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Abstract
In-transit metastases of malignant melanoma pose a significant clinical challenge, particularly in patients with contraindications to systemic therapies. While surgical excision and systemic immunotherapies remain standard treatments, localized therapies such as intralesional talimogene laherparepvec (T-VEC) and topical imiquimod, which stimulate tumor-specific T-cell responses, have garnered increasing attention for their potential efficacy and tolerability. Although the individual efficacy of these therapies is well-documented, their combined use and their synergistic effects have not been well-documented. This case series reports on five patients with in-transit melanoma metastases treated with T-VEC and imiquimod at Northwestern Memorial Hospital from November 2018 to May 2023. Patients received a median of 13 (range 8–20) T-VEC injections over a median of 6 months (range 5–9), of which 4 of those months were with concurrent T-VEC and imiquimod cream. Four of the five patients achieved complete response (CR) by the end of the treatment course. One patient developed systemic progression during therapy, leading to early cessation of treatment. All patients with CR elected to continue topical imiquimod applications as maintenance following T-VEC for a median of 6 months (range 2–14 months). Only one of the four patients who achieved CR developed metastatic nodal disease 10 months after the last T-VEC injection. The three other patients are free of cutaneous and systemic disease 2–57 months after their last injection. All patients tolerated treatment well with zero patients discontinuing treatment due to side effects. These findings suggest that the combination of intralesional T-VEC and topical imiquimod can be an effective and safe treatment of in-transit metastases of malignant melanoma.
- Melanoma
- Intralesional
- Immunotherapy
- Oncolytic virus
Data availability statement
All data relevant to the study are included in the article or uploaded as online supplemental information.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.
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Introduction
In-transit metastasis is a unique phenomenon to malignant melanoma. Believed to be associated with the entrapment of tumor cells within the regional lymphatics at the site of the primary tumor, the American Joint Committee on Cancer defines any metastasis more than 2 cm away from the primary lesion but still within regional nodal basin as an in-transit metastasis. A spectrum of therapeutic options is available, including surgical excision, immune checkpoint inhibitors (ICIs), and locoregional therapies like intraarterial regional perfusion, topical immunotherapy, and intralesional injections, like talimogene laherparepvec (T-VEC).1
T-VEC is a genetically modified herpes simplex-1 virus (HSV-1), engineered to express granulocyte-macrophage colony-stimulating factor (GM-CSF) in place of neurovirulence factors and was Food and Drug Administration (FDA)-approved in 2015 for treatment of non-resectable in-transit melanoma metastasis. This oncolytic virus causes tumor lysis through stimulating Major Histocompatibility Complex (MHC) class I activation for better detection and using GM-CSF to contribute to the inflammatory milieu that aids in the antitumor immune effect. Phase 3 trials have demonstrated durable responses to T-VEC alone, but concurrent treatment with T-VEC and other therapies, such as ICIs, have also been evaluated with mixed results.
The value of topical imiquimod has also been analyzed for in-transit metastasis. Imiquimod is a potent immune system modulator that works by binding to toll-like receptors 7 and 8 to induce various immunostimulatory cytokines.2 Prior studies have shown varying degrees of success with imiquimod monotherapy or its combination with adjunctive therapies, like cryotherapy, topical tretinoin, and intralesional injections, such as interleukin-2 or Bacille Calmette-Guerin vaccine.3 Because both T-VEC and imiquimod carry the ability to stimulate tumor-specific T-cell responses, our group previously used this combination approach and reported its efficacy in treating multiple in-transit melanoma metastases in a renal transplant patients after there was inadequate clinical response to T-VEC alone.4 To our knowledge, our group is the first to report this combination therapy. We share this case series to provide an update to our previously published case report and to share the efficacy we have observed in other patients.
Methods
Five patients with in-transit melanoma metastases were referred to our Department of Dermatology at Northwestern Memorial Hospital between November 2018 and May 2023.
Treatment protocol
At each visit, the number of metastatic lesions, locations, size, and side effects were documented on a tumor assessment worksheet. Each lesion was designated an identifying number, which allowed for proper monitoring at subsequent visits. The total T-VEC injection volume was calculated based on the size of the largest metastatic lesion, limited to a maximum of 4 mL per session, and subsequently distributed among the metastatic lesions. Treated metastases were documented with the amount of volume each lesion received.
At the initial visit, a lower concentration of T-VEC was used (106 plaque-forming units (PFU) per mL) and followed by higher concentration (108 PFU/mL) at subsequent injections per protocol. The second injection was scheduled 3 weeks after the loading dose, and subsequent injections were scheduled every 2 weeks. T-VEC injections were continued until the metastatic lesions resolved, as determined by a dermatologist.
