The exploration process of mucosal melanoma: combination therapy ignites the hope of survival, and looks forward to more Chinese wisdom

preface

Mucosal melanoma originates from melanocytes
in a series of internal epithelial tissues located on the epidermis.
In our country, mucosal malignant melanoma is one of
the most common types.
The mouth, nasal cavity, paranasal sinuses, genital tract, and anorectal area are the most common primary sites of
mucosal melanoma.
The cause of mucosal melanoma is unknown
.
Mucosal melanoma has completely different biological properties than cutaneous melanoma, and this subtype is more aggressive
.
The American Cancer Federation (AJCC) TNM stage differs from traditional tumor staging with only T3 and T4 stages, emphasizing the high degree of malignancy of mucosal melanoma^[1].

In recent years, more and more targeted and immunotherapy drugs have carried out clinical research in mucosal melanoma and made relevant progress
.

Adjuvant and neoadjuvant therapy for early mucosal melanoma

Surgery is the most important treatment modality for mucosal melanoma, and for patients with complete resection but at high risk of recurrence, postoperative system-assisted therapy is extremely important
.
The purpose of postoperative adjuvant therapy is to eliminate melanoma micrometastases in patients, thereby reducing the rate of recurrent metastases and prolonging the time
without recurrence.
Adjuvant therapy for mucosal melanoma is mainly chemotherapy, and local radiotherapy can improve the local control rate
of head and neck mucosal melanoma.

Adjuvant radiotherapy

A prospective design, retrospective analysis, and case-control study conducted by Peking University Oncology Hospital at the 2022 ESMO Annual Meeting ^[2] showed that postoperative adjuvant radiotherapy reduced local recurrence of melanoma (NPMM) in the nasal and sinus mucosa
.
A total of 300 patients were enrolled in the study, divided into SA (surgery only, 158 patients) and SR group (surgery plus radiotherapy, 142 patients
).
The recommended total dose of postoperative radiotherapy is GTV 65-70 Gy/30-35 fx and CTV 60 Gy/30 Fx
.
The primary endpoint was recurrence-free survival (RFS
).

At median follow-up of 50.
0 months, the RFS in the SA and SR groups were 9.
8 and 15.
2 months, respectively (HR: 0.
714, 95% CI: 0.
546-0.
933, P=0.
014).

The lifetime (DMFS) without distant metastasis (DMFS) in the SA and SR groups was 23.
8 and 21.
3 months, respectively (HR: 0.
896, 95% CI: 15.
7-31.
9vs.
13.
3-29.
3, P=0.
457).

The overall survival (OS) of the SA and SR groups was 31.
0 and 35.
1 months, respectively (HR: 0.
816, 95% CI: 25.
7-36.
3vs.
27.
1-43.
2, P=0.
178).

For patients with stage IVA, radiation therapy reduces the recurrence rate of NPMM by a factor
of 0.
43.
In patients without adjuvant system therapy, radiation therapy reduced the recurrence rate by a factor
of 0.
85.
Most adverse events are grade 1 to 2 and manageable
.
The study showed that postoperative radiotherapy plays a crucial role in local control of NPMM, particularly in patients with
local resection, observation only, T4a, or IVA stage.

RFS, PFS, DMFS, and OS

Adjuvant immunotherapy

The immune checkpoint inhibitor (ICI), represented by PD-1 monoclonal antibody, is currently the standard adjuvant treatment for patients at high risk of cutaneous melanoma, but whether this treatment strategy is equally applicable to mucosal melanoma needs to be verified by
high-quality research.
A study at ESMO Annual Meeting 2022 evaluated the efficacy of adjuvant PD-1 inhibitor therapy in patients with resected stage III/IV atrial or mucosal melanoma^[3
].

The study included 157 patients with resectable stage III or IV azimutrial or mucosal melanoma from 19 centres
.
Among them, 3 cases (7%) of mucosal melanoma were removed from stage IV disease
.
At a median follow-up of 18 months, 29 patients (71%) had recurrent mucosal melanoma, 9 (22%) patients completed adjuvant therapy with PD-1 inhibitors, and 19 patients (46%) discontinued adjuvant therapy
due to relapse.
The median relapse time in patients with mucosal melanoma was 12.
9 months, and the first recurrence was only local in 55% (16 patients
).
In patients with resected stage III disease, no significant difference was observed between median RFS and DMFS compared to a matched historical cohort
.

RFS data

The study showed that the prognosis of resection of mucosal melanoma was poor
, regardless of whether adjuvant therapy with or without PD-1 inhibitors.
No significant benefit of adjuvant therapy with PD-1 inhibitors was observed in RFS and DMFS compared with historical controls
.

