Spartalizumab (PDR001) is a humanized IgG4 monoclonal antibody targeting programmed cell death protein 1 (PD-1). We conducted a single-arm, phase 2 trial to investigate the efficacy and safety of spartalizumab in patients with refractory esophageal squamous cell carcinoma (ESCC). Patients with histologically confirmed ESCC who experienced disease progression after platinum-based chemotherapy received 300 mg of intravenous spartalizumab every three weeks until disease progression or occurrence of unacceptable toxicity. The primary endpoint was centrally assessed objective response according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Adverse events were closely monitored throughout the study. From March 2020 through April 2021, 44 patients with ESCC were enrolled. Of the 44 patients, the objective response rate was 20.5% (95% confidence interval: 8.5-32.4). With a median follow-up of 10.9 months, median progression-free survival and overall survival were 3.2 months and 11.2 months, respectively. In addition, the median duration of response was 24.7 months. The most common grade 3 or 4 adverse event was grade 3 dysphagia (eight [18%] patients). Biomarker analyses explored programmed cell death ligand 1 and CD20 as potential predictive markers for PD-1 blockade. Spartalizumab showed promising activity with a manageable safety profile, indicating its potential as a new treatment option for patients with refractory ESCC.
UNASSIGNED: The trial was registered at ClinicalTrials.gov under the identifier NCT03785496.

UNASSIGNED: Blocking the colony-stimulating factor 1 (CSF-1) signal on tumor-associated macrophages can lead to an upregulation of checkpoint molecules, such as programmed cell death ligand 1 (PD-L1), thus causing resistance to this blockade. Combining spartalizumab (PDR001), a high-affinity, ligand-blocking, humanized anti-PD-1 immunoglobulin G4 antibody, with lacnotuzumab (MCS110), a high-affinity, humanized monoclonal antibody directed against human CSF-1 can potentially overcome this resistance.
UNASSIGNED: This was a multicenter, phase Ib/II trial using a combination of spartalizumab with lacnotuzumab in patients with advanced cancers, including anti-PD-1/PD-L1 treatment-resistant melanoma, and anti-PD-1/PD-L1 treatment-naïve triple-negative breast cancer, pancreatic cancer, and endometrial cancer (ClinicalTrials.gov identifier: NCT02807844). The primary objective of dose escalation phase Ib was to assess safety, tolerability, and recommended phase II dose. The primary objective of the phase II expansion study was to assess the combination\'s antitumor activity, including objective response rate and clinical benefit rate.
UNASSIGNED: A total of eight patients (five in phase Ib and three in phase II) were evaluable for adverse events (AEs) at our study site. All eight patients experienced at least grade 1 AE. The most common treatment-related AEs were increased serum aspartate aminotransferase (38%), fatigue (38%), anemia (25%), increased alkaline phosphatase (25%), hyperbilirubinemia (25%), hypocalcemia (25%), and hypoalbuminemia (25%). Most of these AEs were grade 1 or 2. None of the patients experienced grade 4 AEs and no drug-related fatal AEs were reported among the eight patients treated in the study. One (13%) patient had stable disease (SD) (captured as unknown by the study sponsor because the evaluation criteria set per protocol was not met) and three (38%) patients had progressive disease. Four (50%) patients developed clinical disease progression based on investigator evaluation. One patient with pancreatic cancer achieved immune-related SD for 26 months while on the study treatments.
UNASSIGNED: The study completed phase Ib dose escalation and phase II. However, gating criteria for efficacy were not met for expansion beyond 80 patients in phase II and the sponsor did not continue development of the combination of spartalizumab and lacnotuzumab for oncology indications. The potential signal of activity in pancreatic cancer should be further explored.

UNASSIGNED: This phase Ib/II trial evaluated the safety and efficacy of capmatinib in combination with spartalizumab or spartalizumab alone in patients with advanced hepatocellular carcinoma (HCC).
UNASSIGNED: Eligible patients who had progressed or were intolerant to sorafenib received escalating doses of capmatinib 200 mg, 300 mg, and 400 mg twice a day (bid) plus spartalizumab 300 mg every 3 weeks (q3w) in the phase Ib study. Once the recommended phase II dose (RP2D) was determined, the phase II study commenced with randomised 1:1 treatment with either capmatinib + spartalizumab (n = 32) or spartalizumab alone (n = 30). Primary endpoints were safety and tolerability (phase Ib) and investigator-assessed overall response rate per RECIST v1.1 for combination vs. single-agent arms using a Bayesian logistic regression model (phase II).
UNASSIGNED: In phase Ib, the RP2D for capmatinib in combination with spartalizumab was determined to be 400 mg bid. Dose-limiting toxicity consisting of grade 3 diarrhoea was reported in one patient at the capmatinib 400 mg bid + spartalizumab 300 mg q3w dose level. The primary endpoint in the phase II study was not met. The observed overall response rate in the capmatinib + spartalizumab arm was 9.4% vs. 10% in the spartalizumab arm. The most common any-grade treatment-related adverse events (TRAEs, ≥20%) were nausea (37.5%), asthenia and vomiting (28.1% each), diarrhoea, pyrexia, and decreased appetite (25.0% each) in the combination arm; TRAEs ≥10% were pruritus (23.3%), and rash (10.0%) in the spartalizumab-alone arm.
UNASSIGNED: Capmatinib at 400 mg bid plus spartalizumab 300 mg q3w was established as the RP2D, with manageable toxicities and no significant safety signals, but the combination did not show superior clinical activity compared with spartalizumab single-agent treatment in patients with advanced HCC who had previously been treated with sorafenib.
UNASSIGNED: Simultaneous targeting of MET and programmed cell death protein 1 may provide synergistic clinical benefit in patients with advanced HCC. This is the first trial to report a combination of capmatinib (MET inhibitor) and spartalizumab (programmed cell death protein 1 inhibitor) as second-line treatment after sorafenib for advanced HCC. The combination did not show superior clinical activity compared with spartalizumab single-agent treatment in patients with advanced HCC who had previously been treated with sorafenib. The results indicate that there is a clear need to identify a reliable predictive marker of response for HCC and to identify patients with HCC that would benefit from the combination of checkpoint inhibitor +/- targeted therapy.
UNASSIGNED: NCT02795429.

