Milhem, Mohammed M

Abstract Purpose: AXL, a receptor tyrosine kinase related to oncogenic processes, is aberrantly expressed in various cancers and associated with treatment resistance. Enapotamab vedotin (EnaV), a novel anti-AXL human IgG1 and monomethyl auristatin E antibody–drug conjugate, demonstrated antitumor activity in preclinical models, including non–small cell lung cancer (NSCLC). This phase 1/2 study assessed the safety and preliminary efficacy of EnaV in solid tumors. Patients and Methods: This study comprised dose-escalation and dose-expansion phases; both phases investigated EnaV once every 3 weeks (Q3W) and EnaV on days 1, 8, and 15 of a 28-day cycle (3Q4W). Primary objectives determined the maximum tolerated dose (dose escalation) and safety (dose expansion). Pharmacokinetic profile, antitumor activity, and AXL expression were also assessed. Results: During dose escalation, 32 patients received EnaV Q3W; 15 received EnaV 3Q4W. The maximum tolerated dose and recommended phase 2 dose were 2.2 mg/kg in Q3W and 1.0 mg/kg in 3Q4W schedules. In dose expansion, 189 patients received EnaV Q3W; 70 received EnaV 3Q4W. Common adverse events in dose expansion included fatigue, constipation, nausea, decreased appetite, and diarrhea. Overall response rates ranged from 4.5% to 12.5% with Q3W dose schedule and from 9.1% to 11.5% with 3Q4W dose schedule. Disease control rates for NSCLC cohorts were 40.9% to 50.0%. NSCLC subset analysis demonstrated correlation between radiomics signature and disease control. The relationship between clinical activity and AXL expression was not apparent. Conclusions: EnaV had an acceptable safety profile; however, because the evaluation of antitumor activity did not show clinically meaningful responses, clinical development of EnaV was discontinued. Significance: EnaV, an anti-AXL human IgG1 and monomethyl auristatin E antibody–drug conjugate, showed single-agent antitumor activity in preclinical models. This phase 1/2 study of EnaV demonstrated a manageable safety profile and antitumor activity in selected tumor types. Further studies exploring alternative targeting modalities, patient selection, and/or combinations are needed.

Background In this open-label, randomized, non-comparative, multicenter phase II study (Alliance A091401) we report on three expansion cohorts treated with nivolumab (N) with and without ipilimumab (N+I) and provide a multi-omic correlative analysis of actionable biomarkers. Methods Patients were randomized (non-comparative) to receive either N or N+I. The primary endpoint was a 6-month confirmed response rate (CRR) defined by Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints included treatment-related adverse events (TRAEs), progression-free survival, and overall survival. Multi-omic correlative analyses were conducted using samples from both the primary and expansion cohorts. Results A total of 66 patients were evaluated for the primary endpoint with disease including gastrointestinal stromal tumor (GIST, n=18), undifferentiated pleomorphic sarcoma (UPS, n=24), and dedifferentiated liposarcoma (DDLPS, n=24). Neither N nor N+I achieved a complete or partial response in the GIST expansion cohort. In DDLPS and UPS, the primary response endpoint of CRR was met with N+I (both 16.6%, 2/12) but not with N alone (both 8.3%, 1/12). In the GIST cohort, TRAE was higher with N+I treatment, halting enrollment as required per protocol. In a correlative analysis of patients for the expansion cohort and the original cohort (n=86), traditional biomarkers of immunotherapy response were not correlated with response in any histological subtype. Markers of genomic instability including the presence of gene fusions and increased subclonal mutations correlated with improved clinical outcomes. Conclusions This expansion cohort reaffirms the outcomes of A091401. There remains a pressing need to determine the role of and predictive biomarkers for immunotherapy in sarcoma. Trial registration number NCT02500797.

