Updates in Melanoma: Findings with Immunotherapy and Targeted Therapy
Presentation by Dr Rino Seedor, Thomas Jefferson University
Treatment of melanoma over the past decade has been vastly improved with the advent of immunotherapies and targeted treatments. Immunotherapies are designed to activate the body’s immune system to attack cancer cells, while targeted therapies are designed to specifically inhibit unique molecular alterations in cancer cells that allow for uncontrolled proliferation and growth. At the 2022 West Oncology APP conference, Dr Rino Seedor highlighted some of the latest updates in melanoma treatment.
Dr Seedor noted that, while the incidence of melanoma, the 5th most common cancer, continues to increase, death rates from melanoma have stabilized. She briefly outlined the staging system in melanoma. Stage I/II tumors are graded by thickness of the tumor and the presence/degree of ulceration, whereas Stage III/IV tumors are graded by the degree of tumor dissemination to the lymph nodes and other parts of the body (metastasis). Metastases in melanoma can be either characterized as microsatellite (only visible with a microscope), satellite, which can be seen visibly within 2 cm of the primary tumor site, and ‘in-transit’ metastases, which are observed beyond 2 cm of the primary tumor. The melanoma field has seen a flurry of drug approvals over the past decade, beginning in 2011 with the approval of the immunotherapy ipilimumab, as well as the targeted treatment vemurafenib.
Dr Seedor outlined the overall course of melanoma therapy which generally consists of biopsy followed by surgery, which may or may not include a sentinel lymph node (SLN) dissection (to assess the degree of cancer dissemination to the lymph nodes). Some patients may also receive adjuvant therapy, which is designed to target any residual cancer present in the body that can lead to a later recurrence. The outcome of surgery can thus be curative in some patients, whereas other patients may have a later recurrence of their melanoma, and some may present with metastatic disease that has spread to other parts of the body at the time of diagnosis. The adjuvant treatment of melanoma includes immunotherapies such as pembrolizumab, nivolumab, and ipilimumab, and the targeted therapy with dabrafenib plus trametinib. Treatment for patients with metastatic disease involves combinations of these therapies and other novel investigational treatments such as tumor infiltrating lymphocytes (TILs).
Adjuvant Therapies: KEYNOTE-716
Dr Seedor noted the recent approval of the immunotherapy pembrolizumab in the adjuvant setting for patients with high-risk, Stage II disease (stage IIB/IIC), based on findings from the KEYNOTE-716 trial. The rationale for this trial was based on the finding that, historically, 10-year melanoma-specific survival outcomes in Stage IIIA patients (for whom adjuvant treatment is currently approved and has a benefit) is actually slightly better (88%) than that of Stage IIB/IIC patients (75% - 82%), who generally do not receive adjuvant treatment. As such, KEYNOTE-716 enrolled Stage IIB and IIC patients with a negative SLN biopsy to undergo adjuvant treatment with the immunotherapy pembrolizumab, or with placebo, for one year. Pembrolizumab therapy is designed to inhibit the interaction of an immune-regulatory molecule, PD-L1, with its receptor PD-1; the former interaction causes immune cells of the body to ignore the tumor cells, and by inhibiting this interaction, the immune system is reactivated to attack and kill the tumor.
The results of the study, published in 2022 in the journal The Lancet, showed a benefit of adjuvant pembrolizumab in these Stage II patients at a median follow up of 20.9 months, with a statistically significant benefit in the primary endpoint of recurrence-free survival (RFS) of 86% versus 77% at the 18-month time point (hazard ratio [HR]=0.61; P=0.0066). There was a benefit of pembrolizumab in all of the relevant subgroups of patients. Dr Seedor noted the adverse events (AEs) which included immune-related AEs (IRAEs) which occurred in 37.7% and 9.1% of patients in the pembrolizumab and placebo arms, respectively. Although most of these IRAEs were mild (Grade 1-2) the rate of more severe (Grade 3-4) IRAEs was 10% and 1% in the treatment arms, respectively. She noted that some of the endocrine related IRAEs such as hypothyroidism and adrenal insufficiency did require long-term hormone replacement therapy, and as such, despite the positive findings of the trial, Dr Seedor noted the importance of selecting the most appropriate Stage IIB/C patients for the treatment, an issue which still needs to be resolved.
