Melanoma Coverage From Every Angle

Talimogene Laherparepvec (Imlygic®)

Posted: Thursday, September 6, 2018

Oncolytic Viral Immunotherapy

Although options for the systemic treatment of melanoma have increased in recent years, local therapy options for unresectable disease remain limited. Talimogene laherparepvec is an oncolytic viral immunotherapy delivered by intratumoral injection.1,2 T-VEC, as it is commonly called, is a genetically modified herpes simplex virus (HSV). It was approved by the U.S. Food and Drug Administration in 2015 for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma that has recurred after initial surgery.3,4 It is listed among intralesional injection options in national treatment guidelines.5

The efficacy of T-VEC was established in the phase III OPTiM trial, which led to its approval. The rate of durable response (complete or partial response sustained for at least 6 months) was 16.3% with intralesional T-VEC compared with 2.1% with subcutaneous GM-CSF among patients with stages IIIB to IV melanoma (odds ratio, 8.9; P<.001).6 The efficacy of T-VEC over GM-CSF was better among patients with stage IIIB or IIIC disease (33% vs 0%) and in the subset of patients with IVM1 disease. The efficacy of T-VEC over GM-CSF was better in all stages among previously untreated patients with metastatic disease (24% vs 0%). Patients experiencing a durable response had significantly better overall survival and a longer treatment-free interval.7

Effective Option for Niche Population

T-VEC is an excellent therapeutic option for certain patients with injectable melanoma lesions, according to Robert H.I. Andtbacka, MD, CM, FACS, FRCSC, Professor in Surgical Oncology, Co-Director of the Melanoma Program, and Director of the Melanoma Clinical Research Program, Huntsman Cancer Institute, Salt Lake City, Utah, who has about a decade of experience using this agent.

“Patients who have earlier stage disease—in-transit disease or lymph node metastases—and patients who, due to medical reasons, may not be candidates for other medical treatments are good candidates for T-VEC,” he noted. “Then we have patients who may not have responded to other therapies, especially checkpoint inhibitors—a programmed cell death protein 1 inhibitor [such as nivolumab] or a cytotoxic T-lymphocyte–associated protein 4 inhibitor such as ipilimumab—but they have an injectable lesion. All of these groups respond extremely well to T-VEC.”

“T-VEC is a great option for a smaller subpopulation of patients,” agreed Kathy Madden, RN, MSN, FNP-BC, AOCNP, APHN, a nurse practitioner in the NYU Langone Cancer Center’s Melanoma Program in New York City, who has worked with this agent for 4 years. “Some patients have a single solitary recurrence; others may have received systemic immunotherapy and now have one or several rogue lesions. Other eligible patients may be elderly and medically fragile or have comorbidities where immunotherapy may be contraindicated,” she told JNCCN 360. “In my practice, we have focused on that older patient who may not be appropriate for a clinical trial or may have had toxicity with standard-of-care immunotherapy, may not have a BRAF mutation, and may have an isolated area of disease. That’s the ideal candidate for T-VEC.”

Patient Education

Educating patients about T-VEC’s safety is important for its successful use, Dr. Andtbacka maintained. “We tell patients about the most common side effects, such as shakes and chills. We also tell them they may experience some pain and redness at the injection site.”

Because T-VEC is a herpes virus, patients often ask about the risk of transmitting it to household members. A recent study assessed viral shedding after injection, centering on factors such as secretion into body fluids and persistence at the injection site.8 “This study helped us to determine the risk to both health-care providers and family members. We did not see any evidence of transmission when recommended precautions are followed,” Dr. Andtbacka said. “Very few risks in life are absolutely zero, but the risk of transmitting T-VEC to family members is exceedingly low.” If T-VEC were to be transmitted,” he explained to JNCCN 360, “it cannot replicate in normal cells, but only in tumor cells.” Additionally, it is sensitive to antiviral agents such as acyclovir.

Patient education is similarly a priority at Ms. Madden’s institution. “We inform patients that T-VEC can be extremely effective, and we want to do everything to keep them on their treatment schedule and hopefully get a nice response,” she said. “Very few of my patients have been side-effect free, so we spend a lot of time educating them about what to look for and encourage them to contact us promptly if they have side effects. Our rule of thumb is that they should report anything that’s out of the ordinary at the onset.”

“We encourage patients to hydrate because T-VEC can cause fever and flu-like symptoms. We don’t want patients, especially older adults, to get dehydrated,” Ms. Madden noted. Providers also assess patients’ reliability in reporting side effects and whether they have help at home, especially as those whose injected lesion is in a hard-to-reach place or who have arthritis or mobility issues may not be able to change their own bandages. “We emphasize the restrictions for caregivers and household members,” she added. “Women who are pregnant or trying to become pregnant and people who are immunocompromised should be cautious around patients receiving T-VEC and not have direct contact with the dressing sites.”

