.45-5.06) in the overall cohort (p&lt;0.05). Neck nodal metastases were associated with higher risk of recurrence in OBS cohort (HR 3.82, 95% CI 1.91-7.66; p&lt;0.05) but not in the PD1 cohort. Rates of ≥ Grade 3 toxicities were 10.9% with PD1 and 20.0% with TT; discontinuation due to toxicity occurred in 25.0% and 30.0%, respectively. No new safety signals were observed. Rates of unresolved toxicity at last follow-up were 26.9% in PD1 and 7.7% in TT cohorts. Conclusions: In this large international study, adjuvant PD1 or TT did not significantly improve RFS or DMFS compared to OBS in pts with resected stage IIIA melanoma. Prognosis in stage IIIA melanoma is favourable and outcomes after adjuvant therapy in this population needs further study in prospective randomised trials. [Table: see text]

Temozolomide plus cisplatin versus toripalimab (anti-PD-1) as adjuvant therapy in resected mucosal melanoma.

9508 Background: Chemotherapy (temozolomide plus cisplatin) has been demonstrated to be a better adjuvant regimen compared to high-dose interferon alpha-2b in resected Mucosal Melanoma (MuM) in the pre-immunotherapy era. Yet in the present immunotherapy era, PD-1 inhibitor was recommended as a standard adjuvant therapy for resected Melanoma. No adjuvant trial comparing chemotherapy with PD-1 inhibitor in resected MuM had been reported. we conducted this study to determine the efficacies of adjuvant chemotherapy versus PD-1 inhibitor in resected MuM. Methods: All patients (pts) with resected MuM received chemotherapy (temozolomide 200 mg/m2/day orally on days 1 to 5 plus cisplatin 75 mg/m2 i.v. on days 1-3, repeated every 3 weeks for six cycles) or Toripalimab (anti-PD-1, 3 mg/kg every 2 weeks via intravenous infusion) as adjuvant therapy from 2013 to 2019 were included retrospectively. Demographic and clinical characteristics between the two groups were matched with 1:1 by propensity score matching (PSM) to reduce the bias. After PSM, the efficacies of the two groups were compared, and subgroup analysis was performed according to the baseline characteristics. The endpoints were relapse-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS). Kaplan-Meier methods and Cox regressions were used to estimate median RFS, DMFS, OS and HR. Results: A total of 247 pts were included, of which 78 were in the Toripalimab group and 169 were in the Chemo group. PSM matched 65 pts from each of the two groups. The baseline characteristics were similar. At a median follow-up of 52.6 months (95%CI, 44.6-60.6 months), patients receiving chemo had a longer median RFS (28.2 vs. 12.0 months; HR=0.64, 95% CI, 0.42 to 0.98; P=0.04), DMFS (42.0 vs. 19.0 months; HR=0.58, 95% CI, 0.36 to 0.92; P=0.02) and OS (93.4 vs. 39.3 months; HR=0.56, 95% CI, 0.33 to 0.94; P=0.03) versus the toripalimab group (Table). Conclusions: Adjuvant chemotherapy (temozolomide plus cisplatin) shows remarkable longer RFS, DMFS, and OS than Toripalimab (anti-PD-1). It suggested that adjuvant chemotherapy may be a better option for patients with resected mucosal melanoma even in the present immunotherapy era. [Table: see text]

Significant durable response with fianlimab (anti-LAG-3) and cemiplimab (anti-PD-1) in advanced melanoma: Post adjuvant PD-1 analysis.

