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  Title	Neoadjuvant oncolytic virus orienx010 and toripalimab in resectable acral melanoma: a phase Ib trial
  ID	4410908
  External ID	7322502805
  Author	Unknown
  Published Date	Nov. 21, 2024, 6:34 p.m.
  Summary	In this phase Ib, open label trial, which included patients with resectable stage III and IVM1a AM, ori combined with tori as neoadjuvant therapy followed by adjuvant tori showed 77.8% pathological re
  Tags	None
  URL	https://www.nature.com/articles/s41392-024-02029-2
  Sentiment	Negative: 0.79231    Neutral: 0.13452    Positive: 0.07316
  Relevance	0.00000

• Content Details

  Content ID	2628383
  Key	4c79331b-3d0c-41b9-948c-82c15312e480
  Content	In this phase Ib, open label trial, which included patients with resectable stage III and IVM1a AM, ori combined with tori as neoadjuvant therapy followed by adjuvant tori showed 77.8% pathological response and 33.3% major pathological response. The 1-year and 2-year RFS rates from operation to recurrence were 85.2% and 81.5%, respectively (Fig. 4), which were much higher than the previously reported RFS rates for adjuvant therapy alone.27 The median RFS was not reached, while the mean RFS reached 40.3 months. Fig. 4 Comprehensive study flow and outcome summary Full size image Randomized clinical trials have been limited in adjuvant or neoadjuvant settings for AM. In the S1801 phase 2 trial, only nine AM patients were enrolled, and no separate data were provided for them.15 There is only one neoadjuvant trial on AM with anti-PD-1 monotherapy (NCT04248387), but no data has been available since Jan 2020. Most data on adjuvant therapy for AM are from retrospective studies, and all show limited efficacy of adjuvant therapy in the AM subtype, RFS, from 14.8 months to 26 months.28 Currently, the largest retrospective AM anti-PD-1 adjuvant therapy study showed a significant decrease in RFS for AM compared to stage III-IV cutaneous melanoma (14.8 months vs 37.4 months, p = 0.002).29 A randomized phase II study explored high-dose interferon α-2b as an adjuvant therapy for AM. The median RFS of the 1-year regimen was 22.5 months, and the 2-year RFS rate was 44.4%,3 which was almost half of that in our trial. However, it remains uncertain whether adjuvant interferon and anti-PD-1 therapy have equivalent efficacy in AM. A retrospective cohort analysis of Chinese patients who received adjuvant PD-1 inhibitors compared with standard high-dose interferon α-2b (HDI) did not find a difference in RFS among patients with AM (median, 7.0 months vs. 15.3 months), but the safety profile of PD-1 inhibitors is better than that of HDI.30 Based on the retrospective study, neither treatment appears to be optimal. The groundbreaking NADINA study published in 2024 is a milestone in the development of neoadjuvant immunotherapy, being the first to validate this strategy in melanoma through a multicenter, international, randomized phase III clinical trial. The NADINA study demonstrated that neoadjuvant immunotherapy of ipilimumab and nivolumab significantly improved the EFS of patients compared with the traditional adjuvant nivolumab treatment (the 12-month EFS rates were 83.7% and 57.2%, respectively),18 may redefining the treatment paradigm for melanoma. The individualized treatment that considers different pathological responses simultaneously along with genetic variations is one of the highlights of the NADINA study, which introduced a regimen for patients with a pathological partial response (pPR) or non-response: when the BRAF mutation is present, dabrafenib in combination with trametinib was applied as adjuvant therapy, otherwise, nivolumab was administered. NADINA study exhibited a marked superiority of the efficacy of neoadjuvant therapy to adjuvant therapy, reconfirming neoadjuvant therapy as a burgeoning trend in the future. AM is less responsive to immunotherapy than non-acral cutaneous melanoma. The data from five clinical trials of anti-PD-1 monotherapy in Asia showed the overall response rate was only 18.0% and median PFS was 3–5 months.8 Compared with cutaneous melanoma, AM samples display a significantly severe immunosuppressive state, including depletion of cytotoxic CD8+ T cells, enrichment of Treg cells, and exhausted CD8+ T cells.4 Anti-PD-1 monotherapy demonstrates limited efficacy in AM, and combination therapy of ICIs has also shown similarly modest results. A study employed the combination of CTLA-4 inhibitor (KD6001) and tori for advanced melanoma patients, including 9 (31.0%) of AM. Among the 13 evaluable patients without brain metastases, the unconfirmed ORR stood at 38.5%, whereas the confirmed ORR was 23.1%.31 Another study also deployed CTLA-4 inhibitor (IBI310) in combination with PD-1 inhibitor (sintilimab) for the treatment of advanced melanoma/urothelial