CX-072 (pacmilimab), a Probody ® PD-L1 inhibitor, in advanced or recurrent solid tumors (PROCLAIM-CX-072): an open-label dose-finding and first-in-human study.

BACKGROUND: Probody® therapeutics are antibody prodrugs that are activated in the tumor microenvironment by tumor-associated proteases, thereby restricting the activity to the tumor microenvironment and minimizing 'off-tumor' toxicity. We report dose-escalation and single-agent expansion phase data from the first-in-human study of CX-072 (pacmilimab), a Probody checkpoint inhibitor directed against programmed death-ligand 1 (PD-L1). METHODS: In the dose-escalation phase of this multicenter, open-label study (NCT03013491), adults with advanced solid tumors (naive to programmed-death-1/PD-L1 or cytotoxic T-lymphocyte-associated antigen 4 inhibitors) were enrolled into one of seven dose-escalation cohorts, with pacmilimab administered intravenously every 14 days. The primary endpoints were safety and determination of the maximum tolerated dose (MTD). In the expansion phase, patients with one of six prespecified malignancies (triple-negative breast cancer [TNBC]; anal squamous cell carcinoma [aSCC]; cutaneous SCC [cSCC]; undifferentiated pleomorphic sarcoma [UPS]; small bowel adenocarcinoma [SBA]; and thymic epithelial tumor [TET]); or high tumor mutational burden (hTMB) tumors were enrolled. The primary endpoint was objective response (Response Evaluation Criteria In Solid Tumors v.1.1). RESULTS: An MTD was not reached with doses up to 30 mg/kg. A recommended phase 2 dose (RP2D) of 10 mg/kg was chosen based on pharmacokinetic and pharmacodynamic findings in the expansion phase. Ninety-eight patients enrolled in the expansion phase: TNBC (n=14), aSCC (n=14), cSCC (n=14), UPS (n=20), SBA (n=14), TET (n=8), and hTMB tumors (n=14). Of 114 patients receiving pacmilimab at the RP2D, grade ≥3 treatment-related adverse events (TRAEs) were reported in 10 patients (9%), serious TRAEs in six patients (5%), and treatment discontinuation due to TRAEs in two patients (2%). Grade ≥3 immune-related AEs occurred in two patients (rash, myocarditis). High PD-L1 expression (ie, >50% Tumor Proportion Score) was observed in 22/144 (19%) patients. Confirmed objective responses were observed in patients with cSCC (n=5, including one complete response), hTMB (n=4, including one complete response), aSCC (n=2), TNBC (n=1), UPS (n=1), and anaplastic thyroid cancer (n=1). CONCLUSIONS: Pacmilimab can be administered safely at the RP2D of 10 mg/kg every 14 days. At this dose, pacmilimab had a low rate of immune-mediated toxicity and showed signs of antitumor activity in patients not selected for high PD-L1 expression. TRIAL REGISTRATION NUMBER: NCT03013491.

Combined ipilimumab and nivolumab first-line and after BRAF-targeted therapy in advanced melanoma.

The combination of ipilimumab and nivolumab is a highly active systemic therapy for metastatic melanoma but can cause significant toxicity. We explore the safety and efficacy of this treatment in routine clinical practice, particularly in the setting of serine/threonine-protein kinase B-Raf (BRAF)-targeted therapy. Consecutive patients with unresectable stage IIIC/IV melanoma commenced on ipilimumab and nivolumab across 10 tertiary melanoma institutions in Australia were identified retrospectively. Data collected included demographics, response and survival outcomes. A total of 152 patients were included for analysis, 39% were treatment-naïve and 22% failed first-line BRAF/MEK inhibitors. Treatment-related adverse events occurred in 67% of patients, grade 3-5 in 38%. The overall objective response rate was 41%, 57% in treatment-naïve and 21% in BRAF/MEK failure patients. Median progression-free survival was 4.0 months (95% CI, 3.0-6.0) in the whole cohort, 11.0 months (95% CI, 6.0-NR) in treatment-naïve and 2.0 months (95% CI, 1.4-4.6) in BRAF/MEK failure patients. The combination of ipilimumab and nivolumab can be used safely and effectively in a real-world population. While first-line efficacy appears comparable to trial populations, BRAF-mutant patients failing prior BRAF/MEK inhibitors show less response.