9501 Background: Previous reports have demonstrated that treatment (Tx) with anti-LAG-3 Ab fianlimab + anti-PD-1 Ab cemiplimab had a 63.8% ORR across two separate cohorts of advanced PD-(L)1 naïve metastatic melanoma (Mel) patients (pts). The benefit the fianlimab + cemiplimab combination in pts exposed to prior anti-PD-1 Tx as adjuvant (adj) Tx is unknown. Here we present phase 1 safety and clinical activity data from pts with advanced Mel including those who received prior adj systemic Tx. Methods: Three separate expansion cohorts of adult pts with unresectable or metastatic Mel (excluding uveal Mel) who were anti–PD-(L)1 Tx-naïve for advanced disease were enrolled. All pts received fianlimab 1600 mg + cemiplimab 350 mg IV Q3W for 12 months (mos) (optional additional 12 mos if clinically indicated). Study enrollment closed in June 2022. Tumor measurements were performed every 6 weeks (wks) for 24 wks, then every 9 wks. Results: 98 pts were enrolled and treated with fianlimab + cemiplimab as of 01 Nov 2022 data cutoff. Median age was 68.0 years, 60.2% were male, and 89.8% were White. 2.0% of pts had received prior metastatic Tx (not anti–PD-(L)1) and 23.5% had received prior systemic Tx for Mel in the adj/neo-adj setting (disease-free interval &gt; 6 mos), including 13.3% treated with an anti-PD-1 (nivolumab or pembrolizumab). Median follow up was 12.6 mos and median treatment duration was 32.9 wks. Grade ≥3 treatment-emergent adverse events (TEAEs), serious TEAEs, and immune-related AEs (irAEs) occurred in 43.9%, 32.7%, and 65.3% of pts, respectively. 16.3% of pts discontinued Tx due to a TEAE. Rates of irAEs were similar to anticipated rates for PD-1 monotherapy with the exception of adrenal insufficiency (AI) with 12.2% (all grades) and 4.1% (grade ≥3). RECIST 1.1-based investigator-assessed overall ORR was 61.2% (12 complete responses; 48 partial responses), with median DOR (mDOR) not reached [NR] (95% CI: 22.6– not estimated [NE]). KM estimation of median PFS (mPFS) was 15.3 (95% CI: 9.4–NE) mos. In pts with any prior adj Tx, ORR, mDOR, and mPFS was 60.9% (14/23), NR, and 13.3 mos, respectively. In pts with prior anti-PD-1 adj Tx, ORR, mDOR, and mPFS was 61.5% (8/13), NR, and 11.8 mos, respectively. Data from subgroup and correlative biomarker analyses, PK and immunogenicity will be included in the presentation. Conclusions: Fianlimab + cemiplimab in advanced Mel pts showed high clinical activity that compares favorably with other approved combinations of immune checkpoint inhibitors in the same clinical setting. This is the first indication that dual LAG-3 blockade can produce high level of activity with significant ORR in pts with advanced Mel post adj anti-PD-1 Tx. The safety profile of fianlimab + cemiplimab is similar to anti-PD-1 monotherapy with the exception of AI. A phase 3 trial (NCT05352672) of fianlimab + cemiplimab in Tx-naïve advanced Mel pts is ongoing. Clinical trial information: NCT03005782 .

Multicenter analysis of melanoma recurrence pattern and management after adjuvant immunotherapy.

e21573 Background: PD-1 inhibitors improve outcomes in resected stage II-IV melanoma. However, recurrence patterns and prognostic factors are less known. Methods: We conducted a retrospective study in resected stage II-IV melanoma patients (p) treated with adjuvant PD-1 inhibitors (clinical practice or clinical trials) from 5 centers. Demographic, disease characteristics, adjuvant therapy, recurrence, treatment at relapse and outcome were recorded. Descriptive assessment for recurrence patterns and analysis for prognostic factors were performed. Results: From June 2017 to June 2022, 181 p were included. Median age was 59 years [22-81], 57% were male, 85% had cutaneous melanoma, 28% had BRAFV600E mutation. 9 p (5%) presented stage II, 147 (81%) stage III and 25 (14%) stage IV. Ulceration was present in 59% p, mitotic rate &gt;1/mm2 in 84%, Breslow index &gt;3 mm in 65% and elevated LDH in 51%. 81% p received PD-1 inhibitors alone and 19% in combination with other immunotherapies. 52% of p completed treatment, 12% discontinued due to toxicity and 26% due to relapse. 13% of p presented grade 3-4 adverse events and there was a grade 5 myocarditis. With a median follow-up of 18,1 months, 68 (37%) p recurred (Table). Median relapse free survival (RFS) was 48,8 months (95% CI 31,1-66,4). Recurrence was significantly associated with a higher stage, mitotic rate, LDH level and Breslow index, BRAFV600E mutation, non-cutaneous melanoma and delayed initiation of adjuvant immunotherapy in univariate analysis (p&lt;0,05). Stage, non-cutaneous melanoma and initiation of immunotherapy &gt;3 months (16% p) were associated with higher recurrence in multivariate analysis (&lt;0,05). Locoregional recurrence was treated in 23 p with surgery (14p), surgery + RT (7p) or RT alone (2). Systemic recurrence was treated in 50 p: all BRAF mutant p received targeted therapy (24p, 43%) with a disease control rate (DCR) of 91% and a median progression free survival (PFS) of 56 months (95% CI 24,1-NR); BRAF wild type p (26p, 47%) were treated with anti-PD-1 alone (9p) or in combination (7p), anti-CTLA-4 (2p), chemotherapy (1p) or best supportive care (7p), with DCR of 33% and a median PFS of 8 months (95% CI 6,9-10,8). Conclusions: We observed a 37% relapse rate and systemic recurrence were more frequent than locoregional recurrence. Treatment at relapse with targeted therapy in BRAF mutant p achieved higher DCR and PFS than immunotherapy in BRAF wild type p; with better outcomes than previously reported.[Table: see text]

