This, together with its low toxicity profile compared with standard chemotherapy treatments often used for advanced melanoma, also means that patients treated with TVEC tend to have far fewer side effects than patients with advanced melanoma typically experience with other therapies.

“TVEC is very easy to tolerate and it’s easy on cancer patients, most [patients] go straight back to work after treatment. They experience minor things like fever and headache; things you can take a Tylenol for. If you can use these in a patient and save them from other therapies, it’s a major improvement in their quality of life and indeed, the cost of their health care,” said Howard Kaufman, MD, lead investigator of the original OPTiM trial and chief medical officer at Replimune, an immuno-oncology–focused company. Dr Kaufman is also a surgical oncologist at Massachusetts General Hospital in Boston.

As the first, and currently only, oncolytic viral therapy to be approved by the FDA, TVEC was understandably met with high expectations from the medical community. Does the new study in a real-world environment live up to expectations?

“I think TVEC has lived up to its early promise,” said Phillip Daschner, MD, program director in the cancer immunology, hematology, and etiology branch at the National Cancer Institute in Bethesda, Maryland. If you look at the survival rates for late-stage melanoma patients and you look 10 years ago, you can see that things have really improved for these patients.”

But there may be even more success ahead for TVEC. A study published last month by researchers at the Netherlands Cancer Institute showed a complete response rate of 61.5%.3 Although undoubtedly impressive, the study represented only 16 out of 26 patients; this suggested that perhaps TVEC has not yet reached its full potential.

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“I don’t think we’ve reached our maximum effectiveness for TVEC,” said Dr Daschner. “The stratification trials are going to be needed to maximize the potential of TVEC.”

A unique aspect of the 3-center trial was that 42.5% of patients didn’t have any therapy prior to TVEC being used; these patients had a better durable response than patients who had received prior therapies.

“When patients received the drug as first-line therapy they tended to do better. I think what we are seeing is clinicians figuring out when to use this the best. Change in clinical practice takes a while. In oncology, we have a lot of new drugs being approved, and deciding when to use them is going to take a while,” said Dr Kaufman.

The source of a significant number of these drug approvals are, unsurprisingly, immunotherapies. One of the most exciting prospects for furthering the success of TVEC appears to be in combination with immune checkpoint inhibitor (ICI) drugs, which block the PD-1/PD-L1 or CTLA-4 pathways, unleashing the immune system on tumor cells.

Early work has shown that TVEC can essentially prime advanced melanoma lesions for a response to anti–PD-1 immunotherapy,4 with similar combinations of TVEC and anti–CTLA-4 agent ipilimumab showing promising early results in a phase II clinical trial of advanced melanoma.5

Dr Kaufman and colleagues have already published preliminary evidence in mouse models of melanoma showing that combining TVEC with MEK inhibitor trametinib increased survival in the mice more than either therapy alone.6 Adding an anti–PD-1 agent further augmented this response.

“The field is going to be quickly moving to 3- and 4-drug regimens. Oncolytic viruses will go well with several drugs, including CAR-T [chimeric antigen receptor T] cells. There [are] emerging data that combining oncolytic viruses with targeted therapy like MEK inhibitors and BRAF inhibitors is useful. Oncolytic viruses could be the ‘on’ switch to immunotherapy,” noted Dr Kaufman.

TVEC has certainly set an impressive benchmark for the potential for the use of viruses in cancer therapy, and with several other oncolytic viruses in development, it may not be long before a second FDA approval of this kind is achieved. However, despite justified excitement, there is still a lot of work to be done to optimize the use of therapeutic vaccines in cancer.

“We are in the early stages of understanding the biomarkers of response to oncolytic viruses. There’s going to be a lot of work before we can figure out how to get the right virus to the right patient,” added Dr Kaufman.

References

  1. Louie RJ, Perez MC, Jajja MR, et al. Real-world outcomes of talimogene laherparepvec therapy: a multi-institutional experienceJ Am Coll Surg. 2019;S1072-7515(19):30024–30029.
  2. Andtbacka RHI, Collichio FA, Amatruda T, et al. OPTiM: A randomized phase III trial of talimogene laherparepvec (T-VEC) versus subcutaneous (SC) granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment (tx) of unresected stage IIIB/C and IV melanomaJ Clin Oncol. 2013;31(18_suppl). doi: 10.1200/jco.2013.31.18_suppl.lba9008
  3. Franke V, Berger DM, Klop WMC, et al. High response rates for T-VEC in early metastatic melanoma (stage IIIB/C-IVM1a) [published online January 29, 2019]. Int J Cancer. doi: 10.1002/ijc.32172
  4. Ribas A, Dummer R, Puzanov I, et al. Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapyCell. 2017;170(6):1109-1119.
  5. Chesney J, Puzanov I, Collichio F, et al. 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 melanomaJ Clin Oncol. 2018;36(17):1658-1667.
  6. Bommareddy PK, Aspromonte S, Zloza A, et al. MEK inhibition enhances oncolytic virus immunotherapy through increased tumor cell killing and T cell activationSci Transl Med. 2018;10(471):eaau0417.