A Phase 2 Clinical Trial of Neoadjuvant Relatlimab and Nivolumab in High Risk, Clinical Stage II Cutaneous Melanoma

Neoadjuvant therapy is feasible in stage II melanoma, and the dual inhibition of the distinct LAG-3 and PD-1 checkpoint pathways with relatlimab and nivolumab has a synergistic effect in the tumour microenvironment leading to a pathological response after 2 doses of therapy.

The incidence of stage II melanoma is significantly higher than for later stages of the disease, but stage II patients account for approximately 50% of all those who subsequently develop metastatic disease and die. Stage II melanomas have a Breslow thickness greater than 1.0 mm, with no clinical evidence of nodal, satellite or distant metastases. Pathological staging requires evaluation of the regional node basin after lymphatic mapping and sentinel node biopsy (SNB), which is required for N categorization of all \>T1 melanomas. Compared to stage III disease, stage IIB and IIC have a worse prognosis than stage IIIA melanomas. Stage IIC even share the same poor prognosis as stage IIIB.

Global management guidelines highlight the importance of an initial diagnostic biopsy to confirm the diagnosis of melanoma and to pathologically stage the tumour. After the diagnosis and Breslow thickness and other features have been established by histological assessment of the initial excision biopsy, the definitive management of primary cutaneous melanoma consists of surgical excision with a safety margin of surrounding skin and subcutaneous tissue. Sentinel lymph node biopsy (SNB) should be considered for melanomas ≥ 1 mm thickness (≥ 0.8 mm if ulcerated or other high-risk features) in which case lymphoscintigraphy must be performed just prior to wider excision of the primary melanoma site.

Despite the equivalent risk, the current standard of care for stage IIB/C melanoma is observation only although this is expected to change given the results from recent studies investigating adjuvant drug therapy in this stage. Importantly, systemic adjuvant therapy is standard for stage IIIB/C/D disease. Although patients with stage II disease contribute the largest population to melanoma-specific mortality, under the current treatment guidelines, these patients represent a population less likely to be treated in the adjuvant setting and have no representation in the neoadjuvant setting.

Patients at low risk of recurrence with stage IIA disease (tumour \>2-4 mm in thickness without ulceration \[T3a\], or \>1 to 2 mm in thickness with ulceration \[T2b\]), have a high probability to be cured by surgery alone. However, the 5-year melanoma-specific survival (MSS) in stage IIA is 94%, which is comparable to the 93% of stage IIIB; patients with stage IIIA disease have a better prognosis than those with stage IIC disease. Patients diagnosed with higher risk stage IIB/C disease have thicker melanomas \> 2.0 mm with ulceration, and \> 4.0 mm with or without ulceration, respectively. These patients have an unmet clinical management need as there is no clear evidence for effective systemic adjuvant therapy to prevent disease recurrence once the primary tumour has been completely resected, which is the current standard of care for these patients. Approximately 15% to 20% of patients diagnosed with Stage IIB and 30% of patients diagnosed with Stage IIC melanoma will have a recurrence of their melanoma at 24 months. Within 5 years of surgical resection, approximately 25% of patients with Stage IIB disease and 40% of patients with Stage IIC disease will have disease recurrence. Among patients with stage IIB and IIC melanoma local recurrence occurs in 19 and 11% respectively; 45 and 58% experience regional recurrence and 44 and 39% have distant recurrence.

Patients who present with localized disease and primary tumours of less than 2.0 mm with ulceration (T2b), or primary tumour of \>2.0 to 4.0 mm without ulceration (T3a) are categorised as having stage IIA melanoma. A subset of these patients have a high risk of recurrence and may benefit from adjuvant treatment. Melanoma Institute Australia has developed a risk prediction tool which will be used to select this additional high-risk population (i.e., those predicted to be at ≥ 20% recurrence at 5 years, melanomarisk.org.au). The high-risk group is identified using the following variables: mitotic rate, (count) presence of ulceration (yes/no), Breslow thickness (mm), lymphovascular invasion (present vs. absent), SNB status (negative vs not known), presence of tumour infiltrating lymphocytes (TILs), age (years), and sex (male vs. female).

The concept of moving immunotherapies from a more advanced setting where their efficacy has been well established, into a setting of stage II disease is well supported by the documented safety and efficacy data of these agents in the adjuvant setting. Introducing systemic treatment earlier in stage II disease is key to improving long term outcomes, but risk stratification is needed to identify those at most risk and manage the risk/benefit ratio given the potential immune-related toxicities.

Neoadjuvant therapy (NAT) in melanoma (and several other solid tumours) is an area of active investigation with numerous completed and ongoing trials studying a variety of therapeutic interventions utilizing diverse designs. Neoadjuvant immunotherapy and targeted therapies results in a high recurrence-free survival rate (2-year RFS \>95%) for pathological responders in stage III melanoma. Subsequent management can be personalised based on the neoadjuvant response to therapy and safely provides large amounts of tissue for analysis of resistance mechanisms from those who do not have a pathological response. The neoadjuvant platform also allows for the rapid testing of novel drug combinations informing decisions to proceed to phase III trials.