Nature and management of melanoma recurrences following adjuvant anti-PD-1 (PD1) therapy.

9575 Background: Despite improved outcomes with the use of adjuvant PD1 therapy, approximately 50% of patients (pts) develop recurrent disease by 5 years. Data to define best management of recurrences is lacking, including whether retreatment with PD1 has benefit. Methods: This was a multicentre, international retrospective study of pts with resected stage II-IV melanoma who commenced adjuvant PD1 therapy before January 2022 and then recurred. Demographics, disease characteristics, treatment, toxicity, recurrence patterns, management and outcomes were collected. Results: 711 pts from 17 sites were included. Med age was 60 [range 16-92], 64% (N=451) were male. 641 (91%) pts were stage III (A 7%, B 24%, C 54%, D 3%), 18 (2%) stage II, 51 (7%) stage IV. 80% (N=536) underwent SLNB prior to PD1, of which 44% (N=236) went onto CLND. 635 pts (90%) received PD1, 74 (10%) PD1 + other. Med time to recurrence was 6.2 months (m) (0-68.5); 63% (N=444) recurred ON PD1, while 36% (N=257) recurred OFF. 338 pts (48%) recurred within 6m of starting adjuvant, 166 (23%) between 6-12m, 140 (20%) 12-24m and 59 (8%) after 24m. Initial recurrences were locoregional (LR) alone in 315 (44%), 307 (43%) distant alone, and 78 (11%) both. Patients with LR recurrences alone underwent definitive surgery, or surgery + radiation in 98 (31%) and 42 (13%) respectively. After initial LR management, 164 (52%) had a further local and 129 (41%) distant recurrence. Those with initial distant recurrences were managed with definitive surgery (21, 7%), surgery + radiation (8, 3%) and radiation alone (14, 5%). Further ‘second’ adjuvant therapy was given in 27% (N=86) of LR and 6% (N=25) of distant recurrences. Definitive systemic therapy at first recurrence was given in 77% (N=296) distant and 23% (N=73) LR recurrences (Table). Conclusions: Patients recurring after adjuvant PD1 therapy do so early, and often while on drug. Patients with resected recurrences often receive “second adjuvant” therapy, although whether adjuvant or definitive, outcomes are poor. Novel drug therapies and clinical trials are required for those who recur despite PD1 therapy. [Table: see text]

Efficacy of salvage therapies after failure of adjuvant anti-PD-1 monotherapy for melanoma in the Chinese population: a multi-institutional cohort study

SummaryThe majority of melanoma patients experience relapse during adjuvant therapy or after the end of therapy. Sixty-one patients from 3 melanoma centres who experienced recurrence and received adjuvant pembrolizumab for resected stage III/IV melanoma were enrolled. Disease characteristics, recurrence characteristics, subsequent management and outcomes were retrospectively analysed. Sixty-one patients were enrolled in this study. The median time to first relapse from the commencement of adjuvant pembrolizumab was 8 months (1–22 months). The first recurrences were locoregional alone in 25 patients (41%), distant alone in 29 (47.5%) and concurrent locoregional and distant relapse in 7 (11.5%). At the first recurrence, 4 patients (80%) who underwent resection alone experienced further relapse of disease. Three (60%) patients who were treated with adjuvant pembrolizumab following surgery, 2 (100%) patients who were treated with adjuvant chemotherapy, 2 (66.7%) patients who were treated with adjuvant chemotherapy and pembrolizumab combined and 3 (100%) patients who were treated with adjuvant radiotherapy and pembrolizumab combined had further recurrence. Of the three patients treated with adjuvant BRAF/MEKi following the first relapse, none had yet recurred. Of the 8 patients treated with pembrolizumab alone, only one patient (12.5%) who recurred after ceasing adjuvant PD1 had a partial response. The overall response rate to BRAF/MEKi was 75%, 3/4; to pembrolizumab in combination with an oral multitargeted receptor tyrosine kinase inhibitor, it was 22.2%, 2/9; to chemotherapeutic agents alone, it was 33.3%, 1/3; and to chemotherapeutic agents combined with pembrolizumab, it was 37.5%, 3/8. The patient treated with imatinib had progressive disease after 3 months of treatment. Of the 6 patients who received temozolomide combined with pembrolizumab, 3 (3/6, 50%) had a partial response. The median OS of the patients who relapsed locoregionally only was longer than that of the patients who relapsed distally at the first recurrence (35 months and 14 months, respectively; P < 0.01). The outcomes of the patients with disease recurrence during or after the completion of 1 year of adjuvant anti-PD1 therapy were poor despite multimodality treatment.