Administration

T-VEC is injected into cutaneous, subcutaneous, and/or nodal lesions that are visible, palpable, or detectable by ultrasound guidance.1,9 At the initial treatment, the largest lesion is injected first, whereas at subsequent treatments, any newly developed lesion or lesions are injected first; additional lesions are selected in the order of decreasing size. In rare cases, lesions that are near vital organs or sensitive locations such as the trachea or eye might be avoided. This is always an individual clinical judgment made by the provider, Ms. Madden explained.

The injection uses a single insertion point with multiple tracks as far as the needle’s radial reach allows within the lesion to evenly disperse T-VEC.1,9 Lesions larger than that reach may require multiple insertion points. On completion, the needle should be withdrawn slowly to prevent T-VEC leakage at the insertion point. The procedure is repeated with a new needle for each additional lesion.

Providers just starting to use T-VEC should take advantage of the manufacturer’s educators to hone their injection technique, Ms. Madden recommended. “The procedure for giving T-VEC is new for some clinicians. Even those of us accustomed to performing biopsies and injecting anesthesia into lesions appreciated the educational support. We have skill around lesional procedures and care, but there are definitely some nuances involved with T-VEC injections,” she remarked. 

We have skill around lesional procedures and care, but there are definitely some nuances involved with T-VEC injections.

Optimizing Efficacy

“To optimize the efficacy of T-VEC, we follow the package insert,” Dr. Andtbacka reported. That entails giving the first treatment at a lower dose, the second treatment 3 weeks later at a higher dose, and subsequent treatments every 2 weeks thereafter at the higher dose. “However, we have learned that sometimes, we can stretch the schedule a little bit,” he added, whereby patients unable to come back every 2 weeks are treated every 3 weeks instead.

“Providers need to be aware that it takes time for these immunotherapies to work,” Dr. Andtbacka told JNCCN 360; the median time to response on the OPTiM study was 17 weeks.6 “So even if some new lesions are developing or the existing lesions are getting bigger, providers should continue injecting T-VEC as long as the patient is not having clinically substantial disease progression. We need to persist with this treatment, because it is common for patients to turn a corner and then start responding.”

Providers need to be aware that it takes time for these immunotherapies to work.

Another key to optimizing the efficacy of T-VEC is keeping patients on schedule, which means promptly managing any side effects, Ms. Madden said. “We try to catch any adverse effects early so patients don’t feel wiped out from them. The sooner we can intervene and mitigate side effects, the less they interfere with patients’ lives and schedules, as 2 weeks is a relatively short period between treatments.”

Her team also tries to avoid giving patients antiviral agents such as acyclovir and famciclovir because they can reduce the effectiveness of T-VEC.1 “If somebody develops a symptomatic herpes outbreak with draining, oozing herpetic lesions, we certainly treat them. But if they have one little spot that isn’t bothering them, we try to manage it conservatively,” she explained.

Bystander and Priming Effects

T-VEC has been clearly shown to have a bystander effect on regionally noninjected melanoma metastases, with 34% of lesions responding.10 Although it is not injected into visceral melanoma metastases, 15% of those metastases decreased in size. In the initial analysis of overall survival in the OPTiM trial, T-VEC did not statistically improve survival.1 However, in a final survival analysis, when patients had at least 3 years of follow-up, overall survival was better for those treated with T-VEC, though the statistical significance was small.11 Further, whether survival is improved with T-VEC over more-effective therapies than GM-CSF is not clear.

“Providers should consider T-VEC for [some] patients with unresectable earlier [stage] disease, stage IIIB or IIIC, and stage IV M1a disease,” Dr. Andtbacka said. “In these patients, it works extremely well—not only in the injected lesions, but also in the noninjected lesions. T-VEC has the potential to change the tumor immune microenvironment, to turn nonresponders into responders. It may also decrease the risk of those patients developing visceral metastases.”

In addition, there are hints that T-VEC’s immune-activating properties may boost the effectiveness of concurrent or sequential melanoma therapies, according to Ms. Madden. “One of our patients had diffuse disease down the left side of her face and neck. We chose some ‘hot spot’ lesions to treat with T-VEC. Not everything went away, but she had a nice response,” she reported. “The patient was subsequently started on a new treatment, and we think T-VEC may have primed her immune system, aiding in a response resulting in stable disease for about a year.”

Preventing and Managing Adverse Effects

In clinical trials, the most commonly reported any-grade adverse reactions to T-VEC were fatigue (50.3%), chills (48.6%), pyrexia (42.8%), nausea (35.6%), influenza-like illness (30.5%), and injection-site pain (27.7%).1 However, most reactions were mild or moderate, and they generally resolved within 72 hours.

