Tuesday, November 29, 2016

Radiation and ipi = better responses than either alone!!! (AGAIN!!!)

Hopefully, this will soon become routine info and thereby treatment for melanoma patients!!!   Prior posts on the topic:  Better responses when immunotherapy is combined with radiation    

Now this:

A Prospective Clinical Trial Combining Radiation Therapy With Systemic Immunotherapy in Metastatic Melanoma. Hiniker, Reddy, Maecker, et al.  Int J Radiat Oncol Biol Phys. 2016 Nov .

Local radiation therapy (RT) combined with systemic anti-cytotoxic T-lymphocyte-associated protein-4 immunotherapy may enhance induction of systemic antimelanoma immune responses. The primary objective of the present trial was to assess the safety and efficacy of combining ipilimumab with RT in patients with stage IV melanoma. The secondary objectives included laboratory assessment of induction of antimelanoma immune responses.

In our prospective clinical trial, 22 patients with stage IV melanoma were treated with palliative RT and ipilimumab for 4 cycles. RT to 1 to 2 disease sites was initiated within 5 days after starting ipilimumab. Patients had ≥1 nonirradiated metastasis measuring ≥1.5 cm available for response assessment. Tumor imaging studies were obtained at baseline, 2 to 4 weeks after cycle 4 of ipilimumab, and every 3 months until progression. Laboratory immune response parameters were measured before and during treatment.

Combination therapy was well-tolerated without unexpected toxicities. Eleven patients (50.0%) experienced clinical benefit from therapy, including complete and partial responses and stable disease at median follow-up of 55 weeks. Three patients (27.3%) achieved an ongoing systemic complete response at a median follow-up of 55 weeks (range 32-65), and 3 (27.3%) had an initial partial response for a median of 40 weeks. Analysis of immune response data suggested a relationship between elevated CD8-activated T-cells and response.

This is the second prospective clinical trial of treatment of metastatic melanoma using the combination of RT and systemic immunotherapy and the first using this sequence of therapy. The results from the present trial demonstrate that a subset of patients may benefit from combination therapy, arguing for continued clinical investigation of the use of RT combined with immunotherapy, including programmed cell death 1 inhibitors, which might have the potential to be even more effective in combination with RT.

Ipilimumab with stereotactic ablative radiation therapy: Phase I results and immunologic correlates from peripheral T-cells.  Tang, Welsh, de Groot, et al.  Clin Cancer Res. 2016 Sep 20.

Little prospective data is available on clinical outcomes and immune correlates from combination radiation and immunotherapy. We conducted a phase I trial (NCT02239900) testing stereotactic ablative radiation therapy (SABR) with ipilimumab.

SABR was given either concurrently (1 day after the first dose) or sequentially (1 week after the second dose) with ipilimumab (3 mg/kg every 3 weeks for 4 doses) to 5 treatment groups: concurrent 50 Gy (in 4 fractions) to liver; sequential 50 Gy (in 4 fractions) to liver; concurrent 50 Gy (in 4 fractions) to lung; sequential 50 Gy (in 4 fractions) to lung; and sequential 60 Gy (in 10 fractions) to lung or liver. Maximum tolerated dose was determined with a 3+3 dose de-escalation design. Immune marker expression was assessed by flow cytometry.

Among 35 patients who initiated ipilimumab, 2 experienced dose-limiting toxicity and 12 (34%) grade 3 toxicity. Response outside the radiation field was assessable in 31 patients. Three patients (10%) exhibited partial response and 7 (23%) experienced clinical benefit (defined as partial response or stable disease lasting {greater than or equal to}6 months). Clinical benefit was associated with increases in peripheral CD8+ T-cells; CD8+/CD4+ T-cell ratio; and proportion of CD8+ T-cells expressing 4-1BB and PD1. Liver (vs. lung) irradiation produced greater T-cell activation, reflected as increases in the proportions of peripheral T-cells expressing ICOS, GITR, and 4-1BB.  Combining SABR and ipilimumab was safe with signs of efficacy; peripheral T-cell markers may predict clinical benefit; and systemic immune activation was greater after liver irradiation.  

If these latest posts seem like we melanoma patients have been singing the same tune...for YEARS....regarding liquid assays for tumor eval and progression, PD-L1 staining, and radiation COMBINED with immunotherapy....WE HAVE BEEN!!  Come on melanoma researchers, general oncologists and the FDA!!!  This should not be hard to figure out!!! - c

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