Topical imiquimod 5% cream was applied starting 4 days after the last injection in order to keep the injection site initially covered for 4 days to minimize risk of HSV spread by contact with the site. Imiquimod was then applied nightly starting on day 5 until the day of next injection. The amount of imiquimod cream was determined by the total aggregate size of the cutaneous metastatic lesions. One 0.5 g packet was applied to cover approximately 5 cm2 total cumulative area. The frequency of imiquimod application was adjusted based on the patient’s tolerability to the therapy and clinical response, transitioning from daily application to intervals of 3 days on/2 days off or every other night, and finally once a week application as maintenance.
Results
Patient characteristics
Two (40%) female and three (60%) male patients with in-transit metastases were included in our study. The median age of patients at the time of their in-transit melanoma diagnosis was 58 years old (range 43–85). Before in-transit recurrence, three patients had initial stage IIIB disease while two patients had stage IIIC disease. Three patients also presented with nodal metastases and no patients had visceral metastases. Four patients with primary melanoma were treated with systemic therapy, of which three patients were treated with adjuvant immunotherapy (ipilimumab/nivolumab, nivolumab, pembrolizumab) and one with adjuvant targeted therapy (encorafenib/binimetinib). Two patients completed systemic therapy and subsequently developed in-transit disease, and two patients developed in-transit metastases while receiving systemic therapy. Only one patient was continued on concurrent immunotherapy with intralesional T-VEC and topical imiquimod. The interval between the primary melanoma diagnosis to in-transit metastases was 10 months (range 3–95 months). The median number of in-transit metastases was 12 (range 9–21). Full patient characteristics are shown in table 1.
Patient characteristics
Response to treatment
Four patients began T-VEC injections as monotherapy without adequate response, and these patients were referred to dermatology who recommended the addition of imiquimod as adjuvant therapy. Topical imiquimod was added after a median of 3 T-VEC injections (range 2–13) for these patients. Only one patient began imiquimod at the start of T-VEC therapy after the successful use of this combination approach in prior patients.
Patients received a median of 13 (range 8–20) T-VEC injections over a median of 6 months (range 5–9), of which 4 of those months were with concurrent T-VEC and imiquimod. Four patients achieved complete response (CR). CR was defined by clinical examination and dermoscopic examination of the treated area to identify any abnormal dermoscopic features suggestive of melanoma. The complete response to treatment in Patient 2 is demonstrated in figure 1. Histology examination was also performed on two patients by taking scouting biopsies, which documented no remaining histological evidence of melanoma. Patient 1 developed progressive metastatic disease during therapy with a combination T-VEC, topical imiquimod, and pembrolizumab, requiring early termination of T-VEC to switch to a different systemic immunotherapy. All patients with CR elected to continue once weekly topical imiquimod application as maintenance following cessation of T-VEC injections for a median of 6 months (2–14 months), though two of these patients are still undergoing maintenance applications at present. Duration of maintenance imiquimod application was determined based on the patient’s tolerability. Scouting biopsies after treatment with T-VEC and imiquimod was performed on two patients which found no residual disease and granulomatous dermatitis, most likely secondary to medication application.
Patient 2 before (A) and after (B) treatment with 20 cycles of T-VEC injections and 4 months of concurrent imiquimod 5% cream application. T-VEC, talimogene laherparepvec.
Of the four patients who achieved CR, only one patient developed metastatic nodal disease 10 months after the last T-VEC injection and was subsequently treated with surgical resection and nivolumab. The three other patients are free of cutaneous and systemic disease 4–59 months after their last injection. The median follow-up for all patients was 16 months. Patient treatment and responses are summarized in table 2.
Treatment summary and response
Side effects
All patients experienced fatigue. Four patients experienced grade 1 influenza-like symptoms, including fevers, chills, and body aches. Two patients also experienced gastrointestinal discomfort, including nausea, vomiting, and diarrhea. Symptom severity peaked at treatment onset but gradually diminished in intensity and duration with subsequent injections. These side effects were consistent with the independent adverse effects reported for T-VEC and imiquimod. Four patients were prescribed a pre-injection regimen of omeprazole, diphenhydramine, and acetaminophen to mitigate side effects.
All patients experienced tenderness at the injection sites. Two patients developed profound skin reactions; one patient developed impetigo, requiring a short course of oral and topical antibiotics and temporary halt of imiquimod application.
Discussion
There is an estimated 4%–10% risk of developing in-transit metastasis after approximately 18 months following diagnosis of primary melanoma.5 There has been an increased focus on localized therapies, especially for patients with multiple comorbidities or contraindications to systemic therapies. To our knowledge, this case series presents the first detailed exploration of the combined use of intralesional T-VEC and topical imiquimod cream for the treatment of in-transit metastases of malignant melanoma. Building on our previous case report, this study provides additional insights into treatment outcomes, recurrence, and side effects of a combination T-VEC and topical imiquimod.
