Intralesional agents show promise in melanoma but may serve ‘narrow clientele’

The dichotomy of trends in the field of melanoma — a sharp rise in incidence, coupled with dramatic improvements in patient outcomes — is unlike that observed in nearly every other malignancy.

The number of melanoma cases in the United States doubled from 11.2 to 22.7 per 100,000 people from 1982 to 2011, according to the CDC. Annual incidence is expected to peak at 112,000 new cases by 2030.

This challenge has been met by a rapid introduction of immunotherapies and targeted therapies.

In the shadow of the immunotherapy revolution, the FDA also approved talimogene laherparepvec (Imlygic; BioVex, Amgen) — commonly referred to as T-VEC — a genetically modified live oncolytic virus therapy derived from herpes simplex virus type-1.

T-VEC — the first FDA–approved oncolytic virus therapy — is injected directly into melanoma lesions. Upon injection, it selectively infects and replicates in tumor cells, causing them to rupture and die.

“Intralesional monotherapies for melanoma are nontoxic and can be easily prescribed to patients who are not candidates for other systemic treatments,” Sanjiv S. Agarwala, MD, professor of medicine at Temple University School of Medicine, chief of hematology and oncology at St. Luke’s Cancer Center in Bethlehem, Pennsylvania, and HemOnc Today’s melanoma section editor, told HemOnc Today. “They might benefit patients who are not suitable for other therapies due to age or comorbidity burden, as well as those who have progressed on other systemic therapies and do not have a lot of options left. In some rare cases, they might be used in patients who have localized disease that is not resectable.”

However, the scrutiny surrounding T-VEC and the design of the OPTiM trial, which served as the basis for the agent’s approval, has impacted the development — and may potentially limit the use — of other oncolytic agents.

HemOnc Today spoke with medical and surgical melanoma specialists about the future of intralesional agents for melanoma, whether oncolytic agents likely will be used as single agents or in combination with immunotherapies, and the lingering questions surrounding T-VEC’s efficacy based on the OPTiM trial.

A therapeutic explosion

Although more than 90% of patients diagnosed with early-stage melanoma are expected to survive 10 years, patients with advanced or metastatic melanoma face dire outcomes.

The 5-year OS rate for patients with stage IV melanoma is between 15% and 20%, and 10-year OS ranges from 10% to 15%.

An abundance of new therapeutic options for the treatment of advanced disease stands to improve patient outcomes.

Since 2011, the FDA has approved eight agents to treat melanoma. They include T-VEC, three other immunotherapies — ipilimumab (Yervoy, Bristol-Myers Squibb), nivolumab (Opdivo, Bristol-Myers Squibb) and pembrolizumab (Keytruda, Merck) — and the targeted agents vemurafenib (Zelboraf, Genentech), cobimetinib (Cotellic, Genentech), dabrafenib (Tafinlar; Novartis) and trametinib (Mekinist; Novartis).

The FDA approved T-VEC in October 2015 on the basis of the randomized, phase 3 OPTiM trial, in which researchers randomly assigned patients with injectable, unresectable melanoma to T-VEC or subcutaneous granulocyte-macrophage colony–stimulating factor.

Patients assigned T-VEC demonstrated a higher durable response rate (16.3% vs. 2.1%; P < .001) and overall response rate (26.4% vs. 5.7%), as well as longer OS (median, 23.3 months vs. 18.9 months).

“If you look specifically at patients with stage IIIB or stage IIIC disease on the OPTiM trial, their response rate was 52%,” Robert H.I. Andtbacka, MD, CM, FACS, FRCSC, associate professor of surgery at Huntsman Cancer Institute at University of Utah, as well as a HemOnc Today Editorial Board member, told HemOnc Today. “None of the other immunotherapies and checkpoint inhibitors have come close to having that response rate in that patient population.”

Andtbacka, who served as an investigator on the OPTiM trial, said the positive outcome and FDA approval signal the utility of intralesional agents in the rapidly expanding melanoma landscape.