Adjuvant PD-1 antibody in recurrent, previously irradiated oral cavity cancer treated with salvage surgery

ObjectivesThe role of re-irradiation after salvage surgery for recurrent oral cavity cancer (OCC) is controversial. We evaluated the efficacy and safety of adjuvant toripalimab (PD-1 antibody) in this patient setting. Materials and methodsIn this phase II study, patients after salvage surgery with OCC occurring in an area of previously irradiated were enrolled. Patients received toripalimab 240 mg once every 3 weeks for 12 months, or combined with S-1 orally for 4–6 cycles. The primary endpoint was 1-year progression-free survival (PFS). ResultsBetween April 2019 and May 2021, 20 patients were enrolled. Sixty percent patients had ENE or positive margins, 80% were restaged as stage IV, and 80% were previously treated with chemotherapy. The 1-year PFS and overall survival (OS) were 58.2%, and 93.8%, respectively, for patients with CPS ≥ 1, which was significantly better than those of the real-world reference cohort (p = 0.001 and 0.019). No grade 4–5 toxicities were reported, and only one patient experienced grade 3 immune related adrenal insufficiency and discontinued treatment. The 1-year PFS and OS were significantly different for patients with CPS < 1, CPS 1–19 and CPS ≥ 20 (p = 0.011 and 0.017, respectively). The peripheral blood B cell proportion was also correlated with PD in 6 months (p = 0.044). ConclusionAdjuvant toripalimab or combine with S-1 after salvage surgery showed improved PFS compared with a real-world reference cohort in recurrent, previously irradiated OCC, and favorable PFS were observed in patients with a higher CPS and peripheral B cell proportion. Further randomized trials are warranted.

P17.15.A Neoadjuvant immunotherapy in the treatment of recurrent glioblastoma: an overview of last decade

Abstract Background Recurrent glioblastoma (ArGB) is one of the most common primary malignant brain tumors in adults, with a poor prognosis, with low patient survival even after treatment. Because of this, several studies were carried out evaluating different therapies for the treatment of ArGB, more recently studies have emerged regarding the use of neoadjuvant immunotherapy and its possible advantages in the treatment of such patients. Therefore, the present study aims to analyze the efficacy of neoadjuvant immunotherapy and its effect on the survival of patients with recurrent glioblastoma. Material and Methods A search was performed in PubMed, Embase and Cochrane databases using the keywords: “Immunotherapy, “neoadjuvant” and "recurrent glioblastoma". Articles from the last 10 years were selected and those that did not meet the inclusion criteria were excluded from the research, totaling 7 selected articles. Results Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy after surgery, had significantly prolonged survival compared to patients who were randomized to receive adjuvant post-surgical PD-1 blockade alone. Neoadjuvant PD-1 blockade was associated with up-regulation of T cells and interferon-γ-related gene expression, but with down-regulation of cell cycle-related gene expression within the tumor, which was not observed in patients receiving adjuvant therapy. isolated. Conclusion Neoadjuvant immunotherapy, through a PD-1 inhibitor, in patients with ArGB, results in positive biological effects, in addition to the clinical benefit of, on average, increasing overall survival considerably due in large part to the improvement of the immune response , with no noticeable adverse effects, thus being advantageous, although these results are early and the current studies are not very comprehensive. Larger studies are needed for greater reliability and statistical relevance.