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Maximizing durable remissions in malignant melanoma: The next steps
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The array of approved and investigative treatment options for patients with unresectable or metastatic melanoma has been truly revolutionized in the past several years.
A disease described as one that “gives cancer a bad name” has become one in which rapid and high response rates and long-term durable remissions are routinely expected.
As illustrated by the FDA approval of vemurafenib (Zelboraf, Genentech) and ipilimumab (Yervoy, Bristol-Myers Squibb), the most fertile areas of new compound development exploit two distinct mechanisms: attacking the mitogen-activated protein kinase (MAPK) pathway, which includes BRAF, and novel immunotherapies. These two classes of therapies clearly have advanced melanoma treatment, yet patient responses remain limited by lack of response durability or failure to induce responses in most patients.
This leads us to an important question: How do we leverage these therapies to provide durable remissions in the greatest number of patients?
Targeted therapies, immunotherapies
Michael K. Wong
Clinical trials are in the works that combine targeted therapy with immunotherapy, or combine different types of immunotherapy. One such candidate that warrants further exploration is interleukin-2 (IL-2). With its predictable toxicity profile and demonstrated ability to induce long-term responses in a subset of patients with advanced melanoma, IL-2 may be an ideal partner for combination therapy.
Vemurafenib inhibits BRAF, a member of the MAPK signal transduction pathway and a key driver of cutaneous melanoma. About half of patients have the V600E mutation in BRAF, which indicates treatment with vemurafenib.
In the phase 3 BRIM-3 trial of vemurafenib vs. dacarbazine combination therapy, vemurafenib was superior, yielding an overall response rate of 48% vs. 5%, and a median PFS of 5.3 months vs. 1.6 months (P<.0001). Later follow-up showed a significant improvement in median OS, as well — an important advance for melanoma. Dabrafenib (Tafinlar, GlaxoSmithKline) is a newer BRAF inhibitor that demonstrated similar results, with a significant improvement in PFS and a response rate of 53% compared with 19% for dacarbazine.
Although the response rates from these compounds are impressive, most responses are partial and short lived, with patients progressing after several months. Multiple mechanisms of resistance appear to be involved, sometimes within the same patient. Thus, further attack on BRAF inhibitor resistance employing the signal transduction approach is unlikely to meet with long-term success.
The long-known ability of IL-2 to induce long-term complete responses in a subset of patients with melanoma has spurred interest in developing other ways to engage the body’s immune system to fight the disease and helped pave the way for the development of ipilimumab. This monoclonal antibody targets cell surface CTLA-4, an immune checkpoint molecule expressed on effector and regulatory T cells that down-regulates the immune system, acting as a brake to prevent autoimmunity.
By binding to CTLA-4, ipilimumab takes the brake off, thus boosting T-cell activity with the goal of attacking tumor cells. In a phase 3 trial of 676 patients with previously treated metastatic melanoma, ipilimumab monotherapy delivered a median OS of 10.1 months vs. 6.4 months for the control arm of glycoprotein 100 vaccination (P<.001). The ORR was 10.9%, composed mostly of partial responses. Fourteen deaths (2.1%) were considered related to the study drugs; of them, seven were attributed to immune-response adverse events.
PD-1/PDL-1 inhibition
An alternative method to activate the immune system is by inhibiting the PD-1/PD-L1 interaction, which also acts like a brake on the immune system. Because PD-L1 is expressed by tumor cells, disrupting this interaction may result in a greater effect on the tumor cells themselves while limiting the immune-related adverse events.
This concept has gained support based on results from a phase 1 trial of an anti-PD-1 antibody, nivolumab (BMS-936558, Bristol-Myers Squibb), in which grade 3/grade 4 treatment-related toxicities were observed in 9% of patients with various types of cancer. In a phase 1 expansion cohort study that included 107 patients with previously treated metastatic melanoma, median OS was 20.3 months for nivolumab dosed at 3 mg/kg, the dose chosen for phase 3 trials; 3-year survival was 40% and the response rate was 31% across all doses. Grade 3/grade 4 treatment-related adverse events were observed in 21% of patients.
Data on another PD-1 antibody, lambrolizumab (MK-3475, Merck), also shows promise. A phase 1 study yielded a 52% confirmed ORR in patients who received 10 mg/kg every 2 weeks, and showed a benefit in patients who had previously received ipilimumab. With a median follow-up of 11 months, 81% of patients continued to show a response. Grade 3/grade 4 adverse events occurred in 13% of patients and included some cases of elevated aminotransferase.
The quest for long-term cures
These new drugs represent truly remarkable innovations in melanoma therapy, and they already provide an important and meaningful benefit to patients. However, both tumor-targeted therapies and immunotherapies have frustrating limitations in terms of patient response.
So what is the best way to combine these exciting new drugs to produce true long-term cures? Given the very different mechanisms as well as the different types of responses seen with MAPK pathway inhibition vs. immunotherapy, the combination of these two types of drugs appears promising and is being explored in clinical trials. Other trials are exploring the combination of compounds that boost the immune system.
