SAFFRON-103: a phase Ib study of sitravatinib plus tislelizumab in anti-PD-(L)1 refractory/resistant advanced melanoma

An estimated 324,635 new cases of melanoma occurred globally in 2020, with incidence rates highest in Australia and New Zealand, followed by Europe and North America [1]. Despite advances in treatment, there were an estimated 57,043 deaths attributed to melanoma worldwide in 2020 [1].

Immune checkpoint inhibitors (ICIs) have altered the treatment landscape of melanoma with remarkable improvements in clinical outcomes for patients [2,3]. Consequently, ICIs are now the established standard of care for patients with unresectable and metastatic melanoma in the first-line setting [4,5]. Approved by the US Food and Drug Administration (FDA) in 2011, ipilimumab is a monoclonal antibody that activates the immune system by targeting cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) [6,7]. Ipilimumab was the first immunotherapy to demonstrate a survival improvement in metastatic melanoma [7,8]. Subsequently anti-programmed cell death protein 1 (PD-1) antibodies, pembrolizumab and nivolumab, showed superiority over ipilimumab, and both were approved for first-line treatment of melanoma [1,9–12]. Combination of anti-CTLA-4 and anti-PD-1 antibodies has been shown to further enhance efficacy [5,9]. Furthermore, the combination of a new ICI, the lymphocyte-activation gene 3 inhibitor relatlimab, with nivolumab has recently been approved by the FDA for treatment of unresectable or metastatic melanoma [13].

Despite the clinical benefits associated with immunotherapy, a subset of patients either do not respond, or initially respond but later relapse and develop drug resistance, and there is still no standard of care for patients with anti-PD-1 resistant melanoma [4,14]. Therefore, there is a need to develop new treatment approaches for metastatic melanoma. A key investigational strategy of interest is the combination of anti-PD-1 or anti-programmed death-ligand 1 (PD-L1) immunotherapies with other agents that exhibit immunomodulatory and antitumor properties, which may enhance antitumor activity and reduce resistance compared with either agent alone [5].

Another combination under consideration is that of sitravatinib and anti-PD-1 therapy, which has demonstrated promising results in non-small-cell lung cancer (NSCLC) [15,16] and is currently being investigated in phase I or II clinical trials in advanced or metastatic kidney cancer and urothelial carcinoma, advanced biliary tract cancer, and recurrent endometrial cancer or other solid tumors with deficient mismatch repair system [17,18].

Sitravatinib (MGCD516), an orally available spectrum-selective tyrosine kinase inhibitor (TKI), targets both TAM family receptors (TYRO3, AXL, MERTK) and split kinase-family domain-containing receptors (including VEGFR and PDGFR families and KIT), plus RET and MET [19,20]. TAM receptor tyrosine kinases are important for immune system homeostasis, particularly in regulating efferocytosis (clearance of dying cells) and suppressing inflammation [21]. TAM receptor signaling has been implicated in melanoma pathogenesis, particularly via TYRO3, a regulator of tumor survival and proliferation in malignant melanoma [21]. Furthermore, AXL has been shown to be enriched in anti-PD-1 resistant melanoma tumors [21]. Targeting these receptors encourages an antitumor immune microenvironment by influencing the phenotype of macrophages, promoting their immunostimulatory properties [19,21]. Additionally, targeting VEGFR and KIT results in a decrease in the number of regulatory T cells and monocytic myeloid-derived suppressor cells (MDSCs), reducing immunosuppression [22,23]. This immunosuppressive environment enhances the antitumor activity of PD-L1 inhibition [19,22]. In addition to targeting innate immune cell types, sitravatinib targets genetically altered oncogenic drivers [20]. The hepatocyte growth factor (HGF/MET) pathway plays a central role in melanoma pathogenesis, and by targeting this pathway, therapeutic resistance can potentially be overcome [24]. Sitravatinib has demonstrated potent in vivo antitumor activity in mice, and enhanced the efficacy of PD-1 inhibition [19]. Preliminary antitumor activity of sitravatinib has been reported in solid tumor phase I/II studies, as monotherapy, and in combination with the anti-PD-1 antibody tislelizumab [20,25].