The results of a phase II clinical trial of terreprimab versus high-dose interferon-alpha-2b (HDI) for complete resected mucosal melanoma conducted by Professor Guo Jun's team at Peking University Cancer Hospital ^were recently published
in the Annals of Oncology.
This study is the first prospective, randomized controlled clinical study
of PD-1 inhibitors versus adjuvant HDI therapy in patients with completely surgically removed mucosal melanoma.
The results suggest that the RFS of triprilizumab adjuvant therapy is similar to HDI (13.
6 months and 13.
9 months), and there is no significant difference between the two groups of DMFS, but for PD-L1-positive patients, terreprimumab is significantly better than HDI and safer, suggesting that terreprimumab may be a new option
for postoperative adjuvant therapy for mucosal melanoma.

Neoadjuvant immunotherapy

Immune checkpoint inhibitors have shown impressive efficacy in neoadjuvant therapy for cutaneous melanoma, but the safety and efficacy in neoadjuvant therapy for mucosal melanoma have not been established
.
The efficacy of combination immune regimens such as navurizumab plus ipimuzumab in unresectable or metastatic mucosal melanoma is 37-43%, but data on efficacy of these agents in neoadjuvant therapy are limited
.
This was explored
in a study at the 2022 ESMO Annual Meeting^[5].

A total of 36 resectable adult mucosal melanoma patients
receiving neoadjuvant anti-PD-1+/anti-CTLA-4 monoclonal antibodies were included in the study.
78% of patients have previously received anti-PD-1+ anti-CTLA4 monoclonal antibody
.
47% of patients have positive or satellite lesions
.
The main sites of the disease are anorectum (53%), genitourinary organs (25%), head and neck (17%) and esophagus (6%)
.
Due to complete remission (n=3,8%) and disease progression (n=6, 17%), a small number of patients did not undergo surgery
.
At a median follow-up of 37.
9 months, the median event-free survival (EFS) was 9.
2 months and the 3-year EFS rate was 29%.

The median OS has not yet been reached, with a 3-year OS rate of 55%.

The objective response rate (ORR) is 47% and the pathological response rate (PRR) is 35%.

Patients with objective and pathological remission have significantly elevated EFS
.
Patients who achieve pathological remission have significantly prolonged
OS.
Grade 3 toxicity was reported in 39% of
patients.

Efficacy data of neoadjuvant immunotherapy

The study showed that neoadjuvant immunotherapy to resect mucosal melanoma is a viable strategy with signs of efficacy and acceptable safety
.
Since there is currently no standard protocol for the removal of mucosal melanoma, further research
is recommended.

Systematic treatment of advanced mucosal melanoma

Immunotherapy

For unresectable mucosal melanoma, a meta-study ^[6] analysed the efficacy of navurizumab + ipimumab versus navurizumab monotherapy in advanced mucosal melanoma, and showed that the ORR in the combined two-drug group was 37%, significantly higher than 23% in the single-agent group, but the efficacy was significantly lower than that of cutaneous melanoma, and the adverse events of combination therapy were higher
.

The 2020 ASCO conference reported on the long-term prognosis
of 79 patients with mucosal melanoma in the CheckMate 067 study.
The median follow-up time was greater than 60 months, and the combination therapy group had higher ORR (43% vs.
30% vs.
7%), 5-year PFS rate (29% vs.
14% vs.
0), 5-year OS rate (36% vs.
17% vs.
7%) compared with the navulliumab monotherapy group and the ipimumab monotherapy group, but the incidence of grade 3 and 4 treatment-related adverse events (TRAEs) was 54%.

Overall, combination immunotherapy may achieve higher ORR and longer OS than monotherapy therapy, but attention should be paid to the occurrence of adverse effects ^[7].

Efficacy data of immunotherapy-related studies

Targeted therapy

High-frequency gene mutations in mucosal melanoma mainly include NRAS, BRAF, NF1, KIT, SF3B1, TP53, SPRED1, ATRX, HLA-A and CHD8
.
Among them, the mutation rates of BRAF and NRAS are 3% to 11% and 5% to 14%, respectively, which are lower than that of cutaneous melanoma, which is about 50% and 10% to 20%,
respectively.
KIT amplification and activation mutations range from 33.
3% to 39.
0%, which is rare in cutaneous ^{melanomas [7}
].
KIT mutation screening in patients with mucosal melanoma in China showed that the rate of KIT mutations detected by second-generation sequencing (NGS) technology reached 15% to 20%, and these patients urgently needed targeted treatment plans
.

