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VBCC - June 2016, Vol 7, No 5 - Melanoma
Walter Alexander

“Intralesional therapy is here to stay,” said Sanjiv S. Agarwala, MD, Section Chief, Hematology/­Oncology, St Luke’s University Health Network, Easton, PA, who moderated a debate on this topic at the recent HemOnc Today Melanoma and Cutaneous Malignancies meeting.

Intralesional Monotherapy

Merrick I. Ross, MD, Chief, Melanoma Section, Department of Surgical Oncology, M.D. Anderson Cancer Center, Houston, supported the role for intralesional therapy as monotherapy or as a component of combinations with systemic immunotherapies. The spectrum of intralesional therapy targets, said Dr Ross, includes 3 situations:

  1. Stage IIIb/c regional metastatic in-transit disease, with or without nodal disease
  2. Stage MIa disease (ie, distant skin, soft-tissue, and nodal metastases)
  3. Stage MIa with low-volume visceral disease.
The top management issue for intra­lesional therapy in patients with advanced regional and injectable stage IV disease relates to how uncontrolled disease can be painful and disfiguring. “You can deliver a high concentration of drug very easily, providing a very good palliation of symptoms, and durable control may be curative,” said Dr Ross. He underscored that intralesional therapies are very well-tolerated.

The second issue is the likelihood that intralesional therapies can provide a priming mechanism for a host-immune response. The 3 intralesional therapies cited by Dr Ross—the recently approved talimogene laherparepvec (Imlygic, also known as T-VEC), and the 2 investigational agents, PV-10 and coxsackievirus A21—each through different mechanisms selectively invades and lyses tumor cells, leading to the ­release of tumor-­derived antigens and potentiating a systemic T-cell–mediated antitumor response.

Focusing on T-VEC and PV-10, the intralesional agents with which he has worked, Dr Ross said that in the 80-patient phase 2 study of PV-10, a chemoablative agent, the complete response rate was 24% in injected lesions and in uninjected “bystander” lesions, with a disease control rate of 71%. The responses in bystander lesions correlated well with the responses in injected target lesions.

In the OPTiM phase 3 trial of T-VEC, objective overall responses were reported in 26.4% of patients. Among responders, the complete response rate was 41%. Lesion decreases of ≥50% were reported in 17% of uninjected visceral lesions.

In the patients with stage IIIb/c melanoma, a group showing the strongest responses to several intralesional therapies, the response rates compared favorably (T-VEC, 52%; PV-10, 49%) with the new systemic immunotherapies, ipilimumab (Yervoy, <30%), pembrolizumab (Keytruda, 27%-39%), and nivolumab (Opdivo, 34%-40%). Grade 3 or 4 adverse event rates, however, were far lower with the intralesional therapies (<2% with T-VEC vs 19% with ipilimumab).

Dr Ross concluded that because of their demonstrated utility as monotherapy in unresectable lesions and their potential as neoadjuvant therapy before surgery to activate the immune system, there is a clear role for intra­lesional therapies.

Intralesional Therapy plus Systemic Therapies

Robert H.I. Andtbacka, MD, CM, Hunstman Cancer Institute, Salt Lake City, presented the case for the superiority of intralesional therapies in combination with systemic therapies (ie, checkpoint inhibitors, such as ipilimumab, nivolumab, and pembrolizumab) based on the following 3 observations:

  1. Intralesional therapies do not add toxicity
  2. They may enhance the effect of checkpoint inhibitors
  3. Response rates with combination therapies are better than with any treatment alone.
In the CheckMate-067 trial of nivolumab plus ipilimumab, the best change from baseline in target lesion volume was –51.9% for the combination, –34.5% with nivolumab alone, and 5.9% with ipilimumab alone. The grade 3 to 4 adverse events rate was 40% with the combination, however, which is concerning. “There clearly are patients who are not candidates for this combination,” Dr Andtbacka said.

In the phase 1b trial of ipilimumab plus T-VEC, the disease control rate was 72% among 18 patients, with durable responses in 44% of the patients and complete regression of uninjected nonvisceral and visceral lesions in 39% (52% had ≥50% regression).

A phase 1b trial of T-VEC plus pembrolizumab is ongoing, with an initial (17-week follow-up) 56% overall response rate and 69% disease control rate. None of the 21 enrolled patients has discontinued their therapy because of treatment-related adverse events.

A 660-patient phase 3 trial of T-VEC plus pembrolizumab versus placebo plus pembrolizumab has just been initiated.

Comparing the response rates in advanced unresectable stage III/IV melanoma between monotherapies and combination therapies, Dr Andtbacka stated, “The future of oncolytic immunotherapy is in combination with other therapies.”

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