Neoadjuvant Immunotherapy for Stage III Melanoma Emerges as New Standard of Care

Emerging neoadjuvant therapy has resulted in a strategy shift for high-risk operable melanoma. This change in the treatment landscape is supported by many clinical trials including the randomized phase 2 SWOG S1801 trial (NCT03698019), which reported a 42% reduction in 2-year event-free survival for neoadjuvant-adjuvant vs adjuvant-only pembrolizumab (Keytruda) for resectable stage IIIB-D/IV melanoma (72% v 49%; HR, 0.58; P = .004).¹

Checkpoint inhibitor immunotherapies, including PD-1 and CTLA-4, and BRAF/ MEK targeted therapies play key roles in the neoadjuvant arena and have substantially improved melanoma survival, with 5-year survival rates of 30% to 50%.¹ These results have led to the development of checkpoint immunotherapy and targeted therapies in both the adjuvant and neoadjuvant settings.

Standard treatments have typically consisted of 12 months of adjuvant therapy after surgical removal of the tumor. This approach had several limitations; approximately 30% of patients with stage III melanoma experienced recurrence within 2 years of completing the adjuvant therapy and roughly 15% to 20% experienced rapid postsurgical recurrence that prevented adjuvant therapy.¹ Other limiting factors include the long duration of adjuvant therapy and a lack of specific rationale, leading to excess expense and stress on the patient. Unfortunately, there are no established biomarkers to determine which patients would best benefit from adjuvant therapy resulting in occurrences where patients are either undertreated or overtreated.¹ Adjuvant therapies also have associated risk where 20% to 25% of patients will experience irreversible adverse events for which there are currently no biomarkers to access this risk for the individual patient.1

Contrary to adjuvant therapy, neoadjuvant therapy is administered for a brief period before complete surgical removal of all known melanoma. This approach provides a direct, visual assessment of the dissected lesion to evaluate how the patient has responded to the neoadjuvant therapy, leading to personalized management and prognostication for the patient going forward. Favorable responders can experience potential de-escalation of continued systemic and local treatments, and nonresponders can be switched to other less toxic, effective alternatives.¹

Moreover, neoadjuvant treatment can also shrink the tumor in the presurgical stage, unintentionally treating the spread of the cancer that may have originally gone undetected. This method can target metastatic disease sooner than initial surgery and potentially improve overall outcome.¹ Additionally, for patients who experience rapid development of metastases, neoadjuvant treatment can be an alternative to surgery that would not provide significant benefit.¹

Stages I through III of melanoma are managed by surgery, with stage I and II tumors confined to the skin and ranging from less than 0.8 mm (stage IA) to greater than 4 mm (stage IIC) in thickness.¹ Patients with a primary tumor greater than 1 mm should undergo sentinel lymph node biopsy for staging purposes. In stage IV, the disease is defined by the presence of distant visceral or nodal metastasis and operable only in rare cases.¹ For patients in this stage, it is of great interest to prevent recurrence and improve survival rates.

Neoadjuvant limitations include a period of time with a possibility for localized progression of the disease that makes surgery unviable. A pooled analysis of 192 patients showed that in 3.6% of patients, the disease recurred while undergoing neoadjuvant therapy; this included 4 patients who developed distant metastases, discontinuing surgery as an option.²

Of the 192 patients, 141 received immunotherapy (104, combination of ipilimumab [Yervoy] and nivolumab [Opdivo]; 37, anti–PD-1 monotherapy), and 51 received targeted therapy.²

Another study (NCT03698019) showed that 32% of patients experienced disease progression during neoadjuvant therapy, making surgery no longer an option.³ Treatment included 3 doses of neoadjuvant pembrolizumab, surgery, and 15 doses of adjuvant pembrolizumab.³ However, it is probable that these patients could have experienced rapid recurrence of the disease even with initial surgery and adjuvant therapy.⁴ Another limitation to neoadjuvant therapy is that it can worsen patient performance status or toxicities, which can also prevent or delay surgery.¹

Initial clinical trials (TABLE) have shown favorable results, leading to the recommendation by the National Comprehensive Cancer Center Network of enrollment in a neoadjuvant trial for stage III melanoma (clinically node-positive or satellite/in-transit—positive).¹ The guidelines state that neoadjuvant therapy should precede surgery by 6 to 8 weeks while measuring various outcomes (pathologic response, event-free survival, recurrence-free survival, overall survival (OS), and safety measures) throughout treatment to evaluate its effectiveness.^1,5

To date, immunotherapy results are the most promising, yielding excellent pathologic response.1 Targeted therapies have also yielded excellent pathologic response; however, long-term studies have shown a pattern of recurrence after 12 to 18 months that is not found with immunotherapy.1 For instance, a single-arm phase 2 study (NCT01972347) consisting of 35 patients with BRAF-mutation–positive, stage III melanoma were treated with dabrafenib (Tafinlar) and trametinib (Mekinist) neoadjuvant therapy.⁶ The results showed a pathologic response of 69% as well as a pathologic complete response (pCR) of 49% in 17 of the patients^.6 However, within 3 years, 60% of patients had recurrence; at 5 years, the recurrence-free survival (RFS) rate was 40% and the OS rate was 80%.⁶ Another phase 2 study (NCT02231775) evaluated 20 patients with stage III/IV melanoma whose tumor harbored a BRAF V600 mutation in 2 arms; patients in the control arm had up-front surgery followed by dabrafenib-trametinib, and those in the second arm (experimental arm) were given dabrafenib-trametinib followed by surgery and up to 44 weeks of adjuvant dabrafenib-trametinib.7 Seven patients in the second arm achieved a pCR of 58%, and this arm was closed early at 18.6 months due to substantially improved results.^1,7