Vedolizumab in combined immune checkpoint therapy-induced infliximab-refractory colitis in a patient with metastatic melanoma: A case report.

BACKGROUND: Dual checkpoint inhibition improves response rates in treatment naïve patients with metastatic melanoma compared to monotherapy. However, it confers a higher rate of toxicity, including immune-related colitis. Steroids may not resolve symptoms in all cases. The use of vedolizumab, a humanized monoclonal antibody against α4ß7 integrin has proven effective in cases refractory to standard treatment. CASE SUMMARY: We report the case of a 27-year-old female with Stage IVd metastatic melanoma treated with ipilimumab and nivolumab. She developed severe colitis refractory to methylprednisolone, infliximab and mycophenolate mofetil but responded to vedolizumab. CONCLUSION: This case report supports vedolizumab use in severe immune related colitis refractory to standard immunosuppression.

Combined immune therapy grade IV dermatitis in metastatic melanoma.

Checkpoint inhibition is the mainstay of treatment in metastatic melanoma. More recently combined cytotoxic T-lymphocyte antigen-4 and programmed-death-1 blockade has resulted in improved response rates and overall survival in treatment naïve patients compared to monotherapy albeit with increased rates of adverse events. Dermatologic toxicities are an emerging consequence of the use of checkpoint inhibitors and have reportedly been more prevalent with the use of combined therapy. However, grade 3 and 4 adverse event rates are still less than 5%. Here, we report a case of a 63-year-old Caucasian male with metastatic melanoma treated with first line combined ipilimumab and nivolumab who then developed a steroid refractory, biopsy confirmed pityriasis lichenoides-like, drug related rash that resolved with cyclosporine. Time of onset was 24 days and presenting symptoms demonstrated a maculopapular rash presenting over the back and chest with pruritus. Unfortunately, the patient subsequently had multi-organ failure with acute kidney injury requiring dialysis, hypotension requiring vasopressor support, hepatic dysfunction, and bilateral lung infiltrates resulting in a fatal outcome. This case report highlights the effective use of cyclosporine as an immunomodulatory agent in the management of severe dermatological toxicity due to combination immunotherapy.

Real-world efficacy and toxicity of combined nivolumab and ipilimumab in patients with metastatic melanoma.

BACKGROUND: There is limited real-world data on the efficacy and safety of combination programmed cell death protein-1 (PD-1) inhibitor, nivolumab and the cytotoxic T-lymphocyte antigen (CTLA-4) inhibitor ipilimumab. METHOD: We retrospectively identified patients (pts) with metastatic melanoma treated with three-weekly nivolumab (1 mg/kg) in combination with ipilimumab (3 mg/kg) for four cycles followed by nivolumab monotherapy (3 mg/kg) fortnightly. Patient demographics and treatment parameters were collected and outcomes determined. RESULTS: A total of 45 pts received combination treatment with a median follow up of 8.7 months (range 0.33-25.9 months). A total of 67% were male, and BRAF V600 mutations detected in 38%. At treatment commencement, 14 (31%) pts had brain metastases, 51% had an elevated LDH and 18 (40%) were treatment-naive. Almost a third (30%) required corticosteroids for symptom control or management of prior toxicities. Nineteen (42%) patients had prior anti-PD-1 therapy. The disease control rate (DCR) was 54% and objective response rate (ORR) was 29%. Of pts treated with prior immune checkpoint inhibitors, the DCR and ORR were 50% and 33%, respectively. Intracranial responses were observed in 18% (n = 2). The median progression-free survival (PFS) was 5.8 months (95% Confidence interval (CI), 2.9-14.1 months). PFS was higher in treatment naïve patients compared to those who had prior immunotherapy (6.2 months vs 4.9 months, P = 0.59). The median OS was 17.4 months (95% CI, 7.1-NR). pts requiring corticosteroids had a shorter PFS (4.9 months vs 6.8 months) and OS (7.1 months vs NR, P = 0.01).Treatment-related adverse events of any grade were experienced by 88% of pts, with 54% having grade 3-4 adverse events. Treatment discontinuation due to adverse events occurred in 44% of pts. CONCLUSION: In this study, responses to combination immunotherapy were lower than reported. Patients treated with prior immunotherapy had similar responses as treatment-naïve pts. The toxicity profile seen in this study is similar to those reported in clinical trials.