“It appears that patients treated with T-VEC have a reduced risk for developing visceral metastases and bone metastases,” Andtbacka said. “These agents can have a very important role as a melanoma monotherapy and can be very effective, and they also can be used as therapy in the neoadjuvant setting.”

T-VEC appears most effective before distant metastases develop, Jeffrey S. Weber, MD, PhD, deputy director of the Laura and Isaac Perlmutter Cancer Center and professor of medicine at NYU Langone Medical Center, told HemOnc Today.

“This is a rather narrow clientele within the melanoma patient world,” Weber said. “Patients with locoregional disease and multiple in-transit metastases will potentially have this as a fairly nontoxic option. But, the pitfall of using this kind of treatment is that the response rate in visceral distant metastases — which virtually all patients will have if they have unresectable disease — is pretty modest.”

Robert H.I. Andtbacka, MD, CM, FACS, FRCSC, chair of the department of cutaneous oncology and director of surgical education at Moffitt Cancer Center, as well as a HemOnc Today Editorial Board member, suggested the benefit of T-VEC may be largely superficial for some patients.

“The major limitation is that, in order to use an injectable therapy, you have to have something to inject,” Sondak said in an interview. “Not every melanoma is close to the surface, so you have to determine how many people have an injectable tumor and how many of those tumors are close enough to reach. If a patient has some little lesions on the skin, but giant tumors in the liver and the lungs, how much does injecting the little thing help the big thing?”

The relatively mild toxicity profile of T-VEC may make it more appealing to some patients than immunotherapies, which can produce virulent adverse events, Sondak added.

“Adverse events can be quite modest when you are just injecting a [lesion], rather than trying to treat the entire patient,” Sondak said. “If we can get the immune system to pay attention to the melanoma and do something good because of it, then you are looking at a low-toxicity means of producing an important, clinically relevant immune response.”

Dale Han, MD, assistant professor of surgical oncology at Yale School of Medicine, agreed.

“A systemic response can be induced by T-VEC in a small percentage of cases,” Han told HemOnc Today. “Regression of the distant lesions are seen, but the rate of systemic response is relatively low.”

Concerns about OPTiM

Although most oncologists agree T-VEC has a role in the melanoma treatment armamentarium, the design of the OPTiM trial has prompted a number of clinicians to question how large that role should be.

The primary reason for concern is the use of GM-CSF as the control.

“T-VEC was approved on the basis of a clinical trial design that will certainly never be replicated,” Sondak said. “The control arm was basically a placebo, with no basis in why one would choose to use that particular regimen. I don’t know if that design would be approved today by the FDA.”

OPTiM researchers enrolled patients between May 2009 and July 2011. The majority of new melanoma therapeutic options were approved after that period, leaving some oncologists to wonder how the results might differ if the trial were conducted now.

“We had none of the currently available therapies [during the design of the trial],” Andtbacka said. “There was no frontline standard of care for patients with advanced melanoma. There were data saying that GM-CSF, given in an adjuvant or a metastatic setting, may be effective to treat melanoma. [Because] T-VEC produces GM-CSF, the FDA felt that it was an appropriate comparator arm.”

Agarwala — who served as an investigator on the OPTiM trial — agreed questions about the control arm are valid.

“I have never seen or heard of a patient responding to subcutaneous GM-CSF, so you had a control arm that really had zero efficacy,” Agarwala said. “The trial was done at a time when that was potentially reasonable, but it is debatable whether the results are clinically meaningful in today’s environment.”

The landscape for the systemic treatment of melanoma has changed dramatically over the last decade, during T-VEC’s evaluation period, Han said.

“We live in a different world now than when T-VEC was being evaluated in the OPTiM trial,” he said. “We now have very effective systemic therapies, whereas the systemic benefits of T-VEC are relatively modest. There may be subsets of patients who benefit from monotherapy with T-VEC; however, we have no way to predict which patients may benefit, as opposed to other systemic therapies. T-VEC has been well received, but we are still cautious, especially in light of new therapeutic options.”

