T-VEC plus ipi vs ipi alone ~ along with additional T-VEC data...

I've been posting updates about T-VEC since 2015.  Put 'T-VEC' in the search bubble and you will find a zillion articles.  Here's one from ASCO of this year, covering intralesional/intratumoral therapies generally and T-VEC in particular:  ASCO 2017: All things intralesional/intratumoral

Now there's this:

Randomized, Open-Label Phase II Study Evaluating the Efficacy and Safety of Talimogene Laherparepvec in Combination With Ipilimumab Versus Ipilimumab Alone in Patients With Advanced, Unresectable Melanoma. Chesney, Ppuzanov, Collichio...Hamid...Lebe...Andtbacka, Kaufman.  J Clin Oncol. 2017 Oct 5.

We evaluated the combination of talimogene laherparepvec plus ipilimumab versus ipilimumab alone in patients with advanced melanoma in a phase II study. To our knowledge, this was the first randomized trial to evaluate addition of an oncolytic virus to a checkpoint inhibitor. 

Patients with unresectable stages IIIB to IV melanoma, with no more than one prior therapy if BRAF wild-type, no more than two prior therapies if BRAF mutant, measurable/injectable disease, and without symptomatic autoimmunity or clinically significant immunosuppression were randomly assigned 1:1 to receive talimogene laherparepvec plus ipilimumab or ipilimumab alone. Talimogene laherparepvec treatment began in week 1 (first dose, less than/= to 4 mL × 10⁶ plaque-forming units/mL; after 3 weeks, less than/= to 4 mL × 10⁸ plaque-forming units/mL every 2 weeks). Ipilimumab (3 mg/kg every 3 weeks; up to four doses) began week 1 in the ipilimumab alone arm and week 6 in the combination arm. The primary end point was objective response rate evaluated by investigators per immune-related response criteria. 

One hundred ninety-eight patients were randomly assigned to talimogene laherparepvec plus ipilimumab (n = 98), or ipilimumab alone( n = 100). Thirty-eight patients (39%) in the combination arm and 18 patients (18%) in the ipilimumab arm had an objective response. Responses were not limited to injected lesions; visceral lesion decreases were observed in 52% of patients in the combination arm and 23% of patients in the ipilimumab arm. Frequently occurring adverse events (AEs) included fatigue (combination, 59%; ipilimumab alone, 42%), chills (combination, 53%; ipilimumab alone, 3%), and diarrhea (combination, 42%; ipilimumab alone, 35%). Incidence of grade greater than/= to 3 AEs was 45% and 35%, respectively. Three patients in the combination arm had fatal AEs; none were treatment related. The study met its primary end point; the objective response rate was significantly higher with talimogene laherparepvec plus ipilimumab versus ipilimumab alone. These data indicate that the combination has greater antitumor activity without additional safety concerns versus ipilimumab.

Patients with the ipi/T-VEC arm certainly did better than ipi alone.  In this post: The Future for Melanoma Treatment = Combo's! Dr. Weber breaks it down -  From the interview the post covers, Dr. Weber notes:

Checkpoint Inhibition Plus Talimogene Laherparepvec
The injectable oncolytic virus talimogene laherparepvec may prove to be a much better therapeutic when paired with a checkpoint inhibitor, vs its solo use, Dr. Weber said. “If you can inject enough tumors with enough volume, I think you will begin to turn cold tumors into hot tumors, and you could follow this with checkpoint inhibition,” he explained.

The combination of ipilimumab and talimogene laherparepvec doubled the response rate over ipilimumab alone, in a study in which even patients with visceral disease (not directly injected) experienced significant responses.⁸ “This looks very promising. Only time will tell whether we see a very good duration of response,” he commented.

Also quite promising is the combination of talimogene laherparepvec and pembrolizumab. In the phase IB ­MASTERKEY-265 trial of 21 previously untreated patients, responses were seen in 57% of patients, including complete responses in 7 patients, with no dose-limiting toxicities.⁹ This regimen is now in phase III trials.

To that last point...combining T-VEC with anti-PD-1 may be even better than combining it with ipi with far fewer side effects:  T-VEC (Talimogene laherparepvec, Imlygic...whatever you want to call it) - oncolytic virotherapy may improve the efficacy of anti-PD-1 by changing the tumor microenvironment!!

One more personal report I can share ~ If you read the first report carefully, you will see that among side effects, researchers note  "chills (combination, 53%; ipilimumab alone, 3%)".  Clearly, if "chills" occur at a rate of 53% with T-VEC plus ipi and only at 3% with ipi alone...the "chills" are due to T-VEC!!!  A dear one of mine is currently taking pembro (Keytruda...an anti-PD-1 product) with T-VEC and tells me that he has been dealing with significant fevers.  Which of course would be the case, if a researcher reports "chills"!!!  Isn't it interesting how folks who are NOT experiencing the side effects report them??????

Thanks for sharing and being an awesome rattie, Mark!!!  Hang tough, the rest of you ratties out there!!! - c