Unfortunately, the most obvious approach of combining a BRAF small-molecule inhibitor and anti-CTLA-4 antibody resulted in early termination of the trial due to unacceptable liver toxicity. In a phase 1 study of concurrent vemurafenib and ipilimumab, dose-limiting toxicity of grade 3 aminotransferase elevation was observed in four of six patients in the first dosing cohort. Signs of liver toxicity also were observed in the second cohort of patients, and one patient from each cohort exhibited grade 2 or grade 3 levels of total bilirubin. Although the hepatotoxicity was reversible, the study was discontinued because the concurrent dosing was deemed too toxic. A phase 2 study is investigating sequential vemurafenib followed by ipilimumab.
Double inhibition of immune checkpoints was investigated by concurrent or sequential therapy in a phase 1 trial of nivolumab plus ipilimumab. The highest response rates were observed in the 53 patients who received concurrent therapy, which yielded an ORR of 40%.
The maximum tolerable dose levels were 1 mg/kg nivolumab and 3 mg/kg ipilimumab, and these doses yielded an ORR of 53%, all with tumor reductions of at least 80%. Three complete responses were observed of six patients treated at the maximum tolerated dose. Grade 3/grade 4 treatment-related adverse events occurred in 53% of patients, and 21% of patients discontinued therapy due to treatment-related adverse events. No treatment-related deaths were reported.
High-dose IL-2 possesses a consistent record of yielding unmaintained durable remissions, with long-term data stretching nearly 3 decades. Yet, the highly selected nature of IL-2 patients and the necessity to administer therapy in specialized IL-2 units have relegated this therapy to second-tier status when structuring a therapeutic plan for patients with metastatic melanoma.
Advantages of IL-2
We now have a choice of immunotherapies on hand for treating patients with metastatic melanoma, each with somewhat different mechanisms of action and toxicity profiles.
When choosing among these options, there are several compelling reasons that make IL-2 an ideal immunotherapy partner in combination or sequential therapy.
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Toxicities from high-dose IL-2 are predictable. These occur at predictable intervals, usually hours, after administering treatment. In contrast, ipilimumab is associated with an array of toxicities that may occur from 3 to 12 weeks after treatment. For the newer immunotherapeutics, the complete toxicity patterns have yet to be fully elucidated.
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Nearly all of the high-grade, acute high-dose IL-2 toxicities occur while the patient is on the unit and resolve before discharge, and lab abnormalities spontaneously revert to normal within days. With ipilimumab, it is not unusual for patients to be on steroids for weeks at a time.
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Response to IL-2 therapy is quickly evident, as 85% of responses occur within the first scheduled evaluation studies, and the response thus becomes evident within 8 weeks of starting IL-2. In contrast, ipilimumab infusion takes 12 weeks, and responses may not become apparent for another 12 weeks thereafter.
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Clinical trial data showed that patients who failed IL-2 did not suffer adversely when subsequently treated with ipilimumab. This is in keeping with the observation that the toxicity profile for IL-2 does not overlap significantly with that for either anti-CTLA-4 or anti-PD-1/PD-L1 therapy. Thus, a stimulatory cytokine such as IL-2 can propagate an immune response once it is unshackled from checkpoint inhibition.
In addition, in vitro studies show that IL-2 can rescue immune cells that have been inactivated through the PD-1 pathway, or can synergize with PD-1 blockage to overcome T-cell exhaustion. These suggest interesting possibilities for the combination of either PD-1 or CTLA-4 inhibitors with high-dose IL-2.
The phase 4 PROCLIVITY 01 trial is currently enrolling patients to explore the combination of sequential vemurafenib followed by high-dose IL-2. Medically fit patients with metastatic melanoma will receive vemurafenib monotherapy for 6 weeks (arm 1) or 7 to 18 weeks (arm 2), followed by two courses of high-dose IL-2 with continued vemurafenib.
Preclinical data suggest that treatment with vemurafenib may prime the tumor by increasing its vulnerability to attack by the immune system. The V600E mutation appears to enhance the ability of tumor cells to escape the immune system.
Blocking mutated BRAF increases the expression of melanocyte differentiation antigen, which improves recognition of melanoma cells by antigen-specific lymphocytes. Alternatively, inducing cell death first with vemurafenib also may result in the release of tumor antigens that in essence lead to a vaccine-like response by the patient’s immune system. Both of these scenarios support the concept of treating the patient first with vemurafenib, followed by immunotherapy with IL-2.
Conclusion
With many new promising drugs in the pipeline, as well as recently approved agents, treatment for metastatic melanoma has taken a great leap forward.
As new compounds become available, the possibility of increasing the proportion of patients who achieve long-lasting remission grows.
With many drugs offering a variety of strategies to inhibit tumor growth and proliferation or to increase the power of an immunological attack, novel combinations are poised to lead once again to major progress in treatment for patients with metastatic melanoma.
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For more information:
Michael K. Wong, MD, PhD, leads the melanoma program at USC Norris Comprehensive Cancer Center and Hospital. He also is a professor of medicine and head of the Solid Tumors Section at Keck School of Medicine at USC. He can be reached at USC Norris Comprehensive Cancer Center, 1441 Eastlake Ave., Los Angeles, CA 90033; email: mike.wong@med.usc.edu.
Disclosure: Wong reports no relevant financial disclosures.