Tislelizumab is a humanized anti-PD-1 antibody with strong affinity for PD-1. It targets different binding epitopes and exhibits a more complete blockade of PD-L1 binding to PD-1 compared with alternative PD-1 antibodies, such as nivolumab and pembrolizumab [26]. Tislelizumab monotherapy was initially shown to have antitumor activity in a phase II study of Chinese patients with advanced solid tumors (almost all of whom had received at least one prior anticancer drug therapy), including 34 with melanoma, in whom the objective response rate (ORR) was 15% (all partial responses [PR]) [27]. By comparison, a study of second-line pembrolizumab treatment in Chinese patients with advanced or metastatic melanoma reported a similar ORR of 17.6% (17 of 18 responses were PRs) [28].

The present phase Ib study was designed to better elucidate the safety and tolerability of sitravatinib when used in combination with tislelizumab, and to provide a preliminary analysis of the antitumor activity of this combination. The current report focuses on the results of sitravatinib plus tislelizumab combination therapy in a cohort of patients with anti-PD-1/PD-L1 antibody refractory or resistant, unresectable, or metastatic melanoma.

Materials & methods

Study design

SAFFRON-103 was an open-label, multicenter, multicohort, single-arm, nonrandomized phase Ib clinical trial conducted at 17 sites in Australia and China (Clinicaltrials.gov identifier NCT03666143), with four sites contributing melanoma patients. The protocol was approved by the relevant Institutional Review Board/Independent Ethics Committee for each study site. The full protocol is available in the supplementary material. The study was conducted in conformance with the International Conference on Harmonization E6 guideline for Good Clinical Practice and the principles of the Declaration of Helsinki, and all applicable local laws and regulations. All patients were required to provide written informed consent prior to participation in the study. Patients were not involved in the design or oversight of the study.

Participants

The study enrolled nine cohorts of patients (N = 216) with various advanced solid tumors, including a cohort of patients with melanoma (Supplementary Figure 1). All patients in the melanoma cohort (n = 25) were required to be aged ≥18 years with histologically or cytologically confirmed anti-PD-1/PD-L1 antibody refractory or resistant unresectable or metastatic melanoma (not including ocular melanoma) with at least one measurable lesion (as defined by Response Evaluation Criteria in Solid Tumors [RECIST] v1.1), have experienced radiographic disease progression per RECIST v1.1 on or after the immediate prior first-line anti-PD-1/PD-L1 monotherapy, have an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤1, have no prior exposure to anti-VEGF or VEGFR TKIs, have not previously received any other immunotherapies (including, but not limited to, anti-CTLA-4, anti-OX40 and anti-CD137 therapies), and have documented BRAF status. Patients with BRAF wild-type, or BRAF mutation but who were not suitable for or refused BRAF inhibitor and/or MEK inhibitor targeted therapy were eligible. Patients with a BRAF mutation who had received prior BRAF inhibitor and/or MEK inhibitor targeted therapy in the metastatic setting were excluded. Full eligibility criteria are provided in the supplementary material. Eligible patients were categorized according to melanoma subtype: cutaneous, acral or mucosal.

Interventions

All patients received sitravatinib 120 mg orally once daily plus tislelizumab 200 mg intravenously every 3 weeks until withdrawal, disease progression, unacceptable toxicity or death. Tislelizumab was initially administered as a 60-min infusion. Subsequent infusions could be administered over 30 min if the initial infusion was well tolerated. No dose reductions were permitted for tislelizumab. If significant toxicities occurred, sitravatinib could be administered at a reduced dose of 80 mg or 60 mg once daily. Re-escalation was not recommended but evaluated on a case-by-case basis. In the case of both tislelizumab and sitravatinib, treatment could be temporarily delayed if necessary for suspected drug-related toxicities (for up to 28 days for sitravatinib and up to 12 weeks for tislelizumab). Resumption of therapy was recommended as soon as possible after recovery of the adverse event (AE) to baseline or grade 1.

Treatment beyond disease progression (as assessed by investigator) was permitted in cases of suspected pseudo-progression until repeat imaging could confirm progressive disease (PD) at least 4 weeks later, but not exceeding 8 weeks from the date of initial documentation of PD. Patients with suspected pseudo-progression must have no clinical signs of PD, ECOG PS ≤1, absence of rapid PD or of progressive tumor at critical anatomical sites that requires urgent alternative medical intervention, and give written consent to continue the study drug.