An early pilot study that focused on the use of checkpoint inhibitors, OpACIN (NCT02437279), evaluated 20 patients with stage III melanoma in 2 arms; the first arm was given a combination regimen of neoadjuvant ipilimumab and nivolumab and the other arm (control) was given the same combination regimen of ipilimumab and nivolumab but as adjuvant therapy.⁸ Findings showed that in the neoadjuvant arm (n = 9), 7 patients experienced a pathologic response, with 3 of them experiencing a pCR, and only 1 patient had recurrence at the 69-month follow-up.⁸ After 5 years, the estimated RFS rate was 70% and the OS rate was 90% with neoadjuvant therapy, and the RFS rate was 60% and the OS rate was 70% in the adjuvant therapy arm.⁸

Further studies comparing neoadjuvant versus adjuvant treatment have been conducted using larger, randomized sample sizes.1 At the 2-year follow-up, the SWOG S1801 trial reported an event-free survival rate of 72% vs 49% for neoadjuvant and adjuvant pembrolizumab, respectively (HR, 0.58; 95% CI, 0.39-0.87; P = .004).^1,3

Further understanding of perioperative immunotherapy will lead to improved cancer treatment for other diseases, refining the neoadjuvant approach. Patients in a recent phase 2 trial (NCT04165772) with mismatch repair–deficient rectal cancer received no further treatment after a complete clinical response of 100% (95% CI, 74%-100%) to neoadjuvant single-agent dostarlimab-gxly (Jemperli).⁹ No patient had recurrence, experienced progression, or required surgery or chemoradiotherapy after 12 months (range, 6-25), indicating that surgery may not be necessary for all patients.^1,9

Other studies have tested neoadjuvant immunotherapy for patients with non–small cell lung cancer and kidney cancer.^10-13 It's not clear whether neoadjuvant immunotherapy will be effective for cancers without a strong immune component; however, it's evident that for melanoma, neoadjuvant therapy has shown significant benefit and the potential to change cancer treatment.¹

REFERENCES

1. Long GV, Menzies AM, Scolyer RA. Neoadjuvant checkpoint immunotherapy and melanoma: the time is now. J Clin Oncol. 2023;41(17):3236-3248. doi:10.1200/JCO.22.02575

2. Menzies AM, Amaria RN, Rozeman EA, et al. Pathological response and survival with neoadjuvant therapy in melanoma: a pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC). Nat Med. 2021;27(2):301-309. doi:10.1038/s41591-020-01188-3

3. Patel SP, Othus M, Chen Y, et al. Neoadjuvant-adjuvant or adjuvant-only pembrolizumab in advanced melanoma. N Engl J Med. 2023;388(9):813-823. doi:10.1056/NEJMoa2211437

4. Bloemendal M, van Willigen WW, Bol KF, et al. Early recurrence in completely resected IIIB and IIIC melanoma warrants restaging prior to adjuvant therapy. Ann Surg Oncol. 2019;26(12):3945-3952. doi:10.1245/s10434-019-07274-2

5. NCCN. Clinical Practice Guidelines in Oncology. Melanoma, version 2.2023. Accessed July 5, 2023. https://bit.ly/46ELy6Y 

6. Long GV, Saw RPM, Lo S, et al. Neoadjuvant dabrafenib combined with trametinib for resectable, stage IIIB-C, BRAFV600 mutation-positive melanoma (NeoCombi): a single-arm, open-label, single-centre, phase 2 trial. Lancet Oncol. 2019;20(7):961-971. doi:10.1016/S1470-2045(19)30331-6

7. Amaria RN, Prieto PA, Tetzlaff MT, et al. Neoadjuvant plus adjuvant dabrafenib and trametinib versus standard of care in patients with high-risk, surgically resectable melanoma: a single-centre, open-label, randomised, phase 2 trial. Lancet Oncol. 2018;19(2):181-193. doi:10.1016/S1470-2045(18)30015-9

8. Blank CU, Rozeman EA, Fanchi LF, et al. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Nat Med. 2018;24(11):1655-1661. doi:10.1038/s41591-018-0198-0

9. Cercek A, Lumish M, Sinopoli J, et al. PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer. N Engl J Med. 2022;386(25):2363-2376. doi:10.1056/NEJMoa2201445

10. Shao L, Lou G. Neoadjuvant immunotherapy in non-small cell lung cancer: a narrative review on mechanisms, efficacy and safety. J Thorac Dis. 2022;14(9):3565-3574. doi:10.21037/jtd-22-1192

11. Singla N, Elias R, Ghandour RA, et al. Pathologic response and surgical outcomes in patients undergoing nephrectomy following receipt of immune checkpoint inhibitors for renal cell carcinoma. Urol Oncol. 2019;37(12):924-931. doi:10.1016/j.urolonc.2019.08.012

12. Carlo MI, Attalla K, Mazaheri Y, et al. Phase II study of neoadjuvant nivolumab in patients with locally advanced clear cell renal cell carcinoma undergoing nephrectomy. Eur Urol. 2022;81(6):570-573. doi:10.1016/j.eururo.2022.01.043

13. Gorin MA, Patel HD, Rowe SP, et al. Neoadjuvant nivolumab in patients with high-risk nonmetastatic renal cell carcinoma. Eur Urol Oncol. 2022;5(1):113-117. doi:10.1016/j.euo.2021.04.002