Under the leadership of Professor Guo Jun, the clinical study carried out by Peking University Cancer Hospital in 2008 showed that the effectiveness rate of imatinib in the treatment of 43 cases of KIT mutant melanoma was about 23%, and the efficacy was up to 30%
only for patients with KIT11 exon mutation.

At this year's ESMO Annual Meeting, Professor Guo Jun's team presented a single-arm phase II clinical study of imatinib combined with terreprimumab in the treatment of patients with advanced melanoma^[8], with a total of 37 patients with
advanced KIT mutant melanoma.
Seventeen patients can be evaluated
by imaging.
The ORR was 58.
8% and the DCR was 82.
4%, with median PFS not reached
.
Notably, in patients carrying the exon 11 mutation (n=10), the ORR was 90.
0%.

In 9 patients who had not previously received treatment, the ORR was 55.
6%.

The incidence of grade 3 TRAEs in ≥ is 20% (4/20), including rash (10.
0%), elevated aspartate aminotransferase (5.
0%), fatigue (5.
0%), and interstitial pneumonia (5.
0%)
.
No treatment-related deaths
were observed.

Optimal percentage change in target lesions from baseline

The study showed that imatinib plus terreprimumab is effective and well tolerated in patients with advanced melanoma with KIT mutation, and longer follow-up and further patient recruitment
are still required.

Mutations in the CDK4 gene are more common
in mucosal melanoma than cutaneous melanoma.
Previous studies have confirmed that CDK4/6 inhibitors have significant antitumor effects
in xenograft models derived from CDK4-amplified head and neck mucosal melanoma.
At this year's ESMO Annual Meeting, a Phase II study conducted by the Ninth People's Hospital affiliated to Shanghai Jiao Tong University School of Medicine evaluated the efficacy and safety of the CDK4/6 inhibitor SHR6390 in patients with recurrent and/or metastatic head and neck mucosal melanoma carrying CDK4 amplification ^[9].

The results of the study showed that of the 15 patients who could be evaluated, 11 patients were disease-stable (SD) and the best clinical response for 1 patient was partial remission (PR).

PR is still going on for more than 13 months (tumor shrinkage >80%)
.
ORR and DCR were 6.
7% and 80.
0%,
respectively.
The median follow-up was 10.
1 months, and the estimated median PFS was 5.
5 months, and the median OS was not reached
.
At the time of data cut-off, 7 patients were still receiving treatment
.
TRAEs occur in 100.
0% of patients, and most TRAEs are of grade
1 to 2.
The most common AEs were decreased neutrophil count (64.
7%), decreased white blood cell count (64.
7%), and fatigue (41.
2%)
.
Only 1 patient developed a grade 3 neutrophil count decrease and a decreased
leukocyte count.
No 4/5 AE was
reported.

SHR6390 Duration of treatment and remission

This study shows that SHR6390 is well tolerated and has potential in CDK4-amplified head and neck mucosal melanoma patients, supporting further exploration of SHR6390 in combination with other drugs for the systematic treatment
of advanced mucosal melanoma.

Efficacy data of immunological and targeted drug-related studies

Anti-angiogenesis therapy

Mucosal melanoma itself is a vasotropic tumor and is more likely to benefit
from antivascular therapy.
However, anti-angiogenesis therapy alone did not show better efficacy than chemotherapy, and the combination of immunity and antivascular drugs achieved good results
.

Professor Guo's team conducted a dose-increasing Phase Ib clinical study of terreprimumab plus acitinib for the first-line treatment of advanced mucosal melanoma^[10], which included 33 patients with mucosal melanoma, and no dose-limiting adverse effects
were observed.
The study found that among the 29 patients with initial treatment of mucosal melanoma, PR14 patients, SD11 patients, ORR was 48.
3%, DCR was 86.
2%, median DOR was 13.
7 months, median PFS was 7.
5 months, and median OS was 20.
7 months
.
This regimen is the most efficient first-line treatment for
advanced mucosal melanoma that has been reported at home and abroad to date.

In addition, the interim results of a randomized controlled phase II trial of terreprimumab combined with acyclitinib and teriprelizumab monotherapy or acyclitinib monotherapy for advanced mucosal melanoma by Professor Guo Jun's team were also announced at this year's ASCO Annual Meeting ^[11].

。 A total of 51 patients (18 patients in the combination therapy group [T+A], 20 in the terreprimumab monotherapy group [T], and 13 patients in the acyclitinib monotherapy group [A]) achieved better median PFS (T+A vs.
T vs.
A: 5.
8 months vs.
2.
8 months vs.
1.
4 months), higher ORR (35.
3% vs.
17.
6% vs.
0), and higher DCR (82.
4% vs.
52.
9% vs.
58.
3%)
。

Data on the efficacy of terreprimab plus axitinib

At the 2022 ASCO Annual Meeting, a prospective one-arm study conducted by Professor Zou Zhengyun's team at Nanjing Drum Tower Hospital evaluated the efficacy and safety of carrelizumab plus apatinib in the treatment of patients with advanced mucosal melanoma ^[12].

