Cutaneous head and neck melanoma in OPTiM, a randomized phase 3 trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor for the treatment of unresected stage IIIB/IIIC/IV melanoma

BACKGROUND: Cutaneous head and neck melanoma has poor outcomes and limited treatment options. In OPTiM, a phase 3 study in patients with unresectable stage IIIB/IIIC/IV melanoma, intralesional administration of the oncolytic virus talimogene laherparepvec improved durable response rate (DRR; continuous response ≥6 months) compared with subcutaneous granulocyte-macrophage colony-stimulating factor (GM-CSF). METHODS: Retrospective review of OPTiM identified patients with cutaneous head and neck melanoma given talimogene laherparepvec (n = 61) or GM-CSF (n = 26). Outcomes were compared between talimogene laherparepvec and GM-CSF treated patients with cutaneous head and neck melanoma. RESULTS: DRR was higher for talimogene laherparepvec-treated patients than for GM-CSF treated patients (36.1% vs 3.8%; p = .001). A total of 29.5% of patients had a complete response with talimogene laherparepvec versus 0% with GM-CSF. Among talimogene laherparepvec-treated patients with a response, the probability of still being in response after 12 months was 73%. Median overall survival (OS) was 25.2 months for GM-CSF and had not been reached with talimogene laherparepvec. CONCLUSION: Treatment with talimogene laherparepvec was associated with improved response and survival compared with GM-CSF in patients with cutaneous head and neck melanoma. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1752-1758, 2016

Cutaneous head and neck melanoma in OPTiM, a randomized phase 3 trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor for the treatment of unresected stage IIIB/IIIC/IV melanoma

BACKGROUND: Cutaneous head and neck melanoma has poor outcomes and limited treatment options. In OPTiM, a phase 3 study in patients with unresectable stage IIIB/IIIC/IV melanoma, intralesional administration of the oncolytic virus talimogene laherparepvec improved durable response rate (DRR; continuous response ≥6 months) compared with subcutaneous granulocyte-macrophage colony-stimulating factor (GM-CSF). METHODS: Retrospective review of OPTiM identified patients with cutaneous head and neck melanoma given talimogene laherparepvec (n = 61) or GM-CSF (n = 26). Outcomes were compared between talimogene laherparepvec and GM-CSF treated patients with cutaneous head and neck melanoma. RESULTS: DRR was higher for talimogene laherparepvec-treated patients than for GM-CSF treated patients (36.1% vs 3.8%; p = .001). A total of 29.5% of patients had a complete response with talimogene laherparepvec versus 0% with GM-CSF. Among talimogene laherparepvec-treated patients with a response, the probability of still being in response after 12 months was 73%. Median overall survival (OS) was 25.2 months for GM-CSF and had not been reached with talimogene laherparepvec. CONCLUSION: Treatment with talimogene laherparepvec was associated with improved response and survival compared with GM-CSF in patients with cutaneous head and neck melanoma. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1752-1758, 2016

Open-label, randomized, multi-center study comparing the sequence of high dose Aldesleukin (Proleukin® (HD IL-2) and Ipilimumab Yervoy® ) in patients with metastatic melanoma (proclivity 02)

Purpose: To investigate whether the sequence of HD IL-2 and a checkpoint inhibitor, Ipilimumab, will have additive or synergistic efficacy or toxicity when used in rapid sequence. Schema: Adult patients with Stage IV or unresectable Stage III metastatic melanoma who are eligible to receive HD IL-2, treatment naïve or have received prior adjuvant therapy are randomized to a sequential administration of 4 doses of Ipilimumab or 4 cycles of HD IL-2 dosed according to their package inserts. Fifty of the patients will start with one drug and 50 the other. The second drug will begin as soon as practically possible, without waiting for relapse. Entry criteria have recently been amended to include prior treatment with anti-PD-1 or anti-PDL-1. Twelve US sites are currently enrolling patients. An independent Data and Safety Monitoring Committee oversees the study. The primary endpoint is the proportional one year survival in the ITT population and a protocol defined population of patients who have received at least half of the planned doses of both study drugs. Clinical response and progression free survival will also be assessed. The primary endpoint is the proportional one year survival in the ITT population and a protocol defined population of patients who have received at least half of the planned doses of both study drugs. Clinical response and progression free survival will also be assessed. Current status: Twelve US sites are currently enrolling patients. To date 16 patients have been enrolled, 9 on the Ipilimumab first and 7 on the HD IL-2 first arms. No synergistic toxicity has been observed, but one death occurred in the HD IL-2 arm and one colectomy on the Ipilimumab arm, both prior to administration of the other drug

Impact of Sequencing Targeted Therapies With High-dose Interleukin-2 Immunotherapy: An Analysis of Outcome and Survival of Patients With Metastatic Renal Cell Carcinoma From an On-going Observational IL-2 Clinical Trial: PROCLAIM

BACKGROUND: This analysis describes the outcome for patients who received targeted therapy (TT) prior to or following high-dose interleukin-2 (HD IL-2). PATIENTS AND METHODS: Patients with renal cell carcinoma (n = 352) receiving HD IL-2 were enrolled in Proleukin RESULTS: Overall, there were 4% complete response (CR), 13% partial response (PR), 39% stable disease (SD), and 43% progressive disease (PD) with HD IL-2. The median overall survival (mOS) was not reached in patients with CR, PR, or SD, and was 15.5 months in patients with PD (median follow-up, 21 months). Sixty-one patients had prior TT before HD IL-2 with an overall response rate (ORR) to HD IL-2 of 19% (1 CR, 9 PR) and an mOS of 22.1 months. One hundred forty-nine patients received TT only after HD IL-2 with an mOS of 35.5 months. One hundred forty-two patients had no TT before or after HD IL-2, and mOS was not reached. The mOS was 8.5 months in PD patients who received HD IL-2 without follow-on TT and 29.7 months in PD patients who received follow-on TT after HD IL-2. CONCLUSIONS: HD IL-2 as sole front-line therapy, in the absence of added TT, shows extended clinical benefit (CR, PR, and SD). Patients with PD after HD IL-2 appear to benefit from follow-on TT. Patients who progressed on TT and received follow-on HD IL-2 experienced major clinical benefit. HD IL-2 therapy should be considered in eligible patients

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival