Liver Metastasis and Treatment Outcome with Anti-PD-1 Monoclonal Antibody in Patients with Melanoma and NSCLC.

We explored the association between liver metastases, tumor CD8+ T-cell count, and response in patients with melanoma or lung cancer treated with the anti-PD-1 antibody, pembrolizumab. The melanoma discovery cohort was drawn from the phase I Keynote 001 trial, whereas the melanoma validation cohort was drawn from Keynote 002, 006, and EAP trials and the non-small cell lung cancer (NSCLC) cohort from Keynote 001. Liver metastasis was associated with reduced response and shortened progression-free survival [PFS; objective response rate (ORR), 30.6%; median PFS, 5.1 months] compared with patients without liver metastasis (ORR, 56.3%; median PFS, 20.1 months) P ≤ 0.0001, and confirmed in the validation cohort (P = 0.0006). The presence of liver metastasis significantly increased the likelihood of progression (OR, 1.852; P < 0.0001). In a subset of biopsied patients (n = 62), liver metastasis was associated with reduced CD8+ T-cell density at the invasive tumor margin (liver metastasis+ group, n = 547 ± 164.8; liver metastasis- group, n = 1,441 ± 250.7; P < 0.016). A reduced response rate and shortened PFS was also observed in NSCLC patients with liver metastasis [median PFS, 1.8 months; 95% confidence interval (CI), 1.4-2.0], compared with those without liver metastasis (n = 119, median PFS, 4.0 months; 95% CI, 2.1-5.1), P = 0.0094. Thus, liver metastatic patients with melanoma or NSCLC that had been treated with pembrolizumab were associated with reduced responses and PFS, and liver metastases were associated with reduced marginal CD8+ T-cell infiltration, providing a potential mechanism for this outcome. Cancer Immunol Res; 5(5); 417-24. ©2017 AACR.

Phase I/II study of the antibody-drug conjugate glembatumumab vedotin in patients with advanced melanoma.

PURPOSE: The antibody-drug conjugate glembatumumab vedotin links a fully human immunoglobulin G2 monoclonal antibody against the melanoma-related glycoprotein NMB (gpNMB) to the potent cytotoxin monomethyl auristatin E. This study evaluated the safety and activity of glembatumumab vedotin in patients with advanced melanoma. PATIENTS AND METHODS: Patients received glembatumumab vedotin every 3 weeks (schedule 1) in a dose escalation and phase II expansion at the maximum-tolerated dose (MTD). Dosing during 2 of 3 weeks (schedule 2) and weekly (schedule 3) was also assessed. The primary end points were safety and pharmacokinetics. The secondary end points included antitumor activity, gpNMB expression, and immunogenicity. RESULTS: One hundred seventeen patients were treated using schedule 1 (n = 79), schedule 2 (n = 15), or schedule 3 (n = 23). The MTDs were 1.88, 1.5, and 1.0 mg/kg for schedules 1, 2, and 3, respectively. Grade 3/4 treatment-related toxicities that occurred in two or more patients included rash, neutropenia, fatigue, neuropathy, arthralgia, myalgia, and diarrhea. Three treatment-related deaths (resulting from pneumococcal sepsis, toxic epidermal necrolysis, and renal failure) occurred at doses exceeding the MTDs. In the schedule 1 phase II expansion cohort (n = 34), five patients (15%) had a partial response and eight patients (24%) had stable disease for ≥ 6 months. The objective response rate (ORR) was 2 of 6 (33%) for the schedule 2 MTD and 3 of 12 (25%) for the schedule 3 MTD. Rash was correlated with a greater ORR and improved progression-free survival. CONCLUSION: Glembatumumab vedotin is active in advanced melanoma. The schedule 1 MTD (1.88 mg/kg once every 3 weeks) was associated with a promising ORR and was generally well tolerated. More frequent dosing was potentially associated with a greater ORR but increased toxicity.

Systemic treatment of metastatic melanoma: new approaches.

The field of melanoma therapeutics has experienced a dramatic paradigm shift over the last 12 months through recent discoveries of novel therapeutics targeting known oncogenes and immunotherapeutic antibodies. In this article, we review these findings and provide a framework to understand these discoveries, their significance in melanoma therapy, and role in clinical care. As this understanding grows, enduring therapeutic success may be achieved through tailored use of molecular markers and immunotherapies in sequential or combinatorial methods.

Pilot study of PD-0325901 in previously treated patients with advanced melanoma, breast cancer, and colon cancer.