Given the similar outcomes with stage III melanoma, the findings from Keynote-716, and the positive results from neoadjuvant immunotherapy trials in stage III disease, introducing neoadjuvant therapy for stage IIB/C melanoma is an opportunity to improve outcomes with 2 doses of treatment 4 weeks apart. The pathological response to immunotherapy may aid the risk stratification and identification of which patients may benefit from adjuvant therapy. The pathological response to treatment is measured by the amount of residual, viable tumour tissue in the resected specimen. In accordance with the International Neoadjuvant Melanoma Consortium criteria, a complete pathological response (pCR) is demonstrated by the complete absence of residual viable tumour cells; a near pCR is \<10% of residual tumour; a partial pathological response (pPR) is 10%-50% residual tumour and no pathological response (pNR) is the presence of \>50% tumour cells.

Dual checkpoint inhibition with the distinct checkpoint inhibitors relatlimab and nivolumab results in enhanced T-cell effector function that is greater than the effects of either antibody alone in murine syngeneic tumour models. The ability of anti-LAG-3 to synergize with anti-PD-1 supports the utility of combined LAG-3 and PD-1 blockade. Anti-PD-1 has already demonstrated potent anti-tumour activity in multiple human malignancies, and it is envisaged that LAG-3, when co-administered with anti-PD-1, will enhance the anti-tumour responses and potentially broaden the spectrum of tumours responsive to anti-PD-1 treatment with an acceptable safety profile.

High risk stage IIA and stage IIB/C resected melanoma represents a population of high unmet need due to the potential for locoregional, nodal or systemic recurrence, which dramatically impacts post-recurrence survival, especially in the case of systemic recurrences. Patients with stage IIB/IIC disease have a thick or ulcerated primary melanoma, with a 10-year overall survival (OS) of 82% and 75%, respectively, similar to that seen in stage IIIA and IIIB melanoma (88% and 77% respectively). In Australia, the current recommended standard of care for patients diagnosed with AJCC (8th edition) Stage IIB/C melanoma is observation.

The robust clinical activity demonstrated by nivolumab and relatlimab in patients with stage III and advanced melanoma, the manageable safety profile, and the lack of standard of care for patients who are at high risk for recurrence after a complete surgical resection of select stage IIA and stage IIB/IIC melanoma supports the further development of this drug combination in this population of patients.

Based upon the improvements seen in PFS with the addition of relatlimab to nivolumab in RELATIVITY 047 and major pathological responses in neoadjuvant treatment of stage III melanoma, this study will investigate the pathological response to 2 doses of this novel combination immunotherapy (on days 1 and 294) in patients with AJCC stage IIB and IIC melanoma (i.e. stage II based on biopsy of the primary melanoma and a clinically negative \[CT and ultrasound scan assessed\] regional lymph node basin(s)). Melanoma Institute Australia's risk prediction tool will be used to select an additional high risk population from those with AJCC stage IIA melanoma in need of adjuvant treatment (i.e., those predicted to be at ≥ 20% recurrence at 5 years (melanomarisk.org.au).

Neoadjuvant treatment will be followed by sentinel lymph node biopsy and complete surgical excision of the primary lesion at 6 weeks. Patients who have a pCR or near-pCR will undergo surveillance only. Remaining patients will receive adjuvant treatment with relatlimab 160 mg and nivolumab 480 mg every 4 weeks for 11 cycles (for an overall total of 13 cycles). Translational studies will be performed on tissue, blood and stool samples collected at baseline and at week 6 to identify potential predictors or response to drug and identification of potential biomarkers of recurrence. Data on the mechanisms of resistance to systemic therapies using tumour and liquid biopsy samples may lead to innovative treatment strategies to prevent resistance and improve outcomes in both the adjuvant and metastatic settings. Patients will be followed up for recurrence and survival for 10 years.

Eligibility Criteria:
Inclusion Criteria:

