Advanced Melanoma

Neoadjuvant–Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma

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Abstract

Background

Whether pembrolizumab given both before surgery (neoadjuvant therapy) and after surgery (adjuvant therapy), as compared with pembrolizumab given as adjuvant therapy alone, would increase event-free survival among patients with resectable stage III or IV melanoma is unknown.

Methods

In a phase 2 trial, we randomly assigned patients with clinically detectable, measurable stage IIIB to IVC melanoma that was amenable to surgical resection to three doses of neoadjuvant pembrolizumab, surgery, and 15 doses of adjuvant pembrolizumab (neoadjuvant–adjuvant group) or to surgery followed by pembrolizumab (200 mg intravenously every 3 weeks for a total of 18 doses) for approximately 1 year or until disease recurred or unacceptable toxic effects developed (adjuvant-only group). The primary end point was event-free survival in the intention-to-treat population. Events were defined as disease progression or toxic effects that precluded surgery; the inability to resect all gross disease; disease progression, surgical complications, or toxic effects of treatment that precluded the initiation of adjuvant therapy within 84 days after surgery; recurrence of melanoma after surgery; or death from any cause. Safety was also evaluated.

Results

At a median follow-up of 14.7 months, the neoadjuvant–adjuvant group (154 patients) had significantly longer event-free survival than the adjuvant-only group (159 patients) (P=0.004 by the log-rank test). In a landmark analysis, event-free survival at 2 years was 72% (95% confidence interval [CI], 64 to 80) in the neoadjuvant–adjuvant group and 49% (95% CI, 41 to 59) in the adjuvant-only group. The percentage of patients with treatment-related adverse events of grades 3 or higher during therapy was 12% in the neoadjuvant–adjuvant group and 14% in the adjuvant-only group.

Conclusions

Among patients with resectable stage III or IV melanoma, event-free survival was significantly longer among those who received pembrolizumab both before and after surgery than among those who received adjuvant pembrolizumab alone. No new toxic effects were identified.

Discussion

In this phase 2, randomized trial involving patients with resectable stage III or IV melanoma, the percentage of patients with event-free survival at 2 years was 23 percentage points higher among those who received neoadjuvant pembrolizumab followed by adjuvant pembrolizumab than among those who received adjuvant pembrolizumab alone. In the neoadjuvant–adjuvant group, disease progression or toxic effects resulting in an inability to undergo surgery occurred in less than 10% of the patients, and the overall incidences of grade 3 or 4 toxic effects were lower than those reported in studies of neoadjuvant immune-checkpoint blockade combining anti–PD-1 and anti–cytotoxic T-lymphocyte antigen 4 (CTLA-4) therapies.8,10

Previous studies of neoadjuvant therapy with anti–PD-1 monotherapy in patients with resectable melanoma showed radiographic responses and an acceptable side-effect profile that were similar to what we report for this trial.10,11 In our trial, the incidence of surgery-related adverse events did not appear to be higher with the use of neoadjuvant pembrolizumab than with surgery first in the adjuvant therapy group. The benefit of neoadjuvant pembrolizumab was seen across all subgroups, although sample sizes are too small to draw conclusions in some distinct subgroups. Because only nine patients had acral melanoma and four patients had mucosal melanoma, we are unable to conclude whether the value of neoadjuvant pembrolizumab would be different for these melanoma subtypes.

Our trial included an adjuvant-therapy period for both treatment groups. However, some adaptively designed trials of neoadjuvant therapy for melanoma are investigating the de-escalation of surgery, the elimination of adjuvant therapy, or both in patients with a complete or near-complete pathological response (ClinicalTrials.gov numbers, NCT02977052. opens in new tab, NCT04949113. opens in new tab, and NCT04133948. opens in new tab).12,13

In a phase 1b, randomized trial involving 20 patients with stage III melanoma, neoadjuvant administration of the anti–PD-1 antibody nivolumab and the anti–CTLA-4 antibody ipilimumab for two cycles before surgery resulted in a larger expansion of tumor-resident T-cell clones than administration of the same therapy postoperatively.8 Several small studies involving patients with resectable melanoma have shown the feasibility and potential clinical benefit of administering neoadjuvant therapy with pembrolizumab,11 the combination of nivolumab and ipilimumab,10,12,13 or the combination of nivolumab and relatlimab.14 Tumor response, as assessed by means of pathological analysis of a surgical specimen obtained after neoadjuvant therapy, is a promising marker of long-term therapeutic benefit. In a pooled analysis of previously reported results of trials of immune-checkpoint blockade as neoadjuvant therapy for melanoma, the combined incidence of pathological complete response was 33% (42% with the combination of anti–PD-1 antibody and anti–CTLA-4 antibody and 20% with anti–PD-1 monotherapy).15 Balanced against the putative benefits of neoadjuvant therapy is the potential for tumor progression or treatment-related toxic effects to interfere with the patient’s ability to undergo surgery in a timely fashion.16

