The US Food and Drug Administration has been rapidly approving new checkpoint inhibitors and targeted therapies for melanoma and other tumors. Recently, it approved the first intralesional therapy, talimogene laherparepvec (T-VEC), for the treatment of metastatic melanoma lesions in the skin and lymph nodes. Several other intralesional therapies (PV-10, interleukin-12 electroporation, coxsackievirus A21 [CVA21]) are entering later-stage testing. Locally injected agents have clearly shown their ability to produce local responses that can be durable. The possibility that they also stimulate a regional and even systemic immune response is exciting, as this potential effect may have utility in combination regimens; such regimens are an area of active research. Favorable responses with minimal toxicities in monotherapy trials have led to the first melanoma studies of T-VEC in combination with the cytotoxic T-lymphocyte–associated antigen 4 inhibitor ipilimumab and, separately, with the programmed death 1–blocking antibody pembrolizumab. Studies of PV-10 with pembrolizumab and of CVA21 with pembrolizumab are also being initiated. Preliminary analyses of the results of the first combination trials, which show higher response rates than with either agent alone, offer some optimism that these locoregional therapies will find application—as treatment for patients who cannot tolerate systemic immunotherapies, to alleviate locoregional morbidity, and perhaps even to “prime” the immune system.
PV-10 (rose bengal disodium 10%), a small-molecule fluorescein derivative, while excluded from normal cells, transits the plasmalemma of cancer cells and accumulates in lysosomes, triggering lysosomal release and complete autolysis within 30 to 60 minutes. “Bystander” effects observed in uninjected tumors are believed to ensue as a consequence of acute exposure of antigenic tumor fragments to antigen-presenting cells. The double benefit is immediately reduced tumor burden and immunologic activation.
Our 80-subject, multicenter, international phase II study enrolled patients with measurable stage III/IV melanoma. PV-10 injections were given in up to 10 target lesions of ≥ 0.2 cm in diameter. Also, investigators observed 1 to 2 biopsy-confirmed bystander lesions in each patient. These were typically small or difficult to access, and included visceral lesions.
The CR rate in target lesions was 24% in preliminary reporting. The disease control rate, which combined the CR rate with the PR rate of 25% and the SD rate of 22%, was 71%. CRs were also observed in 24% of untreated bystander lesions, and regression in target lesions correlated strongly with bystander lesion responses. The ORR for bystander lesions was 37%, and the locoregional control rate was 55%.
By the final analysis of this study, completed in 2012, ORRs had risen to 58% and 40% in target and bystander lesions, respectively, with locoregional disease control at 80% and 60% for the target and bystander lesion groups, respectively. Also, regression or stasis was noted in a few patients in distant visceral lesions.
An analysis of progression-free survival (PFS) in the first 40 patients revealed that those who achieved CRs had significantly longer PFS than those with SD or progressive disease (11.1 months vs 2.8 and 2.7 months, respectively). Also, disease stage and prior treatment appeared to have no effect on ORRs in injected lesions. In a later analysis, the ORR in 28 patients who had all lesions injected was 71%, and the mean PFS was 9.8 months.
Target lesion responses with PV-10 in the phase II trial were consistently more robust in patients with stage III melanoma than in patients with stage IV disease; similarly, response duration was significantly longer in patients with stage III melanoma than in those with stage IV melanoma—9.6 months vs 3.1 months (P < .001). Clearly, the higher tumor burden at baseline in stage IV patients adversely affected responses. Progression of non-study lesions, which precluded repeat treatment, had the same effect.
The choice to exclude all but stage IIIB/C patients in the ongoing phase III trial of PV-10 was influenced by these findings. This international multicenter, open-label, randomized controlled trial will include 225 patients with locally advanced cutaneous melanoma. The trial is enrolling patients who are BRAF V600 wild-type and in whom ipilimumab has failed or who are not otherwise candidates for ipilimumab or another immune checkpoint inhibitor. It is comparing single-agent intralesional PV-10 (every 4 weeks) vs systemic chemotherapy (every 4 weeks) with investigator’s choice of either DTIC or TMZ, in a 2:1 randomization.
Surface intercellular adhesion molecule-1 (ICAM-1) is upregulated in melanoma and some other cancers (eg, prostate, bladder, breast, non–small-cell lung). In preclinical research, tumor cells lysed by coxsackievirus A21 (CVA21), a naturally occurring “common cold” ICAM-1–targeted RNA virus, induced a secondary systemic host-generated antitumor immune response.