Ieramilimab, a humanized anti-LAG-3 monoclonal antibody, was well tolerated in combination with the anti-PD-1 antibody spartalizumab in a phase 1 study. This phase 2 study aimed to further investigate the efficacy and safety of combination treatment in patients with selected advanced (locally advanced or metastatic) solid malignancies. Eligible patients with non-small cell lung cancer (NSCLC), melanoma, renal cell carcinoma (RCC), mesothelioma, and triple-negative breast cancer (TNBC) were grouped depending on prior anti-PD-1/L1 therapy (anti-PD-1/L1 naive or anti-PD-1/L1 pretreated). Patients received ieramilimab (400 mg) followed by spartalizumab (300 mg) every 3 weeks. The primary endpoint was objective response rate (ORR), along with safety, pharmacokinetics, and biomarker assessments. Of 235 patients, 142 were naive to anti-PD-1/L1 and 93 were pretreated with anti-PD-1/L1 antibodies. Durable responses (>24 months) were seen across all indications for patients naive to anti-PD-1/L1 and in melanoma and RCC patients pretreated with anti-PD1/L1. The most frequent study drug-related AEs were pruritus (15.5%), fatigue (10.6%), and rash (10.6%) in patients naive to anti-PD-1/L1 and fatigue (18.3%), rash (14.0%), and nausea (10.8%) in anti-PD-1/L1 pretreated patients. Biomarker assessment indicated higher expression of T-cell-inflamed gene signature at baseline among responding patients. Response to treatment was durable (>24 months) in some patients across all enrolled indications, and safety findings were in accordance with previous and current studies exploring LAG-3/PD-1 blockade.

BACKGROUND: We investigated naporafenib (LXH254), a pan-RAF kinase inhibitor, with or without spartalizumab, in patients with advanced solid tumors harboring MAPK pathway alterations.
METHODS: This first-in-human phase 1 study had two dose-escalation arms: single-agent naporafenib (starting at 100 mg once-daily [QD]) and naporafenib (starting at the recommended dose/regimen)/spartalizumab (400 mg every 4 weeks). The naporafenib/spartalizumab dose-expansion part enrolled patients with KRAS-mutated non-small cell lung cancer (NSCLC) and NRAS-mutated melanoma. The primary objectives were to establish the maximum tolerated doses (MTD)/recommended doses for expansion (RDE) and evaluate tolerability and safety.
RESULTS: A total of 142 patients were included in the naporafenib dose-escalation (n = 87), naporafenib/spartalizumab dose-escalation (n = 12) and naporafenib/spartalizumab dose-expansion (n = 43) arms. The MTD/RDE of naporafenib was 600 mg twice-daily (BID). In naporafenib escalation, five patients experienced 7 dose-limiting toxicities: decreased platelet count (1200 mg QD); neuralgia, maculopapular rash, pruritus (600 mg BID); increased blood bilirubin, hyponatremia, peripheral sensory neuropathy (800 mg BID). No DLTs occurred in the naporafenib/spartalizumab arm: the RDE was established at 400 mg BID. The most common treatment-related adverse events were rash and dermatitis acneiform (each 24.1%; naporafenib), nausea and pruritus (each 33.3%; naporafenib/spartalizumab; escalation) and rash (39.5%; naporafenib/spartalizumab; expansion). Naporafenib reduced DUSP6 expression in tumors. Two partial responses (PRs) occurred in naporafenib escalation, and 1 complete response and 3 PRs in the naporafenib/spartalizumab NRAS-mutated melanoma and KRAS-mutated NSCLC arms, respectively.
CONCLUSIONS: Naporafenib, with or without spartalizumab, showed an acceptable safety profile, pharmacodynamic activity and limited antitumor activity. Additional naporafenib combination therapies are currently under investigation.