Our trial shows that the timing of administration of an immune-checkpoint inhibitor relative to surgery can have a large effect on patient outcomes, even though the same systemic therapy was given to both trial groups. Our results, combined with our understanding of the mechanism of action of PD-1 blockade therapy, support the concept that neoadjuvant administration functionally inhibits the immune checkpoint before antitumor T cells are surgically resected. These data add to the body of knowledge supporting the use of neoadjuvant therapy in oncology. A recent trial showed that among patients with resectable non–small-cell lung cancer, those who received neoadjuvant immune-checkpoint blockade with the use of anti-PD1 therapy in combination with chemotherapy had longer event-free survival than those who received chemotherapy followed by surgery.17 A meta-analysis showed that in patients with breast cancer, neoadjuvant chemotherapy resulted in tumor downsizing and increased use of breast-conserving surgical procedures but was associated with a higher frequency of local recurrence in the breast than the use of adjuvant chemotherapy.18 In other trials involving patients with bladder cancer, the use of neoadjuvant chemotherapy led to tumor downstaging and improved long-term outcomes.19,20

Our trial showed that among patients with high-risk, resectable stage III and stage IV melanoma, those who received pembrolizumab as neoadjuvant therapy followed by adjuvant therapy had longer event-free survival than those who received standard-care adjuvant pembrolizumab alone.

Source: NEJM

Neoadjuvant–Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma

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Abstract

Background

Whether pembrolizumab given both before surgery (neoadjuvant therapy) and after surgery (adjuvant therapy), as compared with pembrolizumab given as adjuvant therapy alone, would increase event-free survival among patients with resectable stage III or IV melanoma is unknown.

Methods

In a phase 2 trial, we randomly assigned patients with clinically detectable, measurable stage IIIB to IVC melanoma that was amenable to surgical resection to three doses of neoadjuvant pembrolizumab, surgery, and 15 doses of adjuvant pembrolizumab (neoadjuvant–adjuvant group) or to surgery followed by pembrolizumab (200 mg intravenously every 3 weeks for a total of 18 doses) for approximately 1 year or until disease recurred or unacceptable toxic effects developed (adjuvant-only group). The primary end point was event-free survival in the intention-to-treat population. Events were defined as disease progression or toxic effects that precluded surgery; the inability to resect all gross disease; disease progression, surgical complications, or toxic effects of treatment that precluded the initiation of adjuvant therapy within 84 days after surgery; recurrence of melanoma after surgery; or death from any cause. Safety was also evaluated.

Results

At a median follow-up of 14.7 months, the neoadjuvant–adjuvant group (154 patients) had significantly longer event-free survival than the adjuvant-only group (159 patients) (P=0.004 by the log-rank test). In a landmark analysis, event-free survival at 2 years was 72% (95% confidence interval [CI], 64 to 80) in the neoadjuvant–adjuvant group and 49% (95% CI, 41 to 59) in the adjuvant-only group. The percentage of patients with treatment-related adverse events of grades 3 or higher during therapy was 12% in the neoadjuvant–adjuvant group and 14% in the adjuvant-only group.

Conclusions

Among patients with resectable stage III or IV melanoma, event-free survival was significantly longer among those who received pembrolizumab both before and after surgery than among those who received adjuvant pembrolizumab alone. No new toxic effects were identified.

Talimogene Laherparepvec (T-VEC): An Intralesional Cancer Immunotherapy for Advanced Melanoma

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Talimogene laherparepvec (T-VEC; IMLYGIC®, Amgen Inc.) is the first oncolytic viral immunotherapy to be approved for the local treatment of unresectable metastatic stage IIIB/C–IVM1a melanoma. Its direct intratumoral injection aim to trigger local and systemic immunologic responses leading to tumor cell lysis, followed by release of tumor-derived antigens and subsequent activation of tumor-specific effector T-cells. Its approval has fueled the interest to study its possible sinergy with other immunotherapeutics in preclinical models as well as in clinical contextes. In fact, it has been shown that intratumoral administration of this immunostimulatory agent successfully synergizes with immune checkpoint inhibitors. The objectives of this review are to resume the current state of the art of T-VEC treatment when used in monotherapy or in combination with immune checkpoint inhibitors, describing the strong rationale of its development, the adverse events of interest and the clinical outcome in selected patient’s populations.

