April 2016, Vol. 5, No. 3
A Role for Intralesional Monotherapy in Melanoma: Debate
Rather than establishing a clear winner, a debate (“Intralesional Monotherapy: Is There a Role?”) at the HemOnc Today Melanoma and Cutaneous Malignancies conference confirmed the words of Sanjiv S. Agarwala, MD, the meeting’s chairman and moderator: “Intralesional therapy is here to stay.” Roles for intralesional therapy as either monotherapy or as a component of combinations with systemic immunotherapies were clearly supported by the debaters, Merrick Ross, MD, MD Anderson Cancer Center, assigned the “yes” position, and Robert H. I. Andtbacka, MD, Hunstman Cancer Institute at the University of Utah, assuming the “no.”
The spectrum of intralesional therapy targets includes: 1) stage IIIB/C regionally metastatic in-transit disease with or without nodal disease; 2) stage MIa (distant skin, soft tissue, and nodal metastases); and 3) the prior with low-volume visceral disease, said Ross. The first of the key management issues addressable through intralesional therapy in patients with advanced regional and injectable stage IV disease pertains to the fact that uncontrolled disease can be very morbid, both 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,” he said. Ross underscored that the intralesional therapies are very well tolerated.
The second boon pertains to the likelihood that intralesional therapies can provide a priming mechanism for a host-immune response. In essence, the 3 intralesional therapies cited by Ross (T-VEC [talimogene laherparepvec], PV-10, and Coxsackievirus A21), each through differing mechanisms, selectively invade and lyse 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, Ross said that in the 80-patient phase 2 study of PV-10, a chemoablative agent, the complete response (CR) rate was 24% in both injected lesions and uninjected “bystander” lesions, with a disease control rate (DCR) of 71%. Responses in bystander lesions correlated highly with responses in injected target lesions.
In the OPTiM phase 3 trial of T-VEC, the objective response rate (ORR) was 26.4%. Among responders, the CR rate was 41%. Fifty percent or higher lesion decreases were reported in 17% of uninjected visceral lesions. Compared with the granulocyte-macrophage colony-stimulating factor control, the risk of developing visceral or bone metastasis was reduced by 59%.
In the stage IIIB/C melanoma patients, a group showing the strongest responses to several intralesional therapies, the response rates have compared favorably (T-VEC 52%; PV-10 49%) with those of the approved systemic immunotherapies (ipilimumab <30%, pembrolizumab 27%-39%, nivolumab 34%-40%). Grade 3/4 adverse event rates, however, are far lower with the intralesional therapies (T-VEC <2%, ipilimumab 19%).
Ross concluded that between the demonstrated utility as monotherapy in unresectable lesions and the potential as neoadjuvant therapy before surgery to activate the immune system, there is a clear role for intralesional therapies.
Andtbacka’s case for the superiority of intralesional therapies combined with systemic therapies (ie, checkpoint inhibitors such as ipilimumab, nivolumab, pembrolizumab), was based on 3 points: intralesional therapies do not add toxicity; they may enhance the effect of checkpoint inhibitors; and response rates with the combinations are better than with either treatment alone.
In the CheckMate 067 trial of nivolumab + 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 40% grade 3/4 adverse event rate with the combination, however, is a concern. “There clearly are patients who are not candidates for this combination,” Andtbacka said.
Among 18 patients in the phase 1b trial of ipilimumab + T-VEC, the DCR was 72%, with durable responses in 44% and complete regression of uninjected nonvisceral and visceral lesions in 39% (52% had ≥50% regression).
A phase 1b trial (MASTERKEY-265) of T-VEC + pembrolizumab is ongoing, with an initial (17-week follow-up) ORR of 56% and a DCR of 69%. In that trial, none of the 21 patients enrolled has discontinued because of treatment-related adverse events.
A 660-patient phase 3 trial (MASTERKEY-265) of T-VEC + pembrolizumab versus placebo + pembrolizumab has just been initiated. Andtbacka listed planned trials, including a phase 2 trial of pembrolizumab + interleukin-12 electroporation, a phase 1b trial of pembrolizumab + Coxsackievirus A21, and a phase 1b trial of pembrolizumab ± PV-10.
Finally, comparing the response rates in advanced unresectable stage III/IV melanoma between monotherapies (ipilimumab 6%-15%; pembrolizumab 27%-38%; nivolumab 34%-40%; T-VEC 26%) and combination therapies (nivolumab + ipilimumab 52%; T-VEC + ipilimumab 50%; T-VEC + pembrolizumab 56%), Andtbacka stated, “The future of oncolytic immunotherapy is in combination with other therapies.”
Secondary pathology review can significantly improve clinical outcomes through precise and accurate pathologic diagnoses, according to Lavinia P. Middleton, MD. “Accurate pathological diagnoses have become a high priority in cancer diagnosis,” said Middleton, Professor, Department of Pathology at The University of Texas MD Anderson Cancer Center in Houston. Increasing costs [ Read More ]
According to Steven O’Day, MD, Professor of Medical Oncology, The John Wayne Cancer Institute, Santa Monica, CA, the essential arguments supporting combinations of checkpoint blockade immunotherapy as the standard for treating metastatic melanoma arise out of their high disease control rates, rapid deep responses, improved response rates, longer progression-free survival, [ Read More ]