Endpoints and assessments

The primary endpoint was safety and tolerability, assessed throughout the study by monitoring AEs and serious AEs (per National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 [NCI CTCAE v5.0]), relevant physical examination, electrocardiograms, and laboratory assessments as needed. AEs were coded to Medical Dictionary for Regulatory Activities (MedDRA) version 25.0, with severity graded according to the NCI CTCAE v5.0. Treatment-emergent adverse events (TEAEs) were defined as those with an onset date (or a worsening in severity from baseline) on or after the first dose of study drug and up to 30 days following study drug discontinuation (any component of combination treatment, whichever was administered last) or initiation of the first new systemic anticancer therapy after the last study treatment, whichever occurred first, or up to 90 days after the last dose of tislelizumab for potential immune-mediated AEs (imAEs), regardless of whether a new anticancer therapy was initiated. Potential imAEs were identified according to a predefined list, developed by the sponsor, of MedDRA preferred terms (based on the established potential imAEs of tislelizumab and other anti-PD-1 antibodies), irrespective of whether the events were considered by investigators to be treatment-related.

Secondary efficacy endpoints comprised the following evaluations, per RECIST 1.1: ORR, defined as the proportion of patients achieving confirmed or unconfirmed complete response (CR) or PR; disease control rate (DCR), defined as the proportion of patients with a best overall response of CR, PR, or stable disease; progression-free survival (PFS), defined as the time from date of first dose of study drugs to the date of the first documentation of PD or death, whichever occurred first; duration of response (DoR), which was assessed among responders (CR or PR) and defined as the time interval between the date of the earliest qualifying response and the date of PD or death, whichever occurred first. Overall survival (OS) was an exploratory end point and was defined as the time from the date of first dose of study drugs to the date of death due to any cause. Further secondary and exploratory end points included pharmacokinetics, pharmacodynamics and biomarker analysis, results of which are not included in this report.

Tumor assessments were performed using computed tomography scans (preferred) or magnetic resonance imaging of the chest, abdomen, and pelvis, together with any other known or suspected sites of disease. Imaging was performed every 6 weeks (±7 days) during the first 12 months of the study, and every 9 weeks (±7 days) thereafter.

Statistical analyses

The study was planned to enroll 220–240 patients, including approximately 20 patients in the melanoma cohort. Safety analyses were evaluated in all patients who received ≥1 dose of either study drug (safety analysis set). Results were summarized using descriptive statistics.

Tumor responses were evaluated in the efficacy evaluable analysis set. This included all patients who received ≥1 dose of either study drug who had measurable disease at baseline (per RECIST v1.1) and had ≥1 evaluable post-baseline tumor assessment, unless treatment was discontinued due to disease progression or death before tumor assessment. Time-to-event efficacy analyses used the safety analysis set.

ORR and DCR are reported with Clopper-Pearson 2-sided 95% confidence intervals (CIs). Median PFS, DoR, and OS were estimated using Kaplan-Meier methodology, with 95% CIs estimated using the Brookmeyer and Crowley method. Event-free rates for each outcome were estimated at various timepoints using Kaplan-Meier methodology, with 95% CIs estimated using the Greenwood's formula.

Results

Patients & treatment

In total, 32 patients with melanoma were screened and 25 patients were enrolled to the melanoma cohort between 6 September 2019 and 28 August 28 2020 (Supplementary Figure 2). As of the data cutoff date (March 31, 2022), 20.0% patients were still receiving treatment, including one patient receiving tislelizumab monotherapy and four patients receiving sitravatinib plus tislelizumab combination therapy (Supplementary Figure 2). In total, 60.0% of patients discontinued from the study, most commonly due to death from PD, which had occurred in 86.7% of patients (Supplementary Figure 2). The median study follow-up time was 19.3 months (range: 5.6–30.8) (Supplementary Figure 2).

Patient demographics and baseline characteristics are shown in Table 1. Among all patients with melanoma, the median age was 51.0 years (range: 23–79 years), 52.0% of patients were male, and 92.0% were Asian. All patients except one (96.0%) had metastatic disease at study entry (Table 1); however, no patients had brain metastases. All patients in the melanoma cohort had American Joint Committee on Cancer stage ≥IIA or unknown stage at initial melanoma diagnosis. The majority of patients (68%) had tumor nodes and metastases stage M0 at initial diagnosis (further details regarding stage at initial diagnosis are reported in Supplementary Table 1). By histology at initial diagnosis, 48.0%, 28.0%, and 16.0% of patients had cutaneous, acral, and mucosal melanoma, respectively (8.0% had unknown histology) (Table 1).

