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Neoadjuvant Toripalimab Combined with Axitinib Demonstrates a Promising Pathologic Response Rate in Resectable Mucosal Melanoma

Findings from a phase II study
05 Dec 2023
Immunotherapy;  Targeted Therapy

Neoadjuvant treatment with toripalimab plus axitinib was well-tolerated in a single-arm, phase II study for patients with resectable mucosal melanoma and showed a promising pathological response rate of 33.3%, including four patients with a pathological complete response (pCR), and a median recurrence-free survival (mRFS) of 11.7 months in responders. Infiltration of CD3+/CD8+ T cells after neoadjuvant treatment was associated with pathologic response.

Findings provide a basis for further research, including potential organ function preservation and improved survival according to Dr. Chuanliang Cui of the Peking University Cancer Hospital and Institute in Beijing, China and colleagues who published the findings on 11 November 2023 in the Annals of Oncology.

The authors wrote in the background that mucosal melanoma is the second most common subtype of melanoma in Asia, primarily affecting areas such as oral and nasal cavities, perineum, rectal region, and anal canal. Mucosal melanoma is more aggressive than cutaneous melanoma with lower tumour mutational burden and poorer responses to treatment. However, it is sensitive to anti-angiogenic inhibitors, which may be due to its highly vascular invasive biological behaviour.

While surgical resection remains the primary treatment for locally confined mucosal melanoma and often achieves favourable outcomes in early-stage, the extensive nature of surgery and the anatomical sites that may limit the ability to obtain clear margins can result in recurrence, distant metastasis, and a poor prognosis. Due to its unique biological characteristics, mucosal melanoma lacks hot spot mutations for targeted therapy, and anti-PD1 monotherapy does not provide the same survival benefits for patients with advanced mucosal melanoma as it does for cutaneous melanomas.

A phase II adjuvant study conducted in patients with mucosal melanoma showed that anti-PD1 monotherapy improved RFS compared to historical data, but RFS was unsatisfactory with 13.6 months. In a phase Ib study, the combination of toripalimab, anti-PD1 antibody and axitinib, a small molecule tyrosine kinase inhibitor of VEGFR 1-3, c-KIT, and PDGFR demonstrated significant efficacy in treatment of patients with metastatic mucosal melanoma with an objective response rate of 48.3% and a median progression-free survival of 7.5 months. Besides these promising results, the effects of use of this combination in a neoadjuvant setting are unknown.

The study team hypothesized that this combination administered in the neoadjuvant setting might induce a pathologic response in resectable mucosal melanoma. In the single-arm phase II study they enrolled patients with resectable mucosal melanoma to receive toripalimab 3 mg/kg Q2W plus axitinib 5 mg BID for 8 weeks as neoadjuvant treatment, then surgery and adjuvant toripalimab 3 mg/kg Q2W starting 2±1week after surgery for 44 weeks. The primary endpoint was the pathologic response rate according to International Neoadjuvant Melanoma Consortium recommendations.

Between August 2019 and October 2021, a total of 29 patients were enrolled and received treatment, of whom 24 underwent resection. The median age was 62 years (range, 34-72 years) and 21 patients (72.4%) were female. In terms of tumour location, 10 patients (34.5%) had tumours located in the female genitourinary area, 10 (34.5%) had tumours located in the ano-rectal area, 5 (17.2%) had tumours located in the oesophageal area, and 4 (13.8%) had tumours located in the nasal/oral cavity. Nine patients had localised disease, 19 had regional lymph node disease, and one patient had oligometastasis in the left lung.

Nine patients had genetic mutations, with c-KIT mutations being the most common (4 out of 29 patients or 13.8%, including one amplification), followed by NRAS mutations (3 out of 29 patients or 10.3%), and BRAF mutations (2 out of 29 patients or 6.9%). Most patients had an ECOG performance status of 0 (89.7%), while 5 (17.2%) had elevated serum LDH levels.

Median follow-up was 34.2 months (95% confidence interval [CI] 20.4 to 48.0). The mRFS for 24 patients who underwent complete resection was 9.5 months (95% CI 2.5 to 16.5) and the 12-month RFS rate was 45.8% (95% CI 19.7 to 71.9). The pathologic response rate was reported in 8 of 24 patients (33.3%), of whom 4 achieved pCR and 4 pathologic partial response. The mRFS for the pathological responders was 11.7 months (95% CI 6.8 to 16.6) and the median overall survival (OS) was not reached. The mRFS for pathological non-responders was 6.2 months (95% CI 1.3 to 11.1), but the difference between pathological responders and non-responders was not statistically significant.

The median distant metastasis survival for patients who achieved a pathological response and those who did not achieve a pathological response were 11.7 months (95% CI 2.0 to 21.4) and 7.6 months (95% CI 0 to 20.9); however, this difference was not statistically significant. None of the 8 patients who achieved a pathological response had died while 4 out of the 16 patients who did not achieve a pathological response died due to melanoma. The median OS was not reached.

Neoadjuvant treatment was tolerable with 8 (27.5%) grade 3-4 treatment related adverse events and no treatment-related deaths. One patient experienced a delayed operation because of hypothyroidism associated with immunotherapy.

Tissue samples of 17 patients at baseline and after surgery were collected, among whom 5 were responders and 12 non-responders. Multiplex immunohistochemistry demonstrated a significant increase of CD3+ (p = 0.0032) and CD3+/CD8+ (p = 0.0038) tumour-infiltrating lymphocytes after neoadjuvant treatment, particularly in those with pathologic response.

The authors concluded that in this phase II study, neoadjuvant toripalimab plus axitinib was associated with a 33.3% pathological response rate in patients with mucosal melanoma who had surgery after neoadjuvant treatment, a high rate not previously reported with traditional treatment. They commented that the improvement in efficacy of combination therapy may be attributed to axitinib's contribution in enhancing the tumour's immune microenvironment and thus further improving the efficacy of anti-PD1, rather than axitinib's inherent antitumour efficacy.

This study was presented in part at the oral session of the ASCO 2021 Annual Meeting (4-8 June 2021, Chicago, IL, US).

The study was supported by Shanghai Junshi Biosciences Co., Ltd. through providing study drugs. 

This work was supported by grants from Beijing Municipal Administration of Hospitals Incubating Programme, Beijing Health Technologies Promotion Programme, Beijing Xisike Clinical Oncology Research Foundation, and Science Foundation of Peking University Cancer Hospital.

The authors acknowledged the support and assistance from the International Neoadjuvant Melanoma Consortium.


Lian B, Li Z, Wu N, et al. Phase II Clinical Trial of Neoadjuvant anti-PD-1 (Toripalimab) Combined with Axitinib in Resectable Mucosal Melanoma. Annals of Oncology; Published online 11 November 2023. DOI: https://doi.org/10.1016/j.annonc.2023.10.793

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