A total of 30 patients were enrolled in the group, of which 21 patients underwent at least one efficacy assessment, with a median follow-up of 8.
1 months
.
The ORR was 42.
9%, of which 1 (4.
8%) patients confirmed complete remission (CR), 6 patients (28.
6%) confirmed PR, and 2 (9.
5%) patients did not confirm PR.

The DCR is 81.
0%.

The median PFS in 21 patients was 7.
2 months
.
The most common treatment-related adverse events were fatigue (63.
0%), hypertension (55.
6%), and elevated aminotransferases (51.
9%)
.
No treatment-related deaths
occurred.
The study showed that carrelizumab combined with apatinib showed good ORR and DCR in patients with advanced mucosal melanoma, with an acceptable safety profile
.

Data on the efficacy of carrelizumab in combination with apatinib

In summary, targeted and immunomonotherapy has limited benefit in advanced mucosal melanoma, and current research is directed at combination therapy
between different drugs.
Among them, the combination therapy of anti-vascular endothelial growth factor receptor tyrosine kinase inhibitor and immunotherapy has achieved higher ORR and PFS, which is worth further exploration
.

Efficacy data of immunological, targeted, and antiangiogenic drugs related to research

References: (Swipe up to read)

Zhai Xuesong, Wen Shuxin, Zhao Xiaojuan, et al.
Progress in the treatment of head and neck mucosal melanoma[J].
Chinese Journal of Otorhinolaryngology, Head and Neck Surgery, 2020, 55(1): 73-77.

[2] Bin Lian,et al.
Postoperative adjuvant radiotherapy can reduce the local recurrence of nasal cavity and paranasal sinus mucosal melanoma: a prospective design, retrospective analysis and case–control study.
2022 ESMO.
Abstract 808P.

[3] Sarah Jacques,et al.
Outcomes of patients with resected stage III/IV acral or mucosal melanoma treated with adjuvant antiPD-1 therapy.
2022 ESMO.
Abstract 809P.

[4]B.
Lian, et al.
Toripalimab (anti-PD-1) versus High-Dose Interferon-α2b as Adjuvant Therapy in Resected Mucosal Melanoma: A Phase II Randomized Trial.
Annals of Oncology.
2022.
doi: 10.
1016/j.
annonc.
2022.
07.
002.

[5] Joel Ho, et al.
Neoadjuvant Checkpoint Inhibitor Immunotherapy for Resectable Mucosal Melanoma.
2022 ESMO.
Abstract 801P.

[6] D'Angelo SP, Larkin J, Sosman JA, et al.
Efficacy and safety of nivolumab alone or in combination with ipilimumab in patients with mucosal melanoma: A pooled analysis[J].
J Clin Oncol, 2017, 35(2):226-235.

Sheng Xinan, Yan Xieqiao, Lian Bin, et al.
Exploration and treatment strategy of mucosal melanoma[J].
Chinese Journal of Oncology, 2021, 48(7):336-340.

[8]L.
Si, et al.
A single-arm, phase II clinical study of imatinib mesylate/toripalimab combo in patients (pts) with advanced melanoma harboring c-Kit mutation or amplification.
2022 ESMO.
Abstract 815P.

[9] Chaoji Shi, et al.
Phase II trial of the cyclin dependent kinase 4/6 inhibitor SHR6390 in patients with advanced head and neck mucosal

melanoma harboring CDK4 amplification.
2022 ESMO.
Abstract 880P.

[10] Sheng X, Yan X, Chi Z, et al.
Axitinib in combination with toripalimab,a humanized immunoglobulin G4 monoclonal antibody against programmed cell death-1, in patients with metastatic mucosal melanoma:An open-label phase Ⅰb trial[J].
J Clin Oncol, 2019, 37(32):2987-2999.

[11] Chuanliang Cui,et al.
Toripalimab plus axitinib versus toripalimab or axitinib alone in patients with treatment-naive unresectable or metastatic mucosal melanoma: Interim results from a randomized, controlled, phase II trial.
2022 ASCO.
Abstract 9512.

[12] Zhengyun Zou, et al.
Camrelizumab plus apatinib for patients with advanced mucosal melanoma: A prospective single-arm study.
2022 ASCO.
Abstract 9550.

Editor/Typesetting: Jiang Zhou

Executive: Tourist