Others have questioned the use of a surrogate endpoint — durable response rate — as the basis for the FDA’s approval of T-VEC.

“It is a reasonable surrogate for the ultimate endpoint of OS, but it is hardly a perfect one,” Weber said. “If you are a patient presented with two relatively similar options, you are probably going to say, ‘Doctor, which is going to give me longer survival?’ At the end of the day, survival is going to be your endpoint, with reasonable side effects.”

Photo courtesy of Jeffrey S. Weber, MD, PhD.

An analysis of patients treated with T-VEC on the OPTiM trial — conducted by Kaufman and colleagues and published in Journal of Immunotherapy for Cancer — showed durable response correlated with OS.

Patients who achieved durable response were much more likely to be alive at 9 months (HR = 0.08; 95% CI, 0.01-0.56), 12 months (HR = 0.05; 95% CI, 0.01-0.39) and 18 months (HR = 0.13; 95% CI, 0.03-0.54).

The bigger question concerns what endpoint should be used for all trials of injectable agents, Han said.

“Durable response is not a standard endpoint,” he said. “OPTiM brought out the fact that injection therapy can be efficacious, but we have to look at what kind of endpoint we want to use in future trials of intralesional agents. In today’s world, will response or survival be the measure of efficacy for intralesional agents among patients with metastatic melanoma?”

Survival data from the OPTiM trial have not yet been presented.

“It would seem unlikely that the survival would match data from nivolumab or pembrolizumab alone, which are both pretty safe drugs,” Weber said. “So, I don’t see it making a big headway in metastatic melanoma. In frontline treatment, we have drugs now that show significant 2- to 5-year treatment plateaus, which suggest that some of those patients are cured.”

Five-year OS is around 35% for nivolumab alone, and 2-year OS is around 62% — with a plateau starting to develop after that — for ipilimumab plus nivolumab, Weber said.

“It seems unlikely that you are going to see those kinds of long-term survival with T-VEC alone,” Weber added.

Utility of combinations

Combination regimens that include immunotherapies have become a standard of care in many cancers, including advanced melanoma.

Because T-VEC can enhance the efficacy of checkpoint inhibitors, its optimal use may be in a combination.

“There are many patients who have tumors that do not have tumor-infiltrating lymphocytes, and checkpoint inhibitors cannot work unless those lymphocytes are there,” Andtbacka said. “Using an oncolytic therapy can actually change the tumor microenvironment, and essentially make a ‘cold’ tumor become a ‘hot’ tumor. When we do that, it appears that we can make a nonresponder into a responder.”

Several studies have evaluated an immune checkpoint inhibitor in combination with T-VEC.

A preliminary analysis of a multicenter trial investigating T-VEC in combination with ipilimumab — presented by Puzanov and colleagues at the ASCO Annual Meeting in 2014 — showed an ORR of 41% (complete response, 24%; partial response, 18%), a median time to response of 2.9 months and a stable disease rate of 35%. The adverse event profile appeared tolerable, with no dose-limiting toxicities.

Additional data from the trial show the ORR for the combination reached 56%.

“The preliminary data for T-VEC combinations look promising,” Han said. “The whole idea of treating systemic melanoma has really blossomed into the idea of combination therapy. Combining T-VEC with other effective systemic treatments was the natural next step to see if we could further improve outcomes.”

Long and colleagues have initiated the MASTERKEY-265 trial, a study of T-VEC in combination with pembrolizumab for patients with unresected stage IIIB or stage IV melanoma.

Preliminary safety data presented last year at the European Cancer Congress showed a treatment-related adverse event rate of 19%, with no dose-limiting toxicities and no patients discontinuing treatment due to adverse events.

“The beauty of combinations is that you can take a patient who has an in situ tumor reachable by a needle and inject it with something that makes the tumor more immunogenic,” Agarwala said. “If you throw in a confirmed immunotherapy that works well, you have the potential for synergy.”

Because melanoma has been shown to respond to combinations, the use of these regimens should be considered when possible, Agarwala added.