“T-VEC is extremely well tolerated. Patients have very few grade 3 and higher toxicities,” Dr. Andtbacka commented. “If you just keep an eye on the more common ones and premedicate patients if needed, you can use T-VEC in patients of all ages and with all comorbidities.”

Chills and Rigors

Patients may experience chills and rigors after the first few injections of T-VEC. “If that happens, we often premedicate with acetaminophen and diphenhydramine to lessen those side effects. On a rare occasion, we may give corticosteroids,” Dr. Andtbacka said.

“We don’t automatically premedicate everyone or give everyone medications post-treatment, but we might do so in those who had cytokine-release type of symptoms with the first treatment,” Ms. Madden agreed. Her clinic likewise uses acetaminophen or ibuprofen and occasionally low-dose diphenhydramine, exercising caution in older patients who may be more sensitive to that drug.

Patients are instructed to resume these medications starting 8 hours after their injection. “We usually follow up with them about 24 hours after their injection(s) to make sure they are okay,” Ms. Madden said. “Depending on how they are feeling, we’ll determine how long we continue postinjection medications. Typically, patients don’t need them beyond 2 to 3 days.”

Redness and Discomfort at Injection Site

Redness and discomfort occurring at the T-VEC injection site typically represent an inflammatory response signaling activation of the immune system. “Patients need to be told that it is uncommon for redness to signal an infection. It is usually just inflammation due to infiltration of lymphocytes into the area of injection,” Dr. Andtbacka explained.

“If patients experienced considerable discomfort from a previous T-VEC injection, instead of applying lidocaine cream, which may not penetrate the lesion well, we apply ice on the area before we inject it. The ice numbs the area and can be quite helpful,” he reported. “In patients who have a lot of inflammation at the injection site, we may hold T-VEC and wait 1 more week before we administer the next injection, but that’s extremely uncommon.”

Cellulitis

An uncommon but potentially serious adverse effect of T-VEC is cellulitis at the injection site. In Ms. Madden’s experience, only a single patient had to stop T-VEC because she became bacteremic from recurrent cellulitis.

“It is something we certainly have to monitor,” she said. “If someone has developed milder cellulitis after a previous T-VEC injection, we remind them to report symptoms very early with subsequent injections. I wouldn’t start prophylactic antibiotics, but I would partner with an infectious disease specialist if the cellulitis was caused by an organism that needed long-term monitoring.”

Logistical Considerations

“Some providers perceive T-VEC to be difficult to use and are concerned that it can disrupt clinic flow, but that’s not really the case,” Dr. Andtbacka commented. “Once you’ve set up a process for giving T-VEC, things flow very easily. We do not use a special room. We clean the room the same way we would between any other (non–T-VEC) patients.”

The approach differs at Ms. Madden’s institution, and she recommended that clinics planning to use this therapy first consider facility issues. “Our patients usually receive treatments in our main clinic area, which is much more public and where we conduct our exams. We worked with our biosafety specialists to designate a room for T-VEC administration,” she explained. “You can do a quicker clean down of a room used for T-VEC injections between successive patients receiving this treatment. In contrast, if the next patient is neutropenic because of chemotherapy, the room has to be taken out of commission and terminally cleaned.”

T-VEC treatments may require careful scheduling and coordinating a variety of staff members. “Scheduling includes our receptionists, who generate a bracelet and scannable ID for our patients, and our floor manager, who communicates with our facility staff so they can stock the room with personal protective equipment and supplies. We also need to coordinate with our pharmacy to ensure that proper procedures and preparation are followed and that there is enough time to ‘thaw’ the T-VEC, as it needs to come to room temperature before being drawn up,” Ms. Madden explained. [Editor’s Note: T-VEC is usually stored and delivered to clinicians in frozen form.]

Future Relevance and Directions

T-VEC monotherapy will remain an important option in the melanoma treatment armamentarium, Dr. Andtbacka shared with JNCCN 360. In addition, ongoing trials are assessing its performance as part of combination therapy,12 with encouraging data suggesting that T-VEC works well when paired with immune checkpoint inhibitors such as ipilimumab13 and pembrolizumab.14

“Moving forward, combinations will be the key,” he predicted. “If you have injectable lesions, T-VEC adds minimally to the adverse events of these other therapies. The combinations are well tolerated. Most of the grade 3 and worse toxicities are from the checkpoint inhibitor. So, T-VEC will be used in combination, and I think it’s going to become an important drug in that respect.”

Research also suggests that T-VEC is efficacious when given as neoadjuvant therapy in patients with resectable melanoma.15 “When used in this way, it likely activates the immune system prior to surgery, which may ultimately decrease the risk of recurrence,” Dr. Andtbacka explained.