Talimogene laherparepvec (T-VEC) plus ipilimumab has demonstrated greater antitumor activity versus ipilimumab alone, without additional toxicity, in patients with advanced melanoma. Here, we report the 5-year outcomes from a randomized phase II study. These data provide the longest efficacy and safety follow-up for patients with melanoma treated with a combination of an oncolytic virus and a checkpoint inhibitor. Eligible patients with unresectable stage IIIB‒IV melanoma were randomized 1:1 to receive T-VEC plus ipilimumab or ipilimumab alone. T-VEC was administered intralesionally at 10 6 plaque-forming units (PFU)/mL in week 1, followed by 10 8 PFU/mL in week 4 and every 2 weeks thereafter. Ipilimumab (3 mg/kg every 3 weeks; ≤4 doses) was administered intravenously starting at week 1 in the ipilimumab arm and week 6 in the combination arm. The primary end point was investigator-assessed objective response rate (ORR) per immune-related response criteria; key secondary end points included durable response rate (DRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Overall, 198 patients were randomized to receive the combination (n=98) or ipilimumab (n=100). The combination improved the ORR versus ipilimumab (35.7% vs 16.0%; OR 2.9; 95% CI 1.5 to 5.7; p=0.003). DRR was 33.7% and 13.0% (unadjusted OR 3.4; 95% CI 1.7 to 7.0; descriptive p=0.001), respectively. Among the objective responders, the median DOR was 69.2 months (95% CI 38.5 to not estimable) with the combination and was not reached with ipilimumab. Median PFS was 13.5 months with the combination and 6.4 months with ipilimumab (HR 0.78; 95% CI 0.55 to 1.09; descriptive p=0.14). Estimated 5-year OS was 54.7% (95% CI 43.9 to 64.2) in the combination arm and 48.4% (95% CI 37.9 to 58.1) in the ipilimumab arm. Forty-seven (48.0%) and 65 (65.0%) patients in the combination and ipilimumab arms, respectively, received subsequent therapies. No new safety signals were reported. At the 5-year follow-up, the improved response rates observed with T-VEC plus ipilimumab were durable. This is the first randomized controlled study of the combination of an oncolytic virus and a checkpoint inhibitor that meets its primary end point.Trial registration number: NCT01740297 .

Abstract Purpose: Mucosal melanoma is a rare, aggressive form of melanoma with extremely high recurrence rates despite definitive surgical resection with curative intent. Currently there is no consensus on adjuvant therapy. Data on checkpoint inhibitors for adjuvant therapy are lacking. Patients and Methods: We performed a single-arm, multicenter clinical trial using “flip dose” ipilimumab (1 mg/kg q3w × 4 cycles), and nivolumab (3 mg/kg q3w × 4 cycles), then nivolumab 480 mg q4w × 11 cycles to complete a year of adjuvant therapy. Participants must have had R0/R1 resection ≤90 days before registration, no prior systemic therapy (adjuvant radiotherapy allowed), ECOG 0/1, and no uncontrolled autoimmune disease or other invasive cancer. Patients were recruited through the Midwest Melanoma Partnership/Hoosier Oncology Network. Results: From September 2017 to August 2021, 35 patients were enrolled. Of these, 29 (83%) had R0 resections, and 7 (20%) received adjuvant radiotherapy. Median age was 67 years, 21 (60.0%) female. Recurrence-free survival (RFS) rates at 1 and 2 years were 50% [95% confidence interval (CI), 31%–66%] and 37% (95% CI, 19%–55%), respectively. Overall survival rates at 1 and 2 years were 87% (95% CI, 68%–95%) and 68% (95% CI, 46%–83%), respectively. Median RFS was 10.3 months (95% CI, 5.7–25.8). Most common grade 3 toxicities were diarrhea (14%), hypertension (14%), and hyponatremia (11%), with no grade 4/5 toxicities. Conclusions: Flip-dose ipilimumab and nivolumab after resection of mucosal melanoma is associated with outcomes improved over that of surgical resection alone. Long-term follow-up, subgroup analyses and correlative studies are ongoing.

The treatment of sarcoma necessitates a collaborative approach, given its rarity and complex management. At a single institution, multidisciplinary teams of specialists determine and execute treatment plans involving surgical, radiation, and medical management. Treatment guidelines for systemic therapies in advanced or nonresectable soft tissue sarcoma have advanced in recent years as new immunotherapies and targeted therapies become available. Collaboration between institutions is necessary to facilitate accrual to clinical trials. Here, we describe the success of the Midwest Sarcoma Trials Partnership (MWSTP) in creating a network encompassing large academic centers and local community sites. We propose a new model utilizing online platforms to expand the reach of clinical expertise for the treatment of advanced soft tissue sarcoma.