Abstract

Direct intralesional injection of specific or even generic agents, has been proposed over the years as cancer immunotherapy, in order to treat cutaneous or subcutaneous metastasis. Such treatments usually induce an effective control of disease in injected lesions, but only occasionally were able to demonstrate a systemic abscopal effect on distant metastases. The usual availability of tissue for basic and translational research is a plus in utilizing this approach, which has been used in primis for the treatment of locally advanced melanoma. Melanoma is an immunogenic tumor that could often spread superficially causing in-transit metastasis and involving draining lymph nodes, being an interesting model to study new drugs with different modality of administration from normal available routes. Talimogene laherperepvec (T-VEC) is an injectable modified oncolytic herpes virus being developed for intratumoral injection, that produces granulocyte-macrophage colony-stimulating factor (GM-CSF) and enhances local and systemic antitumor immune responses. After infection, selected viral replication happens in tumor cells leading to tumor cell lysis and activating a specific T-cell driven immune response. For this reason, a probable synergistic effect with immune checkpoints inhibition have been described. Pre-clinical studies in melanoma confirmed that T-VEC preferentially infects melanoma cells and exerts its antitumor activity through directly mediating cell death and by augmenting local and even distant immune responses. T-VEC has been assessed in monotherapy in Phase II and III clinical trials demonstrating a tolerable side-effect profile, a promising efficacy in both injected and uninjected lesions, but a mild effect at a systemic level. In fact, despite improved local disease control and a trend toward superior overall survival in respect to the comparator GM-CSF (which was injected subcutaneously daily for two weeks), responses as a single agent therapy have been uncommon in patients with visceral metastases. For this reason, T-VEC is currently being evaluated in combinations with other immune checkpoint inhibitors such as ipilimumab and pembrolizumab, with interesting confirmation of activity even systemically.

Conclusions

The landscape of options for advanced melanoma is rapidly improving and progressing, with drugs and combinations able to significantly expand patients’ window of expectations. However, adverse events occurring during treatment can limit the dose intensity and duration of those treatments, thus consequently affecting their effectiveness. Moreover, despite their tremendous impact on outcomes, most of the patients still relapse and die of their disease, leading to the need of expanding the therapeutic armamentarium with new drugs, sequences or combinations. Furthermore, with the advent of new technologies, therapeutic options are becoming more and more multidisciplinary, being surgery often avoided thanks to the adoption of new approaches requiring radiotherapy or interventional radiology expertise in order, for example, to reach visceral and deep internal lesions for intralesional injection of drugs.

T-VEC is the first genetically modified herpes simplex virus-1-based oncolytic immunotherapy approved by FDA and EMA for the treatment of unresectable, cutaneous, subcutaneous and nodal lesions in patients with melanoma recurrent after initial surgery [72,73]. This intratumoral injectable drug is designed to preferentially replicate in tumors, produce GMCSF, and stimulate antitumor immune responses both locally and systemically. As extensively discussed in this review, it has shown efficacy in monotherapy and in combination with immune checkpoints inhibitors.

Efficacy has been demonstrated mainly on injected lesion, but also an abscopal systemic effect was evident on metastasis in distant organs. Like most of the immunotherapies effectiveness is not immediately translatable is target lesion reduction and, instead, it is worth noting that progressive disease before observing a response is common both in patients treated with T-VEC alone or in combination with checkpoint inhibitors. This pattern of pseudo-progression has been widely described and reinforces the importance of continuing treatment beyond progression in the event of appearance of a new lesion or limited increase in existing ones [55,74].

In advanced melanoma, the combination of oncolytic viruses has been tested in clinical trials using T-VEC together with systemic administration of a checkpoint inhibitor: ipilimumab or pembrolizumab. A Phase 2 trial of T-VEC in combination with ipilimumab met its primary endpoint, resulting in a significantly higher ORR without additional safety signals than ipilimumab (39% vs. 18%, p = 0.002). Another Phase Ib trial tested the association of T-VEC and pembrolizumab with a confirmed ORR of 67% with a CR rate of 43%. In the coupled translational study, this association was able to increase CD8+ T cells, while PD-L1 and IFN-γ upregulation were observed in tumors from responders.