Improved selection of cancer patients who are most likely to respond to immune checkpoint inhibitors remains an unmet clinical need. Recently, a positive correlation between levels of PD1 mRNA and clinical outcome in response to PD1 blockade across diverse tumor histologies has been confirmed in several datasets. ACROPOLI is a parallel cohort, non-randomized, phase II study that aims to evaluate the efficacy of the anti-PD1 immune checkpoint inhibitor spartalizumab as monotherapy in metastatic patients with solid tumors that express high levels of PD1 (cohort 1; n = 111). An additional cohort of 30 patients with tumors expressing low levels of PD1, where PD1/PD-L1 antibodies in monotherapy are standard treatment, will also be included (cohort 2). Primary end point is overall response rate in cohort 1. Trial registration number: NCT04802876 (ClinicalTrials.gov).

BACKGROUND: Perioperative chemotherapy and surgery are a standard of care for patients with resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma. However, the prognosis remains poor for this population. The FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) regimen is considered as the new standard chemotherapy regimen for perioperative strategy, despite associated with a 5-year overall survival rate (OS) amounting 45% following radical surgery. Immunotherapy with antibodies that inhibit PD-1/ PD-L1 interaction has recently emerged as a new treatment option with promising and encouraging early trial results for patients with advanced or metastatic gastric or GEJ adenocarcinoma. Currently, no trials have investigated the impact of perioperative immunotherapy in combination with chemotherapy for resectable gastric or GEJ adenocarcinoma.
METHODS: GASPAR trial is a multicenter open-label, nonrandomized, phase II trial to evaluate the efficacy and safety of Spartalizumab in combination with the FLOT regimen as perioperative treatment for resectable gastric or GEJ adenocarcinoma. The main endpoint is the proportion of patients with pathological complete regression (pCR) in the primary tumour after preoperative treatment. Systemic treatment will include a pre-operative neoadjuvant and a post-operative adjuvant treatment, during which FLOT regimen will be administered every two weeks for 4 cycles and Spartalizumab every four weeks for 2 cycles. For patients with confirmed tumor resectability on imaging assessment, surgery will be realized within 4-6 weeks after the last dose of preoperative chemotherapy. Post-operative systemic treatment will then be initiated within 4-10 weeks after surgery. Using a Simon\'s two-stage design, up to 67 patients will be enrolled, including 23 in the first stage.
CONCLUSIONS: Currently, no trials have investigated the impact of immunotherapy in combination with FLOT chemotherapy as perioperative treatment for resectable gastric or GEJ adenocarcinoma. Some studies have suggested a change in the tumor immune micro-environment following neoadjuvant chemotherapy in this setting, reinforcing the relevance to propose a phase II trial evaluating efficacy and safety of Spartalizumab in combination with perioperative chemotherapy, with the aim of improving treatment efficacy and survival outcomes.
BACKGROUND: NCT04736485, registered February, 3, 2021.

Increased understanding of the interactive mechanisms between tumors and the immune system led to the development of immune checkpoint inhibitors, which have revolutioned the treatment of metastatic melanoma and subsequently many other tumors. In 2014, nivolumab and pembrolizumab, two checkpoint inhibitors binding to PD-1, were approved for the treatment of metastatic melanoma. Since then, a plethora of new molecules have enriched the armamentarium against melanoma.
This review summarizes the last updates about treatment with nivolumab and pembrolizumab, data on other PD-1/PDL-1 agents such as spartalizumab and atezolizumab and emerging compounds, new combinations with NKTR-214, anti LAG-3, anti IDO-1 and TVEC, new checkpoint inhibitors (e.g. TIM-3 or TIGIT) and other new molecules for the treatment of metastatic melanoma.
Currently, several ongoing clinical trials are investigating novel molecules, or immunotherapy combinations, in order to achieve even better survival outcomes for patients, overcoming resistance mechanisms and improving toxicity profiles. The challenge in the near future will be to select the most appropriate treatments according to the specific characteristics of the patients.

Introduction: As of today, one of the cornerstones of NSCLC treatment is represented by Immune Checkpoint Inhibitors (ICI) treatment in the form of anti-PD-1/PD-L1 monoclonal antibodies. However, apart from currently approved, recommended and employed agents (nivolumab, pembrolizumab, atezolizumab, durvalumab), several new agents are currently under development and investigation both in monotherapy and in combinational settings.Areas covered: This paper aims to discuss both the current state of the art and the most interesting emerging PD-1 and PD-L1 inhibitors and their present and future role in metastatic NSCLC treatment.Expert opinion: Great scientific interest lies in combinational settings, involving both already developed FDA and EMA approved and not approved agents and anti-PD-1 and PD-L1 inhibitors, that will certainly provide data about pharmacodynamic and clinical properties of these associations, enhancing our understanding of ICIs and cancer immunotherapy. Moreover, new potential predictive biomarkers are much needed, especially considering the less decisive role of PD-L1 in treatment algorithms involving chemo-immune combinations and the current lack of other validated predictive biomarkers.