“I like to say, ‘Make the tumor your friend, and make it your ally,’” he said. “If you can’t remove the tumor — if you’ve tried everything and it keeps coming back — instead of just trying to remove it again or giving systemic therapy, why not add an intralesional agent that gets into the microenvironment and releases antigens? That is a concept that highly appeals to me.”

However, these agents cost thousands of dollars a year when used alone. Use in combinations only increases concerns about cost.

“It is really important to think about cost as we move forward,” Andtbacka said. “How much can we afford as a society, on a per-patient basis, to pay for these drugs? Through research, we should try to figure out which patients are most likely to respond, in an attempt to become ultimately cost conscious.”

The labor involved in preparing a T-VEC injection may drive cost-related considerations.

“The biggest cost factor with an intralesional therapy, aside from the drug, is time,” Agarwala said. “It’s not just a nurse hanging a bag. You have to have a doctor or a provider actually do a procedure, and that procedure is billable. It taxes the provider’s time. I am not sure if anyone has studied the total cost yet, but the short answer is that it’s an issue.”

Weber agreed.

“An injection like this can take up a room for 20 minutes and might be viewed as a hassle by a doctor with a busy practice,” Weber said. “If a nurse practitioner is doing the injection, that’s time she or he is not seeing other patients. I do not think it is unreasonable to say that some busy oncologists view it as more work than it is worth.”

The future of oncolytic agents

T-VEC is the first intralesional agent to be approved as monotherapy for the treatment of advanced melanoma. However, it is far from the only oncolytic agent under investigation.

“These agents are safe and produce good response rates,” Agarwala said. “Some of the ongoing trials of new oncolytic agents can address the concerns left over from the OPTiM trial.”

Agarwala serves as an investigator on a phase 3 study investigating PV-10 (Provectus Biopharmaceuticals), an injectable form of rose bengal disodium that received FDA orphan drug designation for melanoma and hepatocellular carcinoma.

Thompson and colleagues conducted a phase 2 study of PV-10 in 80 patients with stage III or stage IV melanoma. Results, published last year in Annals of Surgical Oncology, showed PV-10 induced an ORR of 51% and a complete response rate of 26%. Median time to response was 1.9 months.

A phase 3 trial began in January, and the first patients enrolled were randomly assigned PV-10 or systemic chemotherapy with dacarbazine or temozolomide.

“The current PV-10 randomized trial only includes patients who have failed immunotherapy or are not candidates,” Agarwala said. “In that sense, it is much more of a real-world trial [than OPTiM]. The control arm of the trial is chemotherapy, which is reasonable, because if you have tried everything else, it is a fair comparator.”

Other research has evaluated the use of coxsackievirus type A21 (Cavatak, Viralytics) — a formulation of the common cold virus that is also called CVA21 — to target melanoma. Andtbacka and colleagues presented final phase 2 data from the CALM trial at the ASCO Annual Meeting last year. Results showed 38.6% of patients treated with CVA21 achieved 6-month immune-related PFS and 75.4% achieved 1-year survival.

These data prompted the initiation of an extension study in which researchers evaluated biopsies from CVA21–injected and –noninjected lesions. Researchers observed increases in immune cell infiltrates in all four patients who had failed immune checkpoint blockade.

“Cavatak can be administered intravenously, at very high doses, with really only grade 1 toxicities,” Andtbacka said. “When we deliver it, it seeks out and gets into tumors. It provides a mechanism to use oncolytic immunotherapies in patients who do not have an injectable lesion, or a lung or liver metastasis. In this case, we can go beyond intralesional agents.”

These agents also are being compared in combinations. The MITCI study is evaluating CVA21 plus ipilimumab for patients with unresectable melanoma. Early data demonstrated signs of antitumor activity at 14 weeks in metastatic visceral and nonvisceral lesions.

A phase 1b/2 trial is evaluating the combination of PV-10 with pembrolizumab in patients with stage IV melanoma (NCT02288897).