PURPOSE: To assess further the tolerability and preliminary antitumor activity of PD-0325901 in previously treated patients with advanced melanoma, breast cancer, and colon cancer. METHODS: This pilot study evaluated PD-0325901 on an intermittent dosing schedule. PD-0325901 was administered orally at 20 mg twice daily (BID) for 21 consecutive days followed by 7 days of no treatment. This dose was not well tolerated and consequently changed to 15 mg BID. RESULTS: Between October and December 2005, 13 patients with metastatic measurable disease were entered into the study (seven melanoma, three breast cancer, and three colon cancer). All patients had received prior systemic therapy and were treated with a total of 61 cycles of PD-0325901 (nine received an initial dose of 20 mg BID, four an initial dose of 15 mg BID). The study was terminated early because of an unexpected high incidence of musculoskeletal and neurological adverse events, including gait disturbance, memory impairment, confusion, mental status changes, mild to moderate visual disturbances, and muscular weakness including neck weakness ("dropped-head syndrome"). Other common toxicities were diarrhea, acneiform rash, fatigue, and nausea. There was no significant hematologic toxicity, and chemistry abnormalities were rare. One patient achieved a confirmed complete response, and five patients had stable disease. CONCLUSIONS: PD-0325901 can cause significant musculoskeletal, neurological, and ocular toxicity at doses ≥ 15 mg BID. Future studies with adaptive designs might evaluate doses ≤ 10 mg BID in tumor types with a high incidence of Ras and Raf mutations. ClinicalTrials.gov identifier NCT00147550.

Enhanced survival associated with vitiligo expression during maintenance biotherapy for metastatic melanoma.

Vitiligo, an autoimmune skin disorder, was evaluated in 49 metastatic melanoma patients treated with an immunotherapy regimen of maintenance biotherapy (mBT) following induction concurrent biochemotherapy (cBCT). Patients receiving mBT demonstrated a stable or better response to cBCT. The mBT regimen consisted of outpatient subcutaneous injections of low-dose IL-2 (1 MIU/m(2)) 5/7 days weekly, GM-CSF (125 mcg/m(2)) 14 days monthly, and high-dose pulses of in-patient continuous infusion decrescendo IL-2 (54 MIU/m(2)) over 48 hours monthly for the first 6 months and every 2 months thereafter. The majority of patients had poor prognostic features. Forty-nine patients were without evidence of vitiligo at the start of mBT. Of these, 21 patients (43%) developed vitiligo during mBT and had a median overall survival from the start of mBT of 18.2 months (95% CI, 12.3-N/A) compared to 8.5 months (95%CI <6.7-12.7) for 28 non-vitiligo patients (P=0.027). Six of 21 vitiligo patients (29%) expressed IgG antibody titers to tyrosinase-related protein-2 compared to four of 28 non-vitiligo patients (14%) (P=NS). The development of vitiligo in metastatic melanoma patients on cBCT/mBT immunotherapy correlates with a better therapeutic outcome.

Circulating DNA microsatellites: molecular determinants of response to biochemotherapy in patients with metastatic melanoma.

Although biochemotherapy appears to be a promising treatment for metastatic melanoma, its impact remains unpredictable. Microsatellite markers for loss of heterozygosity (LOH) appear to have prognostic significance when identified in primary tumors and serum and/or plasma from cancer patients. However, their association with response to systemic therapy has yet to be assessed. To determine whether microsatellite markers are associated with response to therapy, serum from 41 patients with metastatic melanoma, drawn before the initiation of biochemotherapy, was analyzed for LOH with nine microsatellite markers. During a median follow-up of 13 months, the overall response rate for these 41 patients was 56%, including 13 (32%) complete responses and 10 (24%) partial responses. LOH was detected in sera from 12 (29%) of the 41 patients. The response rate of these 12 patients was 17% (95% confidence interval [CI] = 5% to 45%), whereas that of the 29 patients without LOH was 72% (95% CI = 54% to 85%) (P =.001). All statistical tests were two-sided. The presence of LOH was statistically significant and independently associated with disease progression (multivariable analysis, P =.003). Circulating tumor DNA markers may be useful in assessing prognosis for advanced melanoma patients and their response to biochemotherapy.

Biochemotherapy for metastatic melanoma with limited central nervous system involvement.