carcinoma, enrolling 8 (23.5%, Phase 1b) AM patients, and reported an ORR of 17.6%.32 Given the low efficacy of anti-PD-1 monotherapy or anti-PD-1 plus CTLA-4 in AM, we selected a treatment regimen combination of anti-PD-1 with oncolytic virus for this neoadjuvant study, which showed a 77.8% pathological response rate. Even in comparison with the NADINA study, and despite being a small Phase I trial, the efficacy of this combination in the neoadjuvant treatment of AM is remarkable. We are encouraged by the potential of anti-PD-1 plus oncolytic virus therapy in advanced AM. An oncolytic virus is able to modify the tumor microenvironment to make it more susceptible to concurrent ICI.23 There was evidence that T-VEC intratumoral administration produced a systemic increase in circulating CD4+ and CD8+ T cells and increased CD8+ T cell infiltration into tumors. Injection of the oncolytic virus T-VEC can change the tumor microenvironment by attracting T cells that may induce a systemic response to distant metastases after subsequent blockade of PD-1 with pembrolizumab.23 Cytokines and chemokines analysis revealed that the combination therapy of ori+tori significantly increased the secretion of cytokines critical for tumor elimination through various mechanisms. The elevated cytokines include those involved in direct tumor cell killing (TNF, TNFR, IFN-γ, Fas ligand); granzymes secreted immune cells (GZMA, GZMH, and GZMB), chemokines that promote cell recruitment and activation (CXCL9, CXCL10, CXCL11, CXCL13, CCL19, and CCL23); and interleukins regulating immune cell function (IL-12, IL-18, and IL-10). This extensive elevation in cytokines and chemokines suggests that virotherapy enhances immune cell activity, thereby improving sensitivity to immunotherapy.33 To date, oncolytic virus in combination with ICI has only been evaluated in clinical trials with patients with unresectable stage IIIB IV M1c melanoma.23,34,35 The combination of oncolytic virus with ICI in the phase III trial of T-VEC combined with pembrolizumab for advanced melanoma showed that this combination did not significantly improve PFS or OS compared with placebo-pembrolizumab,36 which may be due to different immune-microenvironments in cutaneous melanoma and AM. The immune reversal effect of oncolytic viruses in AM may not alter the prognosis of highly immune-sensitive cutaneous melanoma. So, in combination with anti-PD-1 therapy, intratumoral injection of ori engineered to enhance immune recognition of cancer resulted in a high response rate in patients with AM, especially after neoadjuvant treatment, which has the ability to elicit a broader tumor-specific T cell response.12 Although T-VEC has demonstrated its efficacy in the neoadjuvant treatment of melanoma with a 2-year RFS rate of 29.5%,24 our study confirmed the enhanced potential with a 2-year RFS rate of 81.5% for AM. The preliminary results revealed that compared to oncolytic virus neoadjuvant monotherapy, neoadjuvant therapy of ori+tori offered significant advantages in AM. Pathologic response is a critical indicator for assessing the efficacy of neoadjuvant therapy in melanoma patients and is closely related to outcomes. Neoadjuvant treatment with relatlimab and nivolumab has demonstrated a similar trend of 2-year RFS rates (92% vs. 55% for those with or without pathologic response).37 Among patients treated with T-VEC plus surgery, 17.1% achieved a pCR, corresponding to a 2-year RFS rate of 75.5%, compared to 63.6% for those without pCR.24 Based on a comparison between the pathological response to ICIs and the pCR to T-VEC, the RFS rate remains numerically superior for ICIs. The reasons may be that T-VEC principally targets the localized tumor by intralesional administration,24 while ICIs lead to more widespread immune activation by inhibiting immune checkpoints systemically. Therefore, we utilized an oncolytic virus in combination with ICI, and achieved a superior efficacy to T-VEC monotherapy, along with a high correlation between pathological response and RFS. Although neoadjuvant therapy has achieved creditable results, the question of whether to apply adjuvant therapy for patients who have achieved a major pathology response in the context of neoadjuvant therapy raises debate. PRADO trial demonstrated that patients with a major pathological response to neoadjuvant ipilimumab and nivolumab could forgo subsequent surgery and adjuvant therapy, as the plan would mitigate the AEs of adjuvant therapy and improve the quality of life for patients.38 The high pCR rate, the absence of recurrence, and good safety profiles confirmed that neoadjuvant therapy may be sufficient in certain cases.37 Furthermore, the PRADO trial showed that therapeutic lymph node dissection could be a treatment option for patients with pathologic non-response (pNR), followed by adjuvant therapy.38 In the NADINA trial, 59.0% of patients in the neoadjuvant treatment group achieved a major pathological response, thereby eliminating the adjuvant therapy.18 Nevertheless, the generalizability of findings from melanoma trials must be cautiously considered in the context of AM, since the immunosuppression AM exhibiting would lead to different responses to immunotherapies. From our trial, since most grade 3 AEs were associated with the adjuvant period, and patient outcomes were satisfactory after neoadjuvant treatment, we also tend to hold an opinion that sequent adjuvant therapy may not be necessary for patients with AM when major pathological response presented, due to the limited benefit of adjuvant therapy and the incurring increased risk of AEs. In future neoadjuvant trials for AM, the subsequent treatment and surgery with different pathologic response patterns still need to be explored. In our trial, the majority of TEAEs were grade 1/2. Only 13.3% of patients had grade 3 AEs. The incidence of grade 3 or 4 AEs was similar to that of previous studies combining anti-PD-1 inhibitors and oncolytic virus.24,39,40 In comparison to NADINA, AEs of ori + tori were conspicuously lower in our trial. The grade 3 or higher in NADINA reached 47.2% in the neoadjuvant group.18 Among the grade 3 AEs, two patients experienced soft tissue infections after lymph node dissection. Wound infection complications were observed in 7.4% of cases, and this proportion did not increase after neoadjuvant treatment.41 Noteworthy, our trial yielded a pathological response rate of 77.8%, which was significantly higher than the radiographic overall response rate of 36.6%. Despite the increasing role of 18 F-FDG PET/CT in the post-treatment monitoring and staging of high-risk melanoma patients,[39] its applicability in our neoadjuvant trial appears to be limited. The evaluation showed no correlation between PET parameters and pathological response, which is consistent with existing studies.34 This underscores the necessity for new technologies to evaluate the efficacy of neoadjuvant therapy for advanced melanoma, particularly in Ori and tori combination therapy. We acknowledge that the study is limited by its small sample size and that these results are preliminary based on findings at a single center. Our median follow-up went up to 24 months, and we acknowledge that additional follow-up is needed to fully assess the clinical impact and the durability of responses. However, these preliminary data are encouraging and require further confirmation in a controlled trial. The NADINA trial has illustrated the potentiated outcomes conferred by the combined application of a PD-1 inhibitor and a CTLA-4 inhibitor in the neoadjuvant setting.18 In addition, the PIVOTAL study substantiated that daromun, as a neoadjuvant agent in the localized treatment for patients afflicted with locally resectable stage III melanoma, intensified the immunological response within the tumor microenvironment.42 Synergistic neoadjuvant therapeutics of oncolytic viruses with PD-1 inhibitors have garnered evidence supporting their efficacy and safety.26 The confluence of PD-1 inhibitors, CTLA-4 inhibitors, and oncolytic virotherapy may herald a more promising therapeutic horizon for individuals with AM. Moreover, it is necessary to compare this approach head-to-head against combined neoadjuvant ICI for AM. In a future study, conduction of a 3-arm, randomized clinical trial (neoadjuvant therapy of PD-1 inhibitor + CTLA-4 inhibitor + oncolytic virus vs. neoadjuvant therapy of PD-1 inhibitor + CTLA-4 inhibitor vs. neoadjuvant therapy of oncolytic virus + PD-1 inhibitor) is necessary, with a crossover design to determine the role of each agent in this combination. In summary, neoadjuvant oncolytic virus ori and anti-PD-1 tori is a highly active regimen that achieves a 77.8% pathological response rate with a favorable safety profile in patients with high-risk, resectable high-risk AM. A phase 3 randomized controlled study is still needed considering this is a single arm study. These data complement future studies in patients with unresectable metastatic AM, and further support the promise of this new combination immunotherapy regimen in this disease.
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  Publisher Name	Nature (#2153)
  Publisher URL	https://www.nature.com/
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  Trust Flow Score	61
  Citation Flow Score	58

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  Data Source Name	Quantexa News (#5)
  Data Source Type	news
  Data Source URL	https://app.aylien.com/dashboard
  Description	Welcome to Quantexa News API — the most powerful way to aggregate, filter, and integrate global news data into your apps and models.
  Weight	10