The continued study of oncolytic agents may be beneficial for T-VEC, Sondak said.

“These agents may have theoretical or practical advantages compared with T-VEC,” Sondak said. “They are all worthy of investigation, without question, and some could be real advances. There is value to having T-VEC available, but it will also be important for these other agents to have their chance to show what they can do.”

Although T-VEC has been added to the melanoma treatment armamentarium, it remains unclear how best to use it, Han said.

“We are still feeling our way around how T-VEC is going to be incorporated into the available options,” he said. “We can utilize T-VEC as a second-line or salvage therapy to treat injectable lesions that progress on systemic therapy. It gives us another treatment option for lesions that don’t respond and become problematic. But at this point, it is hard to say when we would use T-VEC as a frontline monotherapy for patients with distant metastatic melanoma.”

However, oncologists should keep the demonstrated benefits of T-VEC in mind, Andtbacka said.

“We just presented updated data [from the OPTiM trial], and among all patients treated with T-VEC, the complete response rate was 17%, meaning one in six patients had a complete response,” Andtbacka said. “That is something that is often overlooked, and it is a very important aspect. More than 70% of patients who had a complete response remained without disease after 3 years. That is impressive durability.” – by Cameron Kelsall

References:

Andtbacka RH, et al. Abstract 9030. Presented at: ASCO Annual Meeting; May 29-June 2, 2015; Chicago.

Andtbacka RH, et al. J Clin Oncol. 2015;doi:10.1200/JCO.2014.58.3377.

Andtbacka RH, et al. J Immunother Cancer. 2015;doi:10.1186/2051-1426-3-S2-P343.

Curti B, et al. Abstract CT021. Presented at: AACR Annual Meeting; April 16–20, 2016; New Orleans.

Hersey P and Gallagher S. J Surg Oncol. 2014;doi:10.1002/jso.23494.

Kaufman HL, et al. J Immunother Cancer. 2014;doi:10.1186/2051-1426-2-S3-P91.

Kaufman HL, et al. J Immunother Cancer. 2016;doi:10.1186/s40425-016-0116-2.

Long GV, et al. J Immunother Cancer. 2015;doi:10.1186/2051-1426-3-S2-P181.

Ott PA and Hodi FS. Clin Cancer Res. 2016;doi:10.1158/1078-0432.CCR-15-2709.

Puzanov I, et al. Abstract 9029. Presented at: ASCO Annual Meeting; May 30-June 3, 2014; Chicago.

Puzanov I, et al. Results from a phase 1b multicenter trial evaluating safety and efficacy of talimogene laherparepvec (T-VEC) plus ipilimumab in patients with previously untreated, unresected stage IIIB-IV melanoma. Presented at: HemOnc Today Melanoma and Cutaneous Malignancies; April 10-11, 2015; New York.

Quinn C, et al. Adv Ther. 2016;doi:10.1007/s12325-016-0313-x.

Ribas A, et al. Abstract TPS9081. Presented at: ASCO Annual Meeting; May 29-June 2, 2015; Chicago.

Thompson JF, et al. Ann Surg Oncol. 2015;doi:10.1245/s10434-014-4169-5.

Zhang L, et al. Clin Cancer Res. 2015;doi:10.1158/1078-0432.CCR-14-2085.

For more information:

Sanjiv S. Agarwala, MD, can be reached at ssagarwala0501@gmail.com.

Robert H.I. Andtbacka, MD, CM, FACS, FRCSC, can be reached at robert.andtbacka@hci.utah.edu.

Dale Han, MD, can be reached at dale.han@yale.edu.

Vernon K. Sondak, MD, can be reached at vernon.sondak@moffitt.org.

Jeffrey S. Weber, MD, PhD, can be reached at jeffrey.weber2@nyumc.edu.

Disclosure: Agarwala and Andtbacka report investigator roles on the OPTiM trial. Agarwala also reports an investigator role on trials studying PV-10. Andtbacka reports an investigator role on the CALM trial, as well as honoraria from Amgen and Provectus. Sondak reports consultant roles with Amgen, Bristol-Myers Squibb, Merck and Provectus. Weber reports an advisory board role with Amgen. Han reports no relevant financial disclosures.