In the phase II CALM trial (ClinicalTrials.gov identifier: NCT01227551), 57 patients with stage IIIC (42.1%) or stage IV (57.9%) melanoma and at least 1 injectable dermal, cutaneous, subcutaneous, or lymph node lesion received 10 series of multi-intratumoral CVA21 injections. The primary endpoint was immune-related (ir)PFS—ie, the proportion of patients at 6 months with CR, PR, or SD (immune-related Response Evaluation Criteria in Solid Tumors [irRECIST] 1.1). The secondary endpoint was ORR (CR + PR).
Analysis of CALM revealed an irPFS rate of 38.6% (22/57) and an ORR of 28.1% (16/57), with 8 CRs and 8 PRs. Median OS was 26 months (95% CI, 16.7 months–not reached), and the 1-year survival rate was 75.4% (43/57). Tumor responses were observed in injected lesions, in noninjected cutaneous lesions, and in noninjected visceral lesions. The fact that responses occurred in the presence of high levels of anti-CVA21 antibody and in the absence of circulating infectious CVA21 supports an immune-mediated response as opposed to one caused by the virus entering the tumor.
Multi-dose intralesional CVA21 was well tolerated; no grade 3 or grade 4 treatment-related adverse events were observed.
To further examine systemic antitumor responses, a CALM study extension evaluated sequential tumor biopsies of both injected and noninjected lesions in a cohort of 13 patients. Levels of viral replication and evidence of viral-induced immune activation within the tumor microenvironment were monitored. Serial serum samples were monitored for viral loads, anti-CVA21 neutralizing antibody, and levels of immune-inflammatory cytokines. Increases in immune cell infiltrates were observed in 4/4 patients in whom single- or double-line immune checkpoint blockade had failed. These results, Andtbacka et al concluded, offer a solid rationale for investigating CVA21 given sequentially or concurrently with T-cell checkpoint antibodies.
Early Combination Results Suggest Higher Response Rates
TO PUT THAT INTO CONTEXT
Robert H. I. Andtbacka, MD, CM
University of Utah & Huntsman Cancer Institute, Salt Lake City, Utah
Intralesional Therapies: An Old Treatment Is Reborn
In the late 1800s, William Coley described the use of an intralesional bacteria-free extract, known as “Coley toxins,” in the treatment of sarcomas. Coley’s data showed an over 60% remission rate of sarcomas. Intralesional therapies are especially well suited to the treatment of melanoma, in particular in-transit and lymph node metastases. Intralesional bacillus Calmette-Guérin and interleukin-2 have both shown good responses in injected lesions; however, they have had minimal to no effect on noninjected lesions, likely due to inadequate activation of the adaptive immune system. Yet over the past 15 years, an improved understanding of immune activation has led to the development of intralesional therapies with enhanced immune activation and improved effects in noninjected metastases. More than 20 different intralesional therapies, ranging from viruses and cytokines to glycolipids, plasmids, antibodies, and small molecules, have been tested in clinical trials for metastatic melanoma alone.
What Is the Current Role of Intralesional Therapies in Melanoma?
To date, the only approved intralesional therapy for metastatic melanoma is talimogene laherparepvec (T-VEC), which has been shown to have a durable response not only in injected dermal, subcutaneous, and lymph node metastases, but also in noninjected regional metastases. It also has some effect on visceral noninjected lesions, although this appears less robust. These treatment effects, coupled with its limited toxicity, make T-VEC monotherapy a great addition to the treatment options available to patients with nonvisceral metastases and for patients who, because of comorbidities, may not be candidates for other melanoma therapies. This is likely to be the role for other intralesional monotherapies as well.
What Is Likely to Be the Future Role of Intralesional Therapies?
Early results from combination studies of intralesional therapies with other immunotherapies have indicated no increased toxicity and possibly an additive improvement in response rates above that of single-agent use; these results will likely cement the role of intralesional therapies as important immunomodulatory agents in combination therapies for metastatic melanoma. These agents may also have a future role in neoadjuvant treatment for resectable metastatic melanoma. To date, most of the intralesional agents have been administered in palpable dermal, subcutaneous, and lymph node metastases. There are ongoing studies with injection of T-VEC into visceral lesions, and also of intravenous administration of intralesional therapies, such as coxsackievirus A21. If these new routes of administration are found safe and responses are seen, it will certainly expand the role of these agents, not only in metastatic melanoma, but also in many other cancers. Indeed, intralesional therapies have the potential, in the near future, to transform the way we treat metastatic cancer.
Financial Disclosure: Dr. Andtbacka has received honoraria and/or served on advisory boards for Amgen, Merck, and Provectus; his institution has received research support from Amgen, Provectus, Takara, and Viralytics.