Sequencing and combining T-VEC with other therapies...enhanced effectiveness and boosted the immune response in some of our patients.

“Sequencing and combining T-VEC with other therapies, such as pembrolizumab, enhanced effectiveness and boosted the immune response in some of our patients, both on trial and off trial,” Ms. Madden reported. “We’ve had some patients tolerate it and other patients develop enhanced inflammatory responses. But we just manage those as previously described.”

“T-VEC is going to remain an important treatment for a specific subpopulation,” Ms. Madden told JNCCN 360. “Systemic therapies and combinations are evolving, and this may be a good answer for recalcitrant lesions or clusters of lesions that are not surgically resectable. It will be interesting to see what other therapies T-VEC might work well with, to synergize and enhance the immune response.”

 

Disclosures

Robert H.I. Andtbacka, MD, CM, FACS, FRCSC, disclosed that he received research funding and honoraria from Amgen.

Kathy Madden, RN, MSN, FNP-BC, AOCNP, APHN, disclosed no relevant relationships.

 

References

  1. Imlygic® (talimogene laherparepvec). Highlights of prescribing information. Available at https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM469575.pdf. Accessed August 22, 2018.
  2. National Cancer Institute. Talimogene laherparepvec. Available at https://www.cancer.gov/publications/dictionaries/cancer-drug/def/talimogene-laherparepvec. Accessed August 22, 2018.
  3. NCI Staff, National Cancer Institute. FDA approves talimogene laherparepvec to treat metastatic melanoma. November 25, 2015. Available at https://www.cancer.gov/news-events/cancer-currents-blog/2015/t-vec-melanoma. Accessed August 22, 2018.
  4. Jhawar S, Goyal S, Bommareddy PK, et al. Talimogene laherparepvec (T-VEC) as cancer immunotherapy. Personalized Medicine in Oncology 2017;6. Available at: http://www.personalizedmedonc.com/publications/pmo/march-2017-vol-6-no-1/talimogene-laherparepvec-t-vec-as-cancer-immunotherapy/. Accessed August 30, 2018.
  5. Coit DG, Thompson JA, Albertini MR, et al. NCCN Clinical Practice Guidelines in Oncology: Melanoma. Version 2.2018. Accessed August 22, 2018. To view the most recent version of these guidelines, visit NCCN.org.
  6. Andtbacka RH, Kaufman HL, Collichio F, et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol 2015;33:2780–2788.
  7. Kaufman HL, Andtbacka RHI, Collichio FA, et al. Durable response rate as an endpoint in cancer immunotherapy: insights from oncolytic virus clinical trials. J Immunother Cancer 2017;5:72.
  8. Andtbacka RHI, Mehnert J, Nemunaitis JJ, et al. Phase 2 trial evaluating biodistribution and shedding of talimogene laherparepvec (T-VEC) in patients with unresectable stages IIIB/IV melanoma. Presented at 20th Annual Meeting of the American Society of Gene & Cell Therapy. Washington, DC; May 10–13, 2017. Abstract 16.
  9. Harrington KJ, Michielin O, Malvehy J, et al. A practical guide to the handling and administration of talimogene laherparepvec in Europe. Onco Targets Ther 2017;10:3867–3880.
  10. Andtbacka RH, Ross M, Puzanov I, et al. Patterns of clinical response with talimogene laherparepvec (T-VEC) in patients with melanoma treated in the OPTiM phase III clinical trial. Ann Surg Oncol 2016;23:4169–4177.
  11. Andtbacka RHI, Collichio FA, Amatruda T, et al. Final planned overall survival from OPTiM, a randomized phase III trial of talimogene laherparepvec (T-VEC) versus GM-CSF for the treatment of unresected stage IIIB/C/IV melanoma (NCT00769704). J Immunother Cancer 2014;2(suppl 3):P263.
  12. Orloff M. Spotlight on talimogene laherparepvec for the treatment of melanoma lesions in the skin and lymph nodes. Oncolytic Virother 2016;5:91–98.
  13. Puzanov I, Milhem MM, Minor D, et al. Talimogene laherparepvec in combination with ipilimumab in previously untreated, unresectable stage IIIB-IV melanoma. J Clin Oncol 2016;34:2619–2626.
  14. Ribas A, Dummer R, Puzanov I, et al. Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy. Cell 2017;170:1109–1119.
  15. Andtbacka RHI, Chastain M, Li A, et al. Phase 2, multicenter, randomized, open-label trial assessing efficacy and safety of talimogene laherparepvec (T-VEC) neoadjuvant treatment plus surgery vs surgery for resectable stage IIIB/C and IVM1a melanoma. J Clin Oncol 2015;33(suppl). Abstract TPS9094.

 



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