1. The patient (or legally acceptable representative, if applicable) provides written informed consent for the trial.
2. Male/female patients who are at least 18 years of age on the day of signing informed consent.
3. AJCC (8th edition) clinical stage IIB (T3b and T4a) or IIC (T4b) melanoma, or stage IIA (T2b and T3a) melanoma with a ≥ 20% risk of recurrence at 5 years according to the MIA stage II risk calculator (melanomarisk.org.au). Staging and lymphoscintigraphy (including ultrasound of draining nodal basin(s) will be performed at baseline. Patients with demonstrated clinical stage III melanoma are not eligible.
4. Histologically confirmed primary cutaneous melanoma from a partial core biopsy, punch biopsy, or excisional biopsy with residual macroscopic disease.
5. BRAF / NRAS mutant or wild type melanoma included.
6. Availability of the diagnostic tumour sample for translational studies.
7. Surgery has been planned for sentinel node biopsy and complete resection of stage II disease. Only cases where a complete surgical resection leading to tumour free margins and which can be safely achieved without being overly morbid is considered "resectable". Resectability of each case has been agreed upon within the context of a Multi-Disciplinary Team (MDT) meeting.
8. Eastern Cooperative Oncology Group (ECOG) status 0 to 1.
9. Adequate haematological, hepatic, renal and endocrine function on blood pathology testing.
10. Anticipated life expectancy of \>12 months.
11. Agreement to avoid pregnancy for the duration of treatment: Women of childbearing potential (WOCBP) must not be breastfeeding and must have a negative pregnancy test within 3 days prior to initiation of dosing. She must agree to use an acceptable method of birth control from the time of the negative pregnancy test, through the duration of treatment with the study combination plus 5 half-lives of study treatment for a total of 5 months post-treatment completion.

Exclusion Criteria:

1. Clinical or radiographic evidence of nodal, in-transit, satellite or microsatellite metastases or distant melanoma metastases.
2. Any contraindication to the administration of relatlimab or nivolumab.
3. A history of allergy or hypersensitivity to study treatment components.
4. Prior immunotherapy for any malignancy (including, but not limited to: anti-PD-1, CTLA-4, PDL-1 or anti-LAG3 or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways).
5. Patients with a condition requiring chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone or equivalent) or any other form of immunosuppressive therapy within 14 days prior to the first dose of study treatment. The following are permitted:

   1. Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc)
   2. Inhaled or intranasal corticosteroids (with minimal systemic absorption) may be continued if patient is on a stable dose
   3. Non-absorbed intra-articular steroid injections.
6. Has active autoimmune disease that has required systemic treatment in the past 12 months (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). The following are permitted:

   1. Vitiligo
   2. Type I diabetes mellitus
   3. Residual autoimmune hypothyroidism on stable hormone replacement
   4. Resolved childhood asthma or atopy
   5. Psoriasis not requiring systemic treatment
   6. Autoimmune conditions which are not expected to recur in the absence of an external trigger.
7. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. The following malignancies, if undergone successful definitive resection or curative treatment, are permitted:

   1. Basal cell carcinoma of the skin
   2. Squamous cell carcinoma of the skin
   3. Carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy)
   4. Prostatic intraepithelial neoplasia
   5. Atypical melanocytic hyperplasia
   6. Other malignancies for which the patient has been disease free for 1 year.
8. Uncontrolled or significant cardiovascular disease including, but not limited to, any of the following:

   1. Myocardial infarction or stroke/transient ischemic attack within the 6 months prior to consent
   2. Uncontrolled angina within the 3 months prior to consent
   3. Any history of clinically significant arrhythmias (such as poorly controlled atrial fibrillation, ventricular tachycardia, ventricular fibrillation, or torsades de pointes)
   4. QTc prolongation \> 480 msec
   5. History of other clinically significant cardiovascular disease (i.e., cardiomyopathy, congestive heart failure with New York Heart Association functional classification III-IV, pericarditis, significant pericardial effusion, significant coronary stent occlusion, poorly controlled venous thrombosis, etc)

   (g) Cardiovascular disease-related requirement for daily supplemental oxygen (h) History of 2 or more M.I.s OR 2 or more coronary revascularization procedures (regardless of the number of stent placements during each procedure) (i) Patients with history of myocarditis, regardless of aetiology.
9. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis or current interstitial lung disease.
10. Has an active infection requiring systemic therapy.
11. Treatment with complementary medications (e.g., herbal supplements or traditional Chinese medicines).
12. Any live / live-attenuated vaccine (e.g., varicella, zoster, yellow fever, rotavirus, oral polio and measles, mumps, rubella \[MMR\]) within 30 days of first study treatment, during treatment and until 135 days post last dose. Inactivated / killed vaccines are permitted..
13. Active SARS-CoV-2 infection. The following are permitted

    1. At least 10 days (4 weeks for severe/critical illness) have passed since symptoms first appeared or positive RT-PCR or viral antigen test result.
    2. At least 24 hours have passed since the last fever without the use of fever-reducing medications.
    3. Acute symptoms (e.g., cough, shortness of breath) have resolved.
    4. In the opinion of the investigator, there are no COVID-19-related sequelae that may place the participant at a higher risk of receiving study treatment.
    5. Recommended negative follow-up SARS-CoV-2 RT-PCR or viral antigen test based on institutional / local guidelines.
14. Has a known history of Human Immunodeficiency Virus (HIV). Note: no testing for HIV is required unless mandated by local health authority.
15. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen \[HBsAg\] reactive) or known active Hepatitis C virus (defined as HCV RNA \[qualitative\] is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
16. Has a known history of active TB (Bacillus Tuberculosis).
17. Pregnant or breast feeding females.
18. Concurrent medical or social conditions that may prevent the patient from attending assessments per schedule.