This article is more than 5 years old. Information may no longer be current.
Velimogene aliplasmid, T-VEC studies put intralesional immunotherapy into perspective
Intralesional immunotherapy of recurrent or metastatic melanoma, although its roots can be traced back a century to the use of streptococcal bacteria by Cooley, began in earnest in the early 1970s with studies of intralesional injection of bacille Calmette-Guérin (BCG) or Corynebacterium parvum into superficial melanoma lesions.
These pioneering studies demonstrated that a robust but nonspecific local immune response could not only routinely result in the destruction of injected lesions, but occasionally induce a sufficient systemic immune response to mediate regression of non-injected lesions.
In the ensuing decades, bacteria gave way to genetically engineered cytokines (interferon alfa, interleukin-2 and granulocyte-macrophage colony–stimulating factor) as the preferred agents for injecting into superficial tumors in patients who were poor candidates for surgical clearance of their disease, but none of these cytokines was ever subjected to the large-scale prospective testing required to obtain regulatory approval, and hence none ever achieved widespread use.
Vernon Sondak
Further advances in molecular biology and genetic engineering, however, led to a new generation of agents designed specifically for intralesional immunotherapy, and these have been prospectively tested and compared to systemically administered treatment.
The results of phase 3 trials involving two different agents were reported at the Society for Melanoma Research annual meeting (Agarwala SS. Plasmid DNA-based immunotherapy for metastatic melanoma: A phase 3 trial of velimogene aliplasmid; and Kaufman HL. Interim OS subset analysis in OPTiM, a randomized phase 3 trial of intralesional talimogene laherparepvec vs. subcutaneous granulocyte-macrophage colony–stimulating factor in stage IIIB-IV melanoma). Examining and understanding the disparate results of the trials helps put intralesional immunotherapy of melanoma into perspective.
Talimogene laherparepvec (T-VEC; Amgen) is a modified oncolytic herpes virus genetically engineered to secrete GM-CSF, and it was compared with subcutaneous (systemic, not intralesional) administration of GM-CSF in patients with recurrent or metastatic melanoma. Although systemic GM-CSF is an agent with no established role in the management of melanoma, it served as the control arm for this trial. This trial met its primary endpoint, with a statistically significant improvement in the number of durable (lasting >6 months) objective responses and a trend toward improved OS — a key secondary endpoint — for intralesional T-VEC compared with systemic GM-CSF.
In contrast, intralesional velimogene aliplasmid — an engineered DNA plasmid-encoding HLA B7 and beta-2-microglobulin — was compared with systemic chemotherapy using either dacarbazine (DTIC) or temozolomide (Temodar, Schering-Plough).
In this trial, intralesional immunotherapy was significantly worse than systemic chemotherapy for the primary endpoint of overall response rate at 24 weeks (slightly different than the durable response endpoint of the T-VEC trial), and the trend was for worse survival compared with chemotherapy, as well.
So what do these trials tell us about intralesional immunotherapy — and, in particular, do they provide strong evidence that one agent was better than another?
The trials confirm that intralesional immunotherapy can indeed result in local tumor destruction, and these responses can last for months or even years. Occasionally, uninjected distant tumor nodules can regress, but at a frequency that is low — probably less than can be achieved with relatively ineffective single-agent chemotherapy.
Still, in properly selected patients, intralesional immunotherapy may control injected lesions long enough to actually impact survival — at least compared with an ineffective intervention (or placebo) like systemic GM-CSF, but again probably not compared with chemotherapy, and certainly not compared with more effective antimelanoma therapies like ipilimumab (Yervoy, Bristol-Myers Squibb) or BRAF inhibitors.
In fact, it is possible — if not probable — that the divergent outcomes of these two trials are more reflective of differences in trial design than in the efficacy of the investigational drugs. It’s conceivable that the trial results would have been the same if the investigational drugs were swapped between the two studies: Velimogene aliplasmid might have been shown to be better than GM-CSF, whereas T-VEC might have fared worse than chemotherapy.
At the least, this means that careful attention needs to be paid to trial design when testing intralesional immunotherapy, but it also has implications for what we should be looking for in an intralesional agent: The agent should be easy to use and administer repeatedly, reliably induce local tumor destruction and be well tolerated, even by elderly or infirm patients. Agents meeting those specifications will likely have a niche role in a relatively small segment of the unresectable melanoma population and might be ideal agents to investigate in combination with systemic immunotherapy.
Time will tell if T-VEC is the first in a line of new agents for intralesional immunotherapy, or if it and velimogene aliplasmid are historical footnotes more noteworthy for what they teach us about clinical trial design than about melanoma treatment.
For more information:
Vernon K. Sondak, MD, is chair of cutaneous oncology at Moffitt Cancer Center. He also is a HemOnc Today Editorial Board member. He can be reached at Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612.
Disclosure:
Sondak has served as a paid consultant to Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Merck and Provectus.