It has been generally surmised that intralesional therapies will be combined with the successful systemic immunotherapies—the checkpoint inhibitors or targeted therapies already approved or in development. It has been suggested that the intralesional viral vector and chemoablative activity of the intralesional agents just discussed ruptures the tumor, causing the release and presentation of intact antigens. The observed effect, an influx of T cells to the tumor, is distinct from the programmed cell death produced by the checkpoint inhibitors. The potential of synergies arising from these different mechanisms of action, the safety and lack of dose-limiting toxicities of the intralesional therapies, and the nonoverlapping toxicity profiles of the contemplated combinations, offer an attractive rationale. In addition, the relatively lower toxicity of the PD-1/PD-L1 agents compared with ipilimumab intensifies interest in the ongoing trials of their combination with intralesional therapies.
Early data from a small phase Ib/II study of ipilimumab combined with T-VEC, which demonstrated that the combination offers much higher complete and overall response rates than have been seen with either agent alone, appear to confirm that there are beneficial synergies between these two therapeutic modalities. In 18 patients with stage IIIB/IV M1c melanoma, the investigator-assessed CR rate was 33%, with PR in 22%, SD in 17%, and an overall response rate of 56% (95% CI, 31%–79%). There were no dose-limiting toxicities, and most toxicities appeared to be ipilimumab-related. In a pattern suggestive of T-VEC responses, activated CD8+ T-cell increases were higher in patients with disease control, according to flow cytometry. The trial’s randomized phase II segment is ongoing.
The phase II part of a phase Ib/II study (ClinicalTrials.gov identifier: NCT02263508; MASTERKEY-265) assessing the safety and efficacy of T-VEC in combination with the PD-1–blocking antibody pembrolizumab in previously untreated, unresected stage IIIB/IV melanoma is evaluating confirmed ORR by irRECIST at week 24. T-VEC plus pembrolizumab is being compared against pembrolizumab alone. In early results, of 16 evaluable patients, 9 had objective responses (56.3%); the disease control rate was 68.8%. Although all patients had treatment-related serious adverse events, no grade 4 events or dose-limiting toxicities were reported (Tables 1 and 2).
A phase III study comparing T-VEC plus pembrolizumab vs pembrolizumab alone in 660 patients with treatment-naive, stage III/IV melanoma with injectable lesions is being planned.
The Melanoma Intra-Tumoral CAVATAK and Ipilimumab (MITCI) study of CVA21 in combination with systemic administration of ipilimumab in patients with unresectable melanoma is being conducted at three US sites. Preliminary reports indicate that to date the CVA21 + ipilimumab combination has led to no serious adverse events. Early signs of antitumor activity at 14 weeks after initiation of treatment have been observed in metastatic visceral and nonvisceral lesions, according to a case report.
Similarly, a combination phase Ib/II trial of PV-10 and pembrolizumab has been initiated in patients with stage IV melanoma. The phase Ib portion will include 24 patients. The phase II part, with an expanded cohort of up to 120 patients in a 1:1 randomization to pembrolizumab with or without PV-10, will assess clinical benefit (PFS).
Likely Future and Unresolved Questions
If the ongoing and planned clinical trials confirm initial trends observed in early studies, combinations of systemic immunotherapies with intralesional agents may find a place in the ever-expanding therapeutic toolbox available to clinicians who treat patients with melanoma. As long as a lesion amenable to intralesional injection is available, it may allow clinicians to exploit the potential synergy and nonoverlapping toxicities of these approaches.
Another interesting area for ongoing and future research is in the neoadjuvant setting. Would it be justifiable to consider T-VEC, PV-10, or CVA21 as an upfront strategy in patients with surgically resectable disease before surgery, with the intent of making the tumor our ally? If ablating the patient’s autologous tumor can stimulate a tumor-specific immune response that persists after the tumor is removed, then creating an ally is what we would be doing. However, would the benefits be substantial enough to warrant incurring the risk inherent in delaying surgery? A phase II multicenter, randomized, open-label trial of T-VEC in patients with resectable stage IIIB, IIIC, or IV M1a melanoma testing that hypothesis is in the enrollment phase. About 50 international sites will ultimately participate. Neoadjuvant T-VEC followed by surgery will be compared with surgery alone. Recurrence-free survival from the time of randomization to the date of the first local or distant recurrence of melanoma or death due to any cause is the primary endpoint. Biomarker analyses will look for correlations between baseline CD8+ T-cell density in injected lesions and outcomes.
Through the emergence of new immunotherapies, treatment of melanoma is undergoing a long-awaited revolution. Ongoing research will clarify the outlines of the place that intralesional therapies will occupy in the therapeutic armamentarium in the years ahead.
Financial Disclosure: Dr. Agarwala has acted as an ad hoc consultant to Amgen, Merck, and Provectus.
Acknowledgement: The author gratefully acknowledges medical writing assistance from Walter Alexander.
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