The advent of immune checkpoint inhibition has arguably been the greatest breakthrough for the treatment of metastatic solid tumours, with durable complete responses observed across multiple cancer types. With success in the metastatic setting, pharma companies, researchers and physicians have invested heavily in exploring the use of immune checkpoint inhibitors (ICIs) for the treatment of locally advanced disease, hoping to increase response rates and prevent disease progression.

With existing treatment paradigms for locally advanced disease often including surgery, the optimal timing of ICI treatment within each oncology setting is a subject of intense research. Presentations at the ESMO Congress 2022 have demonstrated the critical importance of therapy sequence, with astounding results for neoadjuvant ICI use in melanoma and microsatellite instability-high or mismatch repair deficient (MSI-H/dMMR) colorectal cancer (CRC).

Since the approval of the first ICI – Bristol-Myers Squibb’s (BMS) Yervoy (ipilimumab) in 2011 for unresectable metastatic melanoma – multiple checkpoint inhibitors have been approved in this disease setting. More recently, ICIs have also been approved for resectable cutaneous melanomas as adjuvant therapy, following surgical resection. The use of neoadjuvant ICI therapy remained largely unexplored. The S1801 Phase II study was set up to investigate the efficacy of neoadjuvant versus adjuvant ICI, with 345 patients with resectable stage IIIB-IV disease randomised to either the adjuvant or neoadjuvant arm.

Patients in the adjuvant arm underwent surgery followed by 18 cycles of Merck’s Keytruda (pembrolizumab). Those in the neoadjuvant arm received three cycles of Keytruda, followed by surgery and 15 additional cycles of Keytruda therapy. Event-free survival (EFS) was the primary endpoint in this study. During a presentation, Dr. Sapna Patel, medical oncologist, The University of Texas MD Anderson Cancer Center in Houston, shared data of a two-year EFS of 72% in comparison to the 49% reported for the adjuvant arm. Overall survival (OS) data remains immature, with too few events for statistical analysis. No additional toxicity concerns were identified in the neoadjuvant versus adjuvant patients. While we await the mature survival data, the highly significant EFS benefit observed with neoadjuvant treatment is likely to set a new standard of care (SOC) in this disease setting.

In 2020, Keytruda was approved for previously untreated metastatic MSI-H/dMMR CRC, with the KEYNOTE-177 study demonstrating an 8.3-month progression-free survival (PFS) benefit over SOC chemotherapy. MSI-H/dMMR