 

 

Should nurses be trained to administer T-VEC without supervision?

Nurses can safely administer T-VEC without supervision.

The FDA has approved a large number of new therapies and therapeutic regimens for melanoma since 2011, the majority of which are systemic therapies. These therapies carry the potential for systemic adverse events, but they are useful and effective in patients with widespread metastatic disease that is not easily resectable. For patients with more localized disease, typically confined to the skin and soft tissue, intralesional therapy can be used to control disease and stave off further progression in a local fashion. Talimogene laherparepvec (Imlygic; BioVex, Amgen) is very well tolerated and can serve a real need in this patient population.

The administration of talimogene laherparepvec, or T-VEC, is viewed by some as burdensome. The preparation and handling of the drug require as much focus and attention as the injection. T-VEC is a virus, so it must be stored at a specific temperature and requires up to an hour to thaw. Once it has thawed, it needs to be administered immediately. These are very expensive drugs, so a pharmacy cannot thaw a dose of T-VEC if there is not 100% certainty that the patient will receive his or her injection.

A problem that many busy practices run into has to do with time. A patient has to come and check in, but it may be several hours before he or she is actually injected. This can interrupt the flow of the office, in addition to being cumbersome for the patient. This is a problem that should be remedied.

There are no restrictions on the type of practitioner who is allowed to administer T-VEC. With appropriate training and guidance on handling, administration and the selection of lesions to inject, mid-level providers such as nurses can safely administer an injectable agent such as T-VEC. These nurses would also need to be provided with the correct information about potential adverse events and necessary cleanliness to impart to the patient. Training nurses to administer T-VEC may serve as an appealing solution for medical practices that are interested in providing T-VEC injections but worry about the time and effort involved if administration is only done by an advanced practice professional.

Marlana M. Orloff, MD, is a melanoma and skin cancer researcher and assistant professor of medical oncology at Sidney Kimmel Cancer Center at Thomas Jefferson University. She can be reached at marlana.orloff@jefferson.edu. Disclosure: Orloff reports no relevant financial disclosures.

Advanced practice professionals should administer intralesional agents.

Intralesional agents such as talimogene laherparepvec (Imlygic; BioVex, Amgen) are directly injected into superficial tumors in the hopes of provoking an immune response to shrink the tumors. For the subset of the melanoma population for whom localized skin or subcutaneous lesions are the most relevant lesions to treat, it is a viable treatment option, and can allow patients to achieve disease control. There is the hope that the systemic effect of the injection, which stimulates the immune system, may delay the development of other new lesions.

At most hospitals or practice centers, talimogene laherparepvec — commonly referred to as T-VEC — is injected by a medical doctor, nurse practitioner or physician assistant. A nurse could probably be trained to inject T-VEC, provided that the injection occurred in an environment where a support team was in place should any type of unusual reaction occur, which we sometimes see with immune-based therapies. Because the therapy is being injected directly into a tumor, the potential for an adverse reaction must be taken seriously, and appropriate medical staff should be in place.

In addition to the need for supervision, additional training would be required to prepare nurses to inject T-VEC. Extra training is accompanied by extra costs, which might be seen as money better spent in other areas. The extra time and effort that would need to be expended by the trainer — be it a physician or nurse practitioner — and the trainee could be spent seeing patients or doing other relevant work.

Nurses are trained to give a number of injections, and they are very qualified to do so. But because of the unique circumstances of administering this particular agent, I think we will continue to see a trend toward injections being performed by advanced practice professionals.

 

Gregory A. Masters, MD, FACP, FASCO, is an attending physician and director of the medical oncology fellowship at Christiana Care’s Helen F. Graham Cancer Center and Research Institute in Newark, Delaware. He can be reached at gmasters@cgb.org. Disclosure: Masters reports no relevant financial disclosures.