Background Most patients with advanced melanomas relapse after checkpoint blockade therapy. Thus, immunotherapies are needed that can be applied safely early, in the adjuvant setting. Seviprotimut-L is a vaccine containing human melanoma antigens, plus alum. To assess the efficacy of seviprotimut-L, the Melanoma Antigen Vaccine Immunotherapy Study (MAVIS) was initiated as a three-part multicenter, double-blind, placebo-controlled phase III trial. Results from part B1 are reported here. Methods Patients with AJCC V.7 stage IIB-III cutaneous melanoma after resection were randomized 2:1, with stage stratification (IIB/C, IIIA, IIIB/C), to seviprotimut-L 40 mcg or placebo. Recurrence-free survival (RFS) was the primary endpoint. For an hypothesized HR of 0.625, one-sided alpha of 0.10, and power 80%, target enrollment was 325 patients. Results For randomized patients (n=347), arms were well-balanced, and treatment-emergent adverse events were similar for seviprotimut-L and placebo. For the primary intent-to-treat endpoint of RFS, the estimated HR was 0.881 (95% CI: 0.629 to 1.233), with stratified logrank p=0.46. However, estimated HRs were not uniform over the stage randomized strata, with HRs (95% CIs) for stages IIB/IIC, IIIA, IIIB/IIIC of 0.67 (95% CI: 0.37 to 1.19), 0.72 (95% CI: 0.35 to 1.50), and 1.19 (95% CI: 0.72 to 1.97), respectively. In the stage IIB/IIC stratum, the effect on RFS was greatest for patients <60 years old (HR=0.324 (95% CI: 0.121 to 0.864)) and those with ulcerated primary melanomas (HR=0.493 (95% CI: 0.255 to 0.952)). Conclusions Seviprotimut-L is very well tolerated. Exploratory efficacy model estimation supports further study in stage IIB/IIC patients, especially younger patients and those with ulcerated melanomas. Trial registration number NCT01546571.

Background The indoleamine 2,3-dioxygenase (IDO) pathway is a key counter-regulatory mechanism that, in cancer, is exploited by tumors to evade antitumor immunity. Indoximod is a small-molecule IDO pathway inhibitor that reverses the immunosuppressive effects of low tryptophan (Trp) and high kynurenine (Kyn) that result from IDO activity. In this study, indoximod was used in combination with a checkpoint inhibitor (CPI) pembrolizumab for the treatment for advanced melanoma. Methods Patients with advanced melanoma were enrolled in a single-arm phase II clinical trial evaluating the addition of indoximod to standard of care CPI approved for melanoma. Investigators administered their choice of CPI including pembrolizumab (P), nivolumab (N), or ipilimumab (I). Indoximod was administered continuously (1200 mg orally two times per day), with concurrent CPI dosed per US Food and Drug Administration (FDA)-approved label. Results Between July 2014 and July 2017, 131 patients were enrolled. (P) was used more frequently (n=114, 87%) per investigator’s choice. The efficacy evaluable population consisted of 89 patients from the phase II cohort with non-ocular melanoma who received indoximod combined with (P). The objective response rate (ORR) for the evaluable population was 51% with confirmed complete response of 20% and disease control rate of 70%. Median progression-free survival was 12.4 months (95% CI 6.4 to 24.9). The ORR for Programmed Death-Ligand 1 (PD-L1)-positive patients was 70% compared with 46% for PD-L1-negative patients. The combination was well tolerated, and side effects were similar to what was expected from single agent (P). Conclusion In this study, the combination of indoximod and (P) was well tolerated and showed antitumor efficacy that is worth further evaluation in selected patients with advanced melanoma.