The positive effect of T-VEC, as a monotherapy or in combination with checkpoint inhibitors, which was observed in both injected and uninjected (including visceral) melanoma lesions, indicated that a systemic antitumor immune response was triggered. These results suggest that T-VEC may improve the efficacy of checkpoint inhibitor immunotherapies by changing the tumor microenvironment and support the rationale that combining immunotherapies with complementary mechanisms of action may yield augmented antitumor responses.

Interestingly, adverse events, both in monotherapy and in combination with immune checkpoints inhibitors are mild and easily reversible, leading to a new efficient and well tolerated treatment opportunity in those melanoma patients with injectable lesion and low tumor burden.

Trials are ongoing to confirm clinical results on larger number of patients and in comparison with the best standards of care, in order to confirm this approach is able to achieve high efficacy with low toxicity. Furthermore, new generation clinical trials incorporate regular sampling of both peripheral blood and tumor tissue, allowing basic and translational research, which will give insight on the mechanisms regulating tumor versus T-cells balance in the microenvironment and will characterize the immune response exploring its correlations with clinical outcomes.

Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced Melanoma

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Abstract

Background

Immune checkpoint inhibitors and targeted therapies have dramatically improved outcomes in patients with advanced melanoma, but approximately half these patients will not have a durable benefit. Phase 1–2 trials of adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) have shown promising responses, but data from phase 3 trials are lacking to determine the role of TILs in treating advanced melanoma.

Methods

In this phase 3, multicenter, open-label trial, we randomly assigned patients with unresectable stage IIIC or IV melanoma in a 1:1 ratio to receive TIL or anti–cytotoxic T-lymphocyte antigen 4 therapy (ipilimumab at 3 mg per kilogram of body weight). Infusion of at least 5×109 TILs was preceded by nonmyeloablative, lymphodepleting chemotherapy (cyclophosphamide plus fludarabine) and followed by high-dose interleukin-2. The primary end point was progression-free survival.

Results

A total of 168 patients (86% with disease refractory to anti–programmed death 1 treatment) were assigned to receive TILs (84 patients) or ipilimumab (84 patients). In the intention-to-treat population, median progression-free survival was 7.2 months (95% confidence interval [CI], 4.2 to 13.1) in the TIL group and 3.1 months (95% CI, 3.0 to 4.3) in the ipilimumab group (hazard ratio for progression or death, 0.50; 95% CI, 0.35 to 0.72; P<0.001); 49% (95% CI, 38 to 60) and 21% (95% CI, 13 to 32) of the patients, respectively, had an objective response. Median overall survival was 25.8 months (95% CI, 18.2 to not reached) in the TIL group and 18.9 months (95% CI, 13.8 to 32.6) in the ipilimumab group. Treatment-related adverse events of grade 3 or higher occurred in all patients who received TILs and in 57% of those who received ipilimumab; in the TIL group, these events were mainly chemotherapy-related myelosuppression.

Conclusions

In patients with advanced melanoma, progression-free survival was significantly longer among those who received TIL therapy than among those who received ipilimumab.

source: NEJM

PD-1 inhibitors surpass ipilimumab in advanced melanoma

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Programmed cell death 1 (PD-1) inhibitors such as pembrolizumab and nivolumab, as monotherapy or in combination with ipilimumab, are better first-line therapies than ipilimumab alone in patients with advanced melanoma, data presented at the American Association for Cancer Research (AACR) 2015 Annual Meeting have shown.

In the phase III KEYNOTE-006 trial (n=834; 65.8 percent previously untreated), pembrolizumab significantly improved progression-free survival (PFS), overall survival (OS) and response rates (RRs) vs ipilimumab, an inhibitor of cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) that is currently a standard first-line therapy for advanced melanoma. [N Engl J Med 2015, doi: 10.1056/NEJMoa1503093]

At 6 months, estimated PFS rates were 47.3 percent for pembrolizumab 10 mg/kg every 2 weeks and 46.4 percent for pembrolizumab 10 mg/kg every 3 weeks, compared with 26.5 percent for ipilimumab (3 mg/kg, 4 doses every 3 weeks) (hazard ratio [HR], 0.58; p<0.001).