Metastatic Disease: CHECKMATE 067 and RELATIVITY 047
Dr Seedor then highlighted developments in the treatment of patients with metastatic melanoma, reviewing first the “game changing” results of the CHECKMATE 067 trial, which examined the efficacy of the immunotherapies ipilimumab (IPI) and nivolumab (NIVO), either alone or in combination, for patients with untreated, inoperable metastatic melanoma. Updated results from the trial (at 90 months), presented at the ASCO 2022 Meeting showed a significant benefit of the IPI/NIVO combination, with a median overall survival (OS) of 72.1 months versus 36.1 and 19.1 months in the NIVO and IPI alone arms, respectively. The results of the trial cannot be overstated, with nearly half of patients (48%) alive at 90 months, whereas in the past, such patients did not survive for more than one year. The results also showed a benefit of the combination immunotherapy in melanoma-specific survival, progression-free survival (PFS), and response rate. Another important finding was that, among those patients alive at 90 months, 77% had not received any further treatment after the combination therapy. Despite the impressive efficacy and durability of response with the combination, however, she also made note of the AEs in the trial, with 59% of patients on the combination treatment having a Grade 3-4 AE.
Another important advance with immunotherapy which Dr Seedor highlighted was the recent approval of relatlimab in combination with nivolumab. Relatlimab is an inhibitor of an immunomodulatory molecule called LAG-3 which contributes to T-cell exhaustion. Accordingly, the inhibition of LAG-3 with relatlimab is intended to activate the T-cell and stimulate tumor cell killing. In the RELATIVITY 047 trial, relatlimab was combined with nivolumab and compared to treatment with nivolumab alone in patients with previously untreated inoperable metastatic melanoma. The primary endpoint of the trial, PFS was significantly better with the combination relative to nivolumab alone (10.2 months versus 4.6 months) after a median follow up of 19.3 months. Importantly, there was also a benefit of the combination across all patient subgroups, and regardless of the degree of LAG-3 expression in their tumors. While OS results from the trial were not yet significantly different, survival curves appear to favor the combination, and response rate was also better (43.1% vs 32.6%). Dr Seedor also noted the relatively low incidence of Grade 3-4 AEs with the combination relative to nivolumab (21.1% vs 11.1%). In this regard, although results cannot be compared across different clinical trials, she noted that Grade 3-4 AEs with relatlimab/nivolumab combination (21%) was less than that seen with the IPI/NIVO combination (55%). Further follow up will be important in evaluating the success of this relatlimab/nivolumab combination, given the impressive long-term success seen with the IPI/NIVO combination. Dr Seedor noted that it still need to be determined where exactly this new immunotherapy combination will fit into the treatment algorithm for metastatic melanoma.
Update on Targeted Therapies: DREAMSeq
In the final portion of her presentation, Dr Seedor noted some updates regarding the use of targeted therapies in melanoma, specifically for patients having a specific molecular alteration, or mutation in their tumors termed BRAF V600. She noted that this alteration is present in approximately 38% of melanomas, and results in activation of the BRAF signaling kinase, which in turn activates another kinase termed MEK. Activation of this signaling pathway ultimately results in uncontrolled proliferation of cancer cells in melanoma, and effective inhibition of this pathway can be achieved using inhibitors of BRAF (encorafenib, dabrafenib, vemurafenib) as well as MEK (trametinib, binimetinib, cobimetinib). As such, combination therapies using these two types of drugs (e.g., dabrafenib + trametinib, vemurafenib + cobimetinib) have been approved for use in melanomas with BRAF mutation, and while the number of pills per day (pill burden) of these therapies varies, Dr Seedor noted that responses to these therapies are generally very rapid and robust, although resistance to the therapy frequently develops.
An important question with regard to the use of targeted therapy in patients with metastatic melanoma having a BRAF mutation had been whether to use immunotherapy, or targeted therapy first. The DREAMSeq trial was thus designed to evaluate outcomes for patients with BRAF mutated metastatic melanoma who received either immunotherapy or the targeted therapy first followed by the other therapy at the time of progression. Overall, the results of DREAMSeq showed that upfront treatment with immunotherapy (IPI/NIVO) was superior to using targeted treatment upfront (dabrafeninb/trametinib) with a 2-year PFS of 42% versus 19% respectively. Dr Seedor noted that the results of DREAMSeq solidified the approach that most oncologists had been taking, such that immunotherapy should be used first for patients with metastatic melanoma and a BRAF mutation, with the possible exception of patients have excessively bulky disease or are unable to tolerate immunotherapy.
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