Overall, 4/5 (80%) patients developed a CR rate (CRR), as defined as complete resolution of their metastatic cutaneous lesions, and 3/5 (60%) achieved a 6-month durable response rate (DRR) when treated with intralesional T-VEC and topical imiquimod. Of the two patients who did not achieve a 6-month DRR, one patient developed progression of disease 5 months into treatment, and one patient has not had sufficient follow-up to determine 6-month DRR. The median treatment duration of T-VEC and imiquimod was 16 weeks, which was comparable to other T-VEC monotherapy studies. The OPTiM phase 3 clinical trial evaluating T-VEC monotherapy for stages III–IV unresectable melanoma demonstrated a CRR and DRR of 10.8% and 16.3%, respectively.6 Though our patient cohort was smaller, the higher CRR and DRR among our patient cohort may suggest an enhanced therapeutic response with the combination treatment.
However, retrospective review of data from the OPTiM trial found that patients with melanoma arising in the head and neck had a particularly favorable response to intralesional TVEC with a CR of 30% and DRR of 36%. In our patient cohort, four of the five patient’s primary melanomas were located in the head and neck, potentially priming them for favorable response to intralesional TVEC. Following initiation of intralesional T-VEC, 2/5 (40%) patients developed new lesions. This clinical finding has been coined “pseudoprogression” and is a phenomenon that was observed in more than 50% of cases in the OPTiM trial.6 Interestingly, our patients’ old and new lesions quickly resolved after adding topical imiquimod to their treatment regimen. Joseph et al’s report detailing two cases of metastatic melanoma treated with ipilimumab and imiquimod noted similar worsening of cutaneous lesions prior to addition of imiquimod and proposed that imiquimod may have desensitized the tolerance of already present T-cells in the area, allowing the lesions to resolve.7 However, it is difficult to determine if the cutaneous lesions in these two patients would have improved regardless of the use of imiquimod. Differentiating between pseudoprogression and true disease progression is challenging, and ideally would be determined by histological tissue examination.
While T-VEC alone or in combination is effective in controlling locoregional disease, its efficacy in systemic disease control is limited. In concordance with prior studies, one patient (patient 5) developed intranodal recurrence while on maintenance imiquimod therapy despite achieving CR and remaining free of in-transit disease for 10 months after cessation of T-VEC injection. Another patient (patient 1) who had the greatest disease burden at treatment initiation developed progression of disease while receiving T-VEC, imiquimod, and immunotherapy, following an initial improvement in the number of metastases. In contrast, Joseph et al showed that the combination of topical imiquimod and ICIs may have a synergistic systemic effect, leading to CR in their cohort and disease-free survival for at least 6 years.7 Additional studies are needed to not only build on this early efficacy data but to also determine the effect on systemic control of disease, the optimal timing of T-VEC administration in relation to immunotherapy, and the desirable patient populations (TVEC+imiquimod vs ICI+imiquimod) for these approaches.
All patients experienced some degree of adverse effects, including fatigue, influenza-like symptoms, and injection site tenderness. Because T-VEC is a modified version of HSV-1, there is a theoretical risk of HSV infection.8 None of our patients developed HSV infection; however, one patient developed impetigo in the treated area requiring antibiotic treatment.
In this small (five patients) case series, the understudied combination of intralesional T-VEC and topical imiquimod 5% cream demonstrated encouraging efficacy results and acceptable safety profiles, supporting the need for further investigations of this treatment combination in larger cohorts. While the longest continuous follow-up has been about 5 years and this patient has remained disease-free, further data on long-term outcomes, recurrences, and side effects are still needed. Additionally, translational studies with pretreatment and post-treatment biopsies may be helpful in evaluating the effect of combination treatment on the tumor microenvironment. Finally, further research with larger sample sizes is essential to better understand this combination treatment’s comparative effectiveness against T-VEC monotherapy and to assess its efficacy in different disease stages.
Conclusion
This report demonstrates the potential of intralesional T-VEC and topical imiquimod as a safe and effective treatment of in-transit metastases of malignant melanoma. Given the locoregional control and minimal adverse effects, this treatment regimen could be especially helpful and considered for patients with transplant histories, chronic immunosuppression, non-resectable disease, and other comorbidities that limit surgical candidacy. This therapeutic combination adds to the armamentarium for treatment of melanoma and may stave off the use of systemic immunotherapy in patients with small volume of cutaneous or in-transit disease.
Data availability statement
All data relevant to the study are included in the article or uploaded as online supplemental information.
Ethics statements
Patient consent for publication
Footnotes
X @MunTheLoon
ML and EC contributed equally.
Contributors All authors contributed to this manuscript and JC is the guarantor.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.