All 25 enrolled patients received ≥1 dose of sitravatinib plus tislelizumab (Supplementary Figure 2) and were included in the safety analysis set. The median duration of sitravatinib exposure was 30.0 weeks (range: 3.0–136.1 weeks) (Supplementary Table 2). The mean relative dose intensity of sitravatinib was 76.8% (standard deviation [Std Dev]: 25.3). The median duration of tislelizumab exposure was 30.0 weeks (range: 3.0–134.9 weeks), with a mean relative dose intensity of 91.2% (SD: 12.1) and a median of 10.0 cycles were received (range: 1–38 cycles) (Supplementary Table 2).

Safety & tolerability

Among the total melanoma population, TEAEs were reported in 100.0% of patients (Table 2). The most common TEAEs were weight decreased in 80.0% of patients, alanine aminotransferase (ALT) increased in 76.0% of patients and aspartate aminotransferase (AST) increased in 76.0% of patients (Table 2). TEAEs of grade 3 or higher were reported in 52.0% of patients, with hypertension (16.0%), gamma-glutamyltransferase increased (12.0%), and ALT increased (12.0%) the most commonly reported ≥grade 3 TEAEs (Table 2). Serious TEAEs were reported in four (16.0%) patients (Table 2); adrenal insufficiency, anal abscess, cholelithiasis, gastric ulcer, and hypophysitis were recorded in one patient (4.0%) each. No TEAEs leading to death were reported (Table 2). TEAEs leading to discontinuation were reported in three (12.0%) patients; these were gastric ulcer, blood creatine phosphokinase increased, and vaginal hemorrhage occurring in one patient (4.0%) each. TEAEs led to dose modification in 72.0% of patients for sitravatinib (including dose reduction or dose interruption), and to dose modification in 40.0% of patients for tislelizumab (all tislelizumab dose modifications were dose delays; there were no infusion interruptions) (Table 2).

Among the total melanoma population, treatment-related AEs (TRAEs) were reported in 100.0% of patients. The most common TRAEs were ALT increased in 76.0% of patients, AST increased in 76.0% of patients, and hypothyroidism in 60.0% of patients (Table 2). TRAEs of grade 3 or higher were reported in 40.0% of patients, with hypertension (16.0%) and ALT increased (12.0%) the most commonly reported ≥grade 3 events (Table 2). Serious TRAEs were reported in four (16.0%) patients; adrenal insufficiency, anal abscess, cholelithiasis, gastric ulcer, and hypophysitis were recorded in one patient (4.0%) each. There were no TRAEs leading to death.

Potential imAEs (as per the predefined list of MedDRA preferred terms, and irrespective of investigator-assessed treatment relationship) were reported in 18 (72.0%) patients with melanoma. The most commonly reported imAEs categories were immune-mediated hypothyroidism (15 patients; 60%), immune-mediated hepatitis (five patients; 20%), immune-mediated hyperthyroidism (five patients; 20%) and immune-mediated type 1 diabetes mellitus (five patients; 20% [all were cases of hyperglycemia]). The most frequent potential imAEs by preferred term were hypothyroidism (15 patients; 60%), hyperthyroidism (five patients; 20%), and hyperglycemia (five patients; 20%) (Supplementary Table 3).

Efficacy: tumor response

In total, 25 patients were included in the efficacy evaluable analysis set. ORR in the melanoma cohort was 36.0% (95% CI: 18.0–57.5) (Table 3). Analysis by sub-histology types showed the ORRs for cutaneous, acral, and mucosal melanoma were 50.0% (95% CI: 21.1–78.9), 42.9% (95% CI: 9.9–81.6), and 0% (95% CI: 0–60.2), respectively (Table 3). Eight patients achieved PR, and one patient with cutaneous melanoma achieved CR (Table 3, Figure 1A & B). Disease control was achieved in the majority of patients (88.0%) (Table 3). Three (12.0%) patients had a best overall response of PD (Table 3 & Figure 1A). Among responders, the median DoR was not reached (95% CI: 2.8–not estimable).