“At 12 months, estimated OS rates were 74.1 percent for pembrolizumab every 2 weeks [HR, 0.63; p=0.0005] and 68.4 percent for pembrolizumab every 3 weeks [HR, 0.69; p=0.0036], vs 58.2 percent for ipilimumab,” reported lead author Dr. Antoni Ribas of the University of California, Los Angeles, CA, US.

RRs were also higher with pembrolizumab (33.7 percent for 2-weekly dosing, 32.9 percent for 3-weekly dosing) vs ipilimumab (11.9 percent; p<0.001).

Treatment-related grade 3-5 adverse events (AEs) were less common with pembrolizumab (13.3 and 10.1 percent for 2-weekly and 3-weekly dosing, respectively) than ipilimumab (19.9 percent).

“These results exceeded our expectations of the benefit of pembrolizumab over ipilimumab,” said Ribas. “The data will change the paradigm of treatment of advanced melanoma.”

Nivolumab, when used in combination with ipilimumab, also showed significant benefits over ipilimumab in patients with previously untreated advanced melanoma.

In a phase II trial of 142 patients, PFS and objective response rate (ORR) were significantly improved with the nivolumab/ipilimumab combination vs ipilimumab alone. [N Engl J Med 2015, doi: 10.1056/NEJMoa1414428]

“Among 109 patients with BRAF wild-type tumours, median PFS was not reached in the combination therapy arm vs 4.4 months with ipilimumab monotherapy [HR, 0.40; p<0.001],” reported lead investigator Dr. Stephen Hodi of the Dana-Farber Cancer Institute in Boston, MA, US.

ORR was 61 percent with combination therapy vs 11 percent with ipilimumab monotherapy (p<0.001). “Importantly, 22 percent of patients achieved complete response with the combination regimen,” said Hodi. “There were no complete responses with ipilimumab monotherapy.”

The investigators reported similar results for PFS and ORR in the 33 patients with BRAF V600 mutation-positive tumours. Again, 22 percent of patients achieved complete response with combination therapy.

However, the combination regimen was associated with higher rates of grade 3/4 drug-related AEs (54 percent vs 24 percent for ipilimumab monotherapy).

Pembrolizumab and nivolumab are currently approved by the US FDA for treatment of unresectable or metastatic melanoma that progressed after treatment with ipilimumab or a BRAF inhibitor.

A Promising New Immunotherapy for Advanced Melanoma

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A small, early-phase trial of a new immunotherapy yielded “durable responses” for patients with advanced melanoma and ocular melanoma.

Each year some 2,000 to 2,500 people in the United States are diagnosed with ocular melanoma, a serious cancer of the eye.

In about half of those diagnosed with this form of cancer, also called uveal melanoma or intraocular melanoma, the disease spreads, often to the liver. The prognosis for patients with metastatic ocular melanoma is poor, with median survival of just two to eight months.

So the report at the American Association for Cancer Research (AACR) Annual Meeting 2015 in April, of results from a phase I/IIa clinical trial of a new type of immunotherapy – albeit in a small group of 17 patients with advancedmelanoma and ocular melanoma – is promising.

The trial was of a first-in-class immunotherapy called IMCgp100. This therapeutic has “two functional ends,” explained Mark R. Middleton, PhD, professor of experimental cancer medicine at the University of Oxford in the United Kingdom. “The targeting end attaches to melanoma cells and the effector end locks on to any neighboring killer T cell [a type of immune cell], resulting in directed destruction of the tumor.”

In essence, IMCgp100 connects the immune cells to the melanoma cells, encouraging them to destroy the cancer.

“Among these patients, we observed lasting tumor responses for both cutaneous and ocular melanoma,” said Dr. Middleton. “Importantly, responses were even observed in patients with advanced melanoma that was resistant to the immune checkpoint inhibitors that have recently become standard of care in many locations.”

Among the 17 patients, three partial responses and one complete response were observed; two of the partial responses are still ongoing and have lasted more than 18 months, Dr. Middleton and his colleagues reported. The complete response in one patient with advanced ocular melanoma lasted over four months.

“It is too early to say if IMCgp100 is particularly effective in ocular melanoma, although the results are encouraging. These observations will be investigated further, both clinically and experimentally,” said Dr. Middleton. “We look forward to continuing to follow all the patients who remain on the trial and to enrolling more patients to firmly establish the utility of IMCgp100 as a treatment for advanced melanoma.”