Although checkpoint inhibitors have been approved in multiple cancers, they are still under investigation in soft tissue sarcoma (STS). We conducted a retrospective review to report the safety, efficacy, and prognostic factors related to checkpoint inhibitors in STS. A sequential cohort of metastatic STS patients from four institutions treated with checkpoint inhibitors was assembled. Logistic and Cox regression models were applied to determine the effect of patient characteristics, prior treatment, and baseline factors on achieving the best overall response of complete response (CR), partial response (PR), or stable disease (SD) as determined by the treating physician. Eighty-eight patients with two median prior therapies received checkpoint inhibitors. Treatments included pembrolizumab in 47, nivolumab in 6, ipilimumab in 1, combination ipilimumab/nivolumab in 27, and other combination immunotherapies in 7 patients. Immunotherapy was discontinued in 54 patients—72.2% for progression, 16.7% for toxicity, and 11.1% for other reasons. Median progression-free survival (PFS) was 4.1 months and median overall survival was 19.1 months. One patient with undifferentiated pleomorphic sarcoma (UPS) achieved a CR, while 20 patients had a PR, including 7 UPS, 9 leiomyosarcoma (LMS), and 1 each with alveolar soft part sarcoma, fibroblastic sarcoma, sclerosing epithelioid fibrosarcoma, and myxofibrosarcoma. Forty-five percent (9 of 20) of LMS patients achieved a PR. Twenty-eight patients had SD. Our results confirm the activity and safety of anti-PD-1 therapy in metastatic STS. A notable response rate was observed in UPS and LMS subtypes. This study expands the knowledge base beyond what is currently available from clinical trials involving checkpoint inhibitors in metastatic STS.

Purpose. Osteosarcoma is a rare cancer and a third of patients who have completed primary treatment will develop osteosarcoma recurrence. The Src pathway has been implicated in the metastatic behavior of osteosarcoma; about 95% of samples examined express Src or have evidence of downstream activation of this pathway. Saracatinib (AZD0530) is a potent and selective Src kinase inhibitor that was evaluated in adults in Phase 1 studies. The primary goal of this study was to determine if treatment with saracatinib could increase progression-free survival (PFS) for patients who have undergone complete resection of osteosarcoma lung metastases in a double-blinded, placebo-controlled trial. Patients and Methods. Subjects with recurrent osteosarcoma localized to lung and who had complete surgical removal of all lung nodules were randomized within six weeks after complete surgical resection. Saracatinib, or placebo, was administered at a dose of 175 mg orally, once daily, for up to thirteen 28-day cycles. Results. Thirty-seven subjects were included in the analyses; 18 subjects were randomized to receive saracatinib and 19 to receive placebo. Intent-to-treat analysis demonstrated a median PFS of 19.4 months in the saracatinib treatment group and 8.6 months in the placebo treatment group (p=0.47). Median OS was not reached in either arm. Conclusions. Although saracatinib was well tolerated in this patient population, there was no apparent impact of the drug in this double-blinded, placebo-controlled trial on OS, and Src inhibition alone may not be sufficient to suppress metastatic progression in osteosarcoma. There is a suggestion of potential clinical benefit as evidenced by longer PFS in patients randomized to saracatinib based on limited numbers of patients treated.

Background This single‐arm, multicenter, phase 2 study evaluated the safety and antitumor activity of pazopanib in patients with unresectable or metastatic conventional chondrosarcoma. Methods Eligible patients had conventional chondrosarcoma of any grade with measurable tumors that were unresectable or metastatic. Patients with mesenchymal, dedifferentiated, and extraskeletal myxoid chondrosarcoma subtypes and patients who received prior tyrosine kinase inhibitor therapy were excluded. Pazopanib at 800 mg once daily was administered for 28‐day cycles. Tumor responses were evaluated by local radiology assessments every 2 cycles. The primary endpoint was the disease control rate (DCR) at week 16 (4 cycles). Results Forty‐seven patients were enrolled. The DCR at 16 weeks was 43% (95% confidence interval [CI], 28%‐58%), which was superior to the null hypothesis rate of 30%, but the 2‐sided P value (exact test) was .09 (1‐sided P = .045). One patient had a partial response. The median overall survival was 17.6 months (95% CI, 11.3‐35.0 months), and the median progression‐free survival was 7.9 months (95% CI, 3.7‐12.6 months). Grade 3 or higher adverse events were infrequent; hypertension (26%) and elevated alanine aminotransferase (9%) were most common. Conclusions This study provides evidence of positive drug activity for pazopanib in conventional chondrosarcoma.