Efficacy: PFS & OS

Patients had median PFS of 6.7 months (95% CI: 4.1–not estimable) (Figure 2A), and median OS of 22.9 months (95% CI: 15.6–not estimable) (Figure 2B). Median PFS in patients with acral subtype of melanoma was 19.2 months (95% CI: 4.1–not estimable) and median OS was not reached (95% CI: 11.5–not estimable). In patients who had cutaneous subtype of melanoma the median PFS was not reached (95% CI: 2.7–not estimable) and median OS was 28.7 months (95% CI: 7.4–not estimable). Patients with mucosal melanoma subtype had a median PFS of 3.5 months (95% CI: 1.4–5.8) and a median OS of 11.6 months (95% CI: 5.6–17.4).

Discussion

In this study, the combination of sitravatinib and tislelizumab had a manageable safety profile, together with preliminary demonstration of antitumor activity, in patients with anti-PD-1/PD-L1 antibody refractory or resistant unresectable or metastatic melanoma. When added to the encouraging data reported in the NSCLC cohorts of the SAFFRON-103 study [16,29,30], these data from the melanoma cohort are also encouraging, and highlight combination sitravatinib plus tislelizumab therapy as a potentially useful treatment option for patients with anti-PD-1/PD-L1 antibody refractory or resistant unresectable or metastatic melanoma.

No new safety signals were identified, and the overall safety profile of the combination treatment was in line with that known for anti-PD-1/PD-L1 and multi-targeted TKI monotherapies [31,32]. Most TEAEs were mild or moderate in severity and manageable, and no TEAEs led to death. The most common TEAEs ≥grade 3 were hypertension (16.0% of patients), ALT increased (12.0%), and gamma-glutamyltransferase increased (12.0%). Serious TEAEs were reported in 16.0% of patients. TRAEs most commonly reported in the study were increased ALT and increased AST (both in 76.0% of patients).

Hepatic toxicities are associated with anti-PD-1/PD-L1 therapies, where they commonly occur at grade 3 or higher [31]. Similarly, hypertension is an AE commonly associated with VEGF inhibitors [33]. In the SAFFRON-103 melanoma cohort neither of the most common ≥grade 3 TRAEs, ALT increased, or hypertension led to treatment discontinuation. The most common TEAEs that led to treatment discontinuation were gastric ulcer, blood creatine phosphokinase increased, and vaginal haemorrhage (all occurring in 4% of patients). Identification of potential imAEs was carried out using a group of predefined MedDRA preferred terms based on the known imAEs associated with tislelizumab and other anti-PD-1 agents, and thus provided a comprehensive collation of potential imAEs. It should be noted that immune-mediated hypothyroidism and Type 1 diabetes mellitus were more frequently reported in this study than in previous studies of other anti-PD-(L)1 therapies [31]. However, the approach had limitations, as the incidences reported do not account for the nature of the events or whether the events were thought to be treatment-related by the investigators, and should therefore be interpreted cautiously. Overall, the safety profile of sitravatinib plus tislelizumab observed here in patients with melanoma was consistent with that observed in other cancer types, including ovarian [34], hepatocellular carcinoma [35], NSCLC [16,29,30], and gastric/gastroesophageal cancer [36].

In the current study, preliminary antitumor activity of sitravatinib and tislelizumab was demonstrated in patients with PD-1 resistant or refractory unresectable or metastatic melanoma, with an ORR of 36.0% (95% CI: 18.0–57.5), adding to the clinical evidence supporting the rationale for combining anti-PD-1/PD-L1 with multi-targeted TKI therapies in this setting. While cross-trial comparisons are confounded by differences in study design, patient characteristics, sample size, etc., the meaningful and durable responses shown here in SAFFRON-103 are encouraging, and complement results of the phase II LEAP-004 study of pembrolizumab plus lenvatinib in patients with unresectable stage III–IV melanoma whose disease progressed after anti-PD-1/PD-L1-based therapy (either alone or combined with other therapies, including anti-CTLA-4 therapy) [37]. In LEAP-004, ORRs were 21.4% in the overall study population and 33.3% among the subgroup of patients with PD on prior anti-PD-1 plus anti-CTLA-4 combination therapy [37]. In the subgroup of patients in LEAP-004 who had experienced PD on anti-PD-1/PD-L1-based therapy without anti-CTLA-4 therapy (i.e., a subgroup more akin to the melanoma cohort in SAFFRON-103), the ORR was 16.4% [37]. The SAFFRON-103 melanoma cohort and LEAP-004 study are therefore consistent in demonstrating that combining anti-PD-1/PD-L1 and multi-targeted TKIs can induce meaningful responses in patients with refractory/resistant melanoma after prior anti-PD-1/PD-L1 therapy. Collectively these data support the need for further investigation of anti-PD-1/PD-L1 plus multi-targeted TKI combination treatment, particularly for patients with anti-PD-1/PD-L1 (±anti-CTLA-4) refractory/resistant disease, for whom there remains an unmet therapeutic need [14].

A potential alternative approach for patients with refractory/resistant disease following anti-PD-1/PD-L1 monotherapy could be the use of anti-CTLA-4 therapies, alone or in combination with anti-PD-1/PD-L1 therapies. In a retrospective cohort study of 355 patients with metastatic melanoma resistant to anti-PD-1 monotherapy, ORRs were 13% with ipilimumab monotherapy and 31% with ipilimumab plus anti-PD-1 therapy (pembrolizumab or nivolumab) [38]. Meanwhile, a smaller prospective phase II study among 70 patients with advanced melanoma refractory to anti-PD-1/PD-L1 therapy reported an ORR of 29% with subsequent pembrolizumab plus low-dose ipilimumab combination therapy [39]. While cross-study comparisons should be interpreted cautiously, the ORR of 36% with sitravatinib plus tislelizumab in the present study compares favorably with these previous reports for anti-PD-1/PD-L1 plus anti-CTLA-4 combination therapy in this setting.

Antitumor response in SAFFRON-103 was observed in patients with cutaneous and acral subtypes of melanoma, with ORRs of 50.0% and 42.9%, respectively. There were no complete or partial responders to treatment in the mucosal melanoma subgroup. Patients with cutaneous and acral melanoma experienced increased survival benefit (median PFS: not reached [95% CI: 2.7–not estimable] and 19.2 months [95% CI: 4.1–not estimable], respectively; median OS: 28.7 months [95% CI: 7.4–not estimable] and not reached [95% CI: 11.5–not estimable], respectively) compared with the overall melanoma population (median PFS: 6.7 months [95% CI: 4.1–not estimable]; median OS: 22.9 months [95% CI: 15.6–not estimable]) and patients who had mucosal subtype of melanoma (median PFS: 3.5 months [95% CI: 1.4–5.8]; median OS: 11.6 months [95% CI: 5.6–17.4]). These findings align with previously reported data, which show that patients with mucosal melanoma typically have a shorter OS in the metastatic setting than the other melanoma subtypes, for which patients have a similar survival [40]. In the LEAP-004 trial, response and survival outcomes by melanoma subtype have not been reported [37], though given that the trial recruited mostly in Europe and North America [37], speculatively it could be assumed that the majority of patients had cutaneous melanoma, most prevalent in people of European descent, and not acral melanoma, which is more prevalent in people of African, Asian, and Latin American descent [41]. The findings in SAFFRON-103 suggest a patient with a diagnosis of acral or cutaneous melanoma may derive more benefit from treatment with a combination of sitravatinib and tislelizumab, as compared with a patient with a mucosal melanoma diagnosis; this requires confirmation in a larger cohort.

Current treatment for melanoma has focused on anti-CTLA-4 and anti-PD-1 antibodies, or combinations of these [4,5]. These ICI therapies have improved outcomes for patients, but there remain subsets of patients who relapse or develop drug resistance [14]. The combination of sitravatinib and tislelizumab provides a way to overcome resistance to anti-PD-1/PD-L1 through a combination of immunomodulatory and antitumor properties; sitravatinib promotes an immune environment that enhances the antitumor activity of PD-L1 by promoting immunostimulatory macrophage phenotypes, reducing the number of regulatory T cells and MDSCs, and targeting genetically altered oncogenic drivers [19,21–23].

There were several limitations to this study, including the fact that the sample size of the overall melanoma population was small, and smaller again when assessing outcomes in patients with melanoma subtypes. The single-arm design of the study meant that it lacked a head-to-head arm to allow for comparison of safety and efficacy against other PD-1/PD-L1 inhibitors.

Conclusion

Sitravatinib in combination with tislelizumab was generally well tolerated and had a manageable safety/tolerability profile in patients with anti-PD-1/PD-L1 refractory/resistant unresectable, advanced, or metastatic melanoma. The combination treatment presented promising antitumor activity in this population, including patients with acral and cutaneous melanoma subtypes. In summary, the results from this phase Ib study support the further investigation of sitravatinib in combination with tislelizumab in larger cohorts of patients with refractory/resistant unresectable, advanced, or metastatic melanoma.