OBJECTIVES: Biochemotherapy outcomes were examined in stage IV melanoma patients with previously treated or active central nervous system (CNS) metastases prior to systemic therapy. PATIENTS AND METHODS: Patients who received biochemotherapy for metastatic melanoma with active or pretreated CNS metastases were compared to patients without evidence of CNS metastases in terms of response, time to progression (TTP), overall survival (OS), and treatment toxicity. RESULTS: Twenty-six (16%) of 159 total patients began biochemotherapy with previously treated or active CNS metastases (group I), compared to 133 (84%) who were radiographically free of CNS involvement (group II). A partial or complete response to biochemotherapy was seen in 13 (50%) group I patients, compared to 56 (42%) group II patients (p = 0.243). The median TTP and median survival were 5.5 and 7.0 months, respectively, for group I patients and 6.0 and 9.9 months, respectively, for group II patients (p = 0.222 and 0.434 for TTP and OS, respectively). Five (19%) group I patients survived longer than 24 months. Gamma Knife radiosurgery or surgical resection of CNS disease prior to biochemotherapy improved survival versus delayed treatment (p = 0.017 and 0.005, respectively). CONCLUSION: Patients with limited CNS metastases and widespread systemic disease can achieve prolonged survival with targeted treatment of CNS lesions and aggressive systemic therapy.

Prolonged survival after complete resection of disseminated melanoma and active immunotherapy with a therapeutic cancer vaccine.

PURPOSE: The curative effect of surgery in certain patients with metastatic melanoma suggests the presence of endogenous antitumor responses. Because melanoma is immunogenic, we investigated whether a therapeutic cancer vaccine called Canvaxin (CancerVax Corporation, Carlsbad, CA) could enhance antitumor immune responses and thereby prolong survival. PATIENTS AND METHODS: Of 263 patients who underwent complete resection of American Joint Committee on Cancer stage IV melanoma, 150 received postoperative adjuvant vaccine therapy and 113 did not. The overall survival (OS) for the two groups was compared by Cox regression. Further survival analysis was performed by matched-pair analysis according to three prognostic variables: sex, metastatic site, and number of tumor-involved organ sites. RESULTS: Five-year OS rates were 39% for vaccine and 19% for nonvaccine patients. On multivariate analysis, vaccine therapy was the most significant prognostic variable in this cohort (P =.0001). Analysis of 107 matched pairs of vaccine and nonvaccine patients revealed a significant OS advantage for vaccine therapy (P =.0009): 5-year OS was 39% for vaccine patients versus 20% for nonvaccine patients. There was a significant delayed-type hypersensitivity (DTH) response to adjuvant vaccine therapy (P =.0001), and OS was significantly correlated with DTH to vaccine (P =.0001) but not with DTH to purified protein derivative (PPD), a control antigen. CONCLUSION: Prolonged survival was observed in patients who received postoperative active immunotherapy with Canvaxin therapeutic cancer vaccine. The correlation of survival with vaccine-DTH responses but not PPD-DTH indicates a treatment-specific effect. These findings suggest that adjuvant active specific immunotherapy should be considered after cytoreductive surgery for advanced melanoma.

Maintenance biotherapy for metastatic melanoma with interleukin-2 and granulocyte macrophage-colony stimulating factor improves survival for patients responding to induction concurrent biochemotherapy.

PURPOSE: A prospective Phase II study of a novel maintenance biotherapy regimen after induction biochemotherapy was conducted in patients with metastatic melanoma in efforts to maintain responses and improve survival. EXPERIMENTAL DESIGN: Thirty-three patients with poor prognosis metastatic melanoma who achieved a partial response (PR) or stable disease (SD) to induction concurrent biochemotherapy were treated with chronic low-dose interleukin (IL)-2 and granulocyte macrophage-colony stimulating factor, and intermittent pulses of intermediate/high-dose decrescendo IL-2 over a 12-month period. The outcome of these patients was compared with a control group of patients at our institution who were treated recently with induction biochemotherapy and achieved a PR or SD. RESULTS: Five patients (15%) achieved a complete response, and 4 patients (12%) maintained SD for at least 6 months on maintenance biotherapy. The median progression-free survival (PFS) and overall survival (OS) were 8.1 months and 18.5 months, respectively, compared with historical controls, which were PFS 5.9 months (P = 0.0015) and OS 9.3 months (P = 0.0004). Administration of maintenance biotherapy was a significant predictor of PFS (P = 0.0008) and OS (P = 0.0001) in multivariate and matched-pair analyses (P = 0.002). The maintenance biotherapy regimen was well tolerated with no dose-limiting acute or cumulative toxicities. CONCLUSION: In this single institution study, maintenance biotherapy with IL-2 and granulocyte macrophage colony-stimulating factor in patients achieving PR or SD to induction biochemotherapy improved PFS and OS compared with historical controls. A larger multicenter Phase II trial has been initiated in an effort to confirm these results.