Tuesday, May 24, 2016

ASCO 2016 - T-VEC: Talimogene laherparepvec (previously - OncoVEX GM-CSF) - now - with pembro and still enrolling!

Back in 2014, within a discussion with Ribas regarding ASCO 2014 reports, Weber said this:  "....Injectable therapies are making a comeback.....eons ago we were injecting BCG, interferon, and IL-2 into local-regional melanoma metastasis.....now there are some interesting drugs, and T-VEC is one of them.  I see this as a niche drug that would be best used to prime the immune system and follow up with a drug such as pembrolizumab, nivolumab, ipi, or a combination of those....that's where I see intralesional therapy going."

I have put together many posts regarding T-VEC....this one recently:  T-VEC: more good news...local and systemic responses

To review ~ my previous review:   Talimogene laherparepvec [now T-VEC] (originally called OncoVex GM-CSF) is.....  "....here's my best interpretation of what it all means.  First of all, let's back up a step!  Yes, the magical "sargramostim" is the same thing as GM-CSF, leukine and used in OncoVex.  It is an immunostimulator used most often to help grow new white cells after a bone marrow transplant or when they have been depleted by conventional chemo in diseases like leukemia."

OR....here's what I noted before in a post about the intralesional therapy OncoVEX: 

  "OncoVEX is a 2nd generation herpes virus embedded with GM-CSF...a substance that causes the body to make more white cells. (GM-CSF can be given to premature babies and leukemia patients with low white cell counts to help build them back up....and reverse immune suppression.) But, in OncoVEX, it is thought to only replicate in the tumor cells.  The white cells produced in the process kill off the tumor cells.  In a phase 2 trial reported in 2012, 20% of patients achieved a complete response and 28% gained an overall response.  92% of the responses were durable to at least 6 months, and the majority were ongoing with a range of 18-40 months.  Responses were found in patients with all stages and systemic tumors were eradicated in some patients."

Here are the new reports from ASCO....and this TVEC/Pembro trial is still enrolling, y'all!!!

A phase 1/3 multicenter trial of talimogene laherparepvec in combination with pembrolizumab for unresected, stage IIIB-IV melanoma (MASTERKEY-265).  ASCO 2016, #TPS9598.  J Clin Oncol 34, 2016.  Long, Drummer, Ribas, Puzanov, et al.

Background: Talimogene laherparepvec, an oncolytic viral immunotherapy, was designed to selectively replicate in tumors resulting in lytic cell death, antigen release, and production of GM-CSF to enhance systemic antitumor immune responses. Talimogene laherparepvec improved durable response rate vs GM-CSF in unresectable stage IIIB-IV melanoma. Pembrolizumab, a human programmed death receptor-blocking antibody approved for the treatment of advanced melanoma, improved PFS and OS vs ipilimumab in patients (pts) with stage III-IV melanoma. Combining talimogene laherparepvec + pembrolizumab may further enhance antitumor immune responses. Here we describe the phase 3 design of a phase 1b/3 double-blind, placebo-controlled study assessing the safety and efficacy of talimogene laherparepvec + pembrolizumab in unresected stage IIIB-IV melanoma. Phase 1b enrolled 21 pts treated with talimogene laherparepvec + pembrolizumab. No dose limiting toxicities were observed (primary endpoint), and preliminary responses were observed in 9 of 16 evaluable pts with median tumor follow-up of 17 weeks (Long et al, SMR 2016). Methods: Approximately 660 pts will receive pembrolizumab + placebo or pembrolizumab + talimogene laherparepvec (1:1 randomization). Co-primary endpoints: PFS and OS. Key secondary endpoints: adverse events and response-based endpoints. Key eligibility criteria: unresectable stage IIIB-IV melanoma naïve to systemic treatment except up to one prior line of BRAF inhibitor-based treatment, measurable and injectable lesions, ECOG PS 0-1, no active cerebral metastases, no autoimmunity/immunosuppression, no active herpetic infection. Talimogene laherparepvec (106 PFU/mL first dose, 108 PFU/mL subsequent doses) or placebo is injected into cutaneous or nodal lesions on day 1, weeks 0, 3, 5, 7 then q3w starting day 1 week 9. Pembrolizumab 200 mg IV is given q3w starting day 1 week 0. Treatment continues until confirmed complete response or progressive disease, intolerance, up to 2 years, or for talimogene laherparepvec or placebo, when there are no longer injectable lesions. Clinical trial information: NCT02263508

Efficacy analysis of MASTERKEY-265 phase 1b study of talimogene laherparepvec (T-VEC) and pembrolizumab (pembro) for unresectable stage IIIB-IV melanoma.  ASCO 2016. #9568.  J Clin Oncol 2016.  Authors as above.

Background: T-VEC is a herpes simplex virus (HSV)-1 -based oncolytic immunotherapy designed to selectively replicate in tumors, produce GM-CSF and stimulate antitumor immune responses in melanoma. T-VEC significantly improved durable response rate vs GM-CSF in stage IIIB-IV melanoma patients (pts) with injectable tumors. Pembro inhibits programmed cell death protein 1 and improves survival in advanced melanoma. The combination may further improve clinical benefit. Here we report phase 1b efficacy, safety and biomarker data from a phase 1b/3 study of T-VEC+pembro in unresectable stage IIIB-IV melanoma with all pts having started on T-VEC+pembro greater than or = to, 6 mo prior. Methods: Key inclusion criteria: unresectable stage IIIB-IV melanoma, injectable lesions; no prior systemic tx; and ECOG PS 0-1. T-VEC: ≤ 4 mL in (sub)cutaneous/nodal lesions, 106 PFU/mL d1, 108PFU/mL d22 then Q2W; pembro: IV, 200 mg d36 then Q2W. Tx until first occurrence of: complete response (CR); no injectable tumors (for T-VEC); confirmed PD per modified immune-related response criteria (irRC); tx intolerance; 24 mo of pembro. T cell subsets were evaluated by flow cytometry at baseline, during T-VEC alone, and during combination. Results: Of the 21 pts enrolled from Dec 2014 – Mar 2015, 48% had IIIB-IVM1a, 52% IVM1b/c, 76% HSV-1+, and 19% BRAFmut+. Median follow-up at data cut was 33 w. All pts received at least one dose of T-VEC+pembro. Tx-related AEs occurred in all pts: 33% G3/4, and no G5. Most common AEs were fatigue (62%), pyrexia (52%), and chills (48%). Per irRC, in 21 pts, confirmed/not yet confirmed objective response rate (ORR) was 48%/57%; CR rate was 14%/24%. Median time to response was 17 wks. Circulating CD8+ T cells including those expressing defined immune modulatory receptors (eg Tim3, BTLA) became elevated during tx with T-VEC initially but decreased after pembro began on d 36. Conclusions: The combination of T-VEC+pembro was associated with clinical benefit in advanced melanoma, as assessed by ORR and CR rate. A randomized, double-blind phase 3 trial of T-VEC+pembro vs T-VEC placebo+pembro is under way. Updated clinical and biomarker data will be presented at the meeting. Clinical trial information: NCT02263508

Way to rock it, ratties.  - c 

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