Presentation by Dr Meredith McKean, Sarah Cannon Research Institute at Tennessee Oncology
At the Total Health 2023 ASCO Review held in Memphis, Tennessee, Dr Meredith McKean, MD, MPH, from Sarah Cannon Research Institute at Tennessee Oncology presented melanoma updates from the 2023 American Society for Clinical oncology (ASCO) Annual Meeting.
Adjuvant Therapy: Keynote 716 and Keynote 942
Dr McKean began by highlighting the updated results from the KEYNOTE-716 trial examining the use of adjuvant (or post-surgical) immunotherapy with pembrolizumab for patients with stage IIB/C melanoma. She noted first that stage IIB/C patients are known to have a “deep primary” tumor with high-risk features like ulceration and have a high risk of relapse, and that previous results from this Phase III study had shown that adjuvant pembrolizumab significantly improved both relapse-free survival (RFS), as well as distant metastasis free survival (DMFS) as compared with placebo across multiple landmark analyses. Patients in the trial had resected stage IIB/C melanoma with negative sentinel lymph node (SLN) status, and no evidence of regional or distant metastasis. The initial results (median follow up, 27.4 months) and updated results (median follow up 39.4 months) for DMFS are shown in Box 1, and confirm that the initial significant benefit of pembrolizumab adjuvant treatment for DMFS persists with longer follow up. A similar benefit was observed regardless of whether they were stage IIB (HR=0.62) or IIC (HR=0.57). The endpoint of RFS also showed a persistent benefit of pembrolizumab at 39.4 months over placebo (36-month RFS rate, 76.2% vs. 63.4%; HR=0.62) and a similar benefit was seen in Stage IIB (HR=0.58) and IIC (HR=0.65) patients. With regard to safety, Dr McKean noted that, while the incidence of Grade 3/4 adverse events (17.2% vs. 5.1%) and adverse events leading to discontinuation (15.9% vs. 2.5%) was higher with pembrolizumab versus placebo, there were no treatment related deaths in the study.
Box 1. Updated DMFS Results, KEYNOTE-716 Trial
Median follow up, 27.4 months:
Median follow up, 39.4 months:
Summarizing the results of KEYNOTE-716, Dr McKean noted the continued benefit of adjuvant pembrolizumab therapy for patients with resected stage IIB or IIC melanoma, with a significant benefit in both DMFS and RFS after a median follow-up of 39.4 months, and no change in safety profile from previous analyses. She added that further results from the trial will be forthcoming, including a “Part 2” analysis for patients with recurrence crossing over from the placebo arm to pembrolizumab, an analysis for overall survival (OS), and a planned biomarker analysis.
Dr McKean also highlighted DMFS results from KEYNOTE-942, a Phase II study examining the use of a personalized melanoma antigen, mRNA-4157-P201, in combination with pembrolizumab immunotherapy versus pembrolizumab alone. The rationale of this treatment is to create a messenger RNA, or “mRNA-type” vaccine for 34 personalized “neoantigens” which are specific for each patient’s tumor based upon their tissue and blood samples, in order to help stimulate their immune system and drive a potent anti-tumor response. Patients in the trial had resected Stage IIIB, IIIC, IIID, or IV cutaneous melanoma, and received treatment with either mRNA-4197 in combination with pembrolizumab or pembrolizumab alone (monotherapy) with the primary endpoint of RFS and the secondary endpoint of DMFS, which was reported at ASCO 2023. The results at 18 months showed an RFS of 78.6% and 62.2% for the combination and monotherapy arms, respectively, with an HR of 0.561 (P=0.0266) corresponding to a 44% relative reduction in the risk for recurrence or death with the combination. The secondary endpoint of DMFS was also significantly improved with the combination, with a DMFS rate at 18 months of 91.8% and 76.8%, respectively, and an HR of 0.347 (P=0.0063), corresponding to a 65% relative reduction in the risk of distant metastasis or death at a median of 2 years’ follow up. The combination therapy was overall well-tolerated with flu-like symptoms being commonly observed after the infusion, and importantly, the combination treatment did not increase the frequency of immune-related adverse events over pembrolizumab monotherapy. Summarizing the results of this trial, Dr McKean suggested that the combination of the neoantigen mRNA-4157 (V940) and pembrolizumab offered a significant benefit over the current standard of care (i.e., pembrolizumab monotherapy) for patients with high-risk resected melanoma, significantly reducing the risk of both recurrence or death, and distant metastasis or death. The treatment was overall well-tolerated with no notable increase in immune related adverse events relative to monotherapy with pembrolizumab alone. She also noted the recent “Breakthrough Therapy” and “PRIME” designation of this combination therapy by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA), respectively, in 2023, as a result of the trial findings.
Neoadjuvant Therapy: PRADO and OpACIN-NEO
Dr McKean then moved into results for the neoadjuvant, or pre-surgical setting, highlighting an abstract combining 3-year data from 2 trials, PRADO and OpACIN-neo. She briefly reviewed some of the benefits for using a neoadjuvant therapy approach, specifically the potential for a more enhanced anti-tumor immune (T-cell) response by using immunotherapy prior to surgery, while the tumor is still in place, as opposed to using immunotherapy after surgery (i.e., as adjuvant therapy), after the tumor has already been removed. Another potential benefit of neoadjuvant treatment is that it allows for a rapid assessment of how the patient is going to respond to the therapy and thus the endpoint of pathologic response with neoadjuvant treatment has been suggested as a surrogate marker for survival (i.e., “how well is the patient going to do” on this therapy). Dr McKean reviewed some data showing that pathologic response after immunotherapy using checkpoint inhibitors (ICI) was associated with a prolonged relapse-free interval in patients with stage III melanoma.
The abstract which Dr McKean reviewed, using data from the PRADO and OpACIN-neo trials, addressed several questions for stage III melanoma patients: 1) do all patients need extensive surgery (including total lymph node dissection [TLND])? 2) do all patients need adjuvant treatment (after surgery), and 3) what is the best adjuvant treatment regimen (with the possible options of anti-PD-1 immunotherapy, BRAF/MEK inhibitor therapy, and radiotherapy)? The answers to these three questions are summarized in Box 2.
Box 2. Answers to Key Questions in Stage III Melanoma: Results From a Combined Analysis of the PRADO and OpACIN-neo Trials
Q1: Do all patients need extensive surgery (i.e., including TLND)? Answer: No. TLND can likely be omitted in patients with an mPR without adversely impacting survival outcomes. Q2: Do all patients need adjuvant treatment (after surgery)? Answer: No. Patients who achieve an mPR most likely do not need adjuvant systemic therapy, but, for patients with pNR, adjuvant systemic therapy seems to improve survival outcomes. Q3: What is the best adjuvant treatment regimen for patients with pNR? Answer: Adjuvant immunotherapy (anti-PD1) might be preferred over adjuvant BRAF/MEK inhibition, and adjuvant radiotherapy might be beneficial for patients who are not eligible for adjuvant systemic therapy (e.g. BRAF unmutated (i.e., “wild type”) patients experiencing high grade immune-related adverse events.
Dr McKean noted the conclusions for the participants of the study (Box 2), which suggest that following neoadjuvant immune checkpoint inhibitor therapy, TLND can be safely omitted for patients who achieve a major pathologic response, or mPR, with no adverse impact on survival outcomes, possibly eliminating the need for extensive surgery with TLND in these patients. In addition, the study suggested that patients who achieve an mPR after immune checkpoint inhibitor therapy might not need adjuvant systemic therapy, whereas those with a pathologic non-response or pNR, appear to benefit from adjuvant systemic therapy. Lastly, regarding the optimal type of adjuvant treatment for patients with pNR, the study conclusions suggested that anti-PD-1 type therapy might be a preferred option over BRAF/MEK inhibitor type drugs, and adjuvant radiotherapy may be beneficical for those patients who are ineligible for adjuvant systemic therapy; this could include those with BRAF wild type status who have serious immune-related adverse events following their neoadjuvant ICI therapy. Dr McKean emphasized that, while these are thought-provoking data, their overall clinical applicability is limited at this time, and will require further study.
Merkel Cell Carcinoma
Dr McKean then reviewed results for the non-melanoma skin cancer Merkel Cell Carcinoma (MCC), specifically, the CheckMate 358 trial, which was a non-comparative, open-label, multicenter, international, Phase 1/2 study investigating the combination of 2 different types of immune checkpoint inhibitors (ICIs), nivolumab (Nivo) and ipilimumab (Ipi), used either alone or in combination, for patients with advanced or metastatic MCC. Dr McKean noted that, while the study design was not optimal to assess efficacy and safety, the trial was nonetheless useful because MCC is a rare tumor type. Patients in the study could have received up to 2 prior therapies or no prior therapy, but could not have received treatment with any immunotherapy. The primary endpoint in the study was ORR, with several secondary endpoints including PFS, OS, and duration of response (DoR). The results for ORR were similar for the Nivo and Nivo+Ipi treatment groups, with 60.0% and 58.1% of patients in the respective treatment groups having a response.
Dr McKean noted that, while the trial was not randomized or designed to compare the treatment cohorts, patients treated with either Nivo, or Nivo+Ipi, had responses that were both frequent and durable, however, the addition of Ipi to Nivo did not appear to improve efficacy in key endpoints like ORR, PFS and OS, and there were higher incidences of Grade 3/4 treatment related adverse events with the combination, which may have resulted in more discontinuations (and therefore possibly compromised efficacy) with the combination treatment. Dr McKean suggested that the use of dual ICI therapy remains to be further investigated for patients with advanced/metastatic MCC, both in patients who have never been treated with an ICI (‘ICI naïve’) as well as those who develop resistance to prior ICI (‘ICI refractory’).
Quick Summary: 2023 ASCO Updates in Melanoma
Merkel Cell Carcinoma (MCC):
Speaker Disclosure Information: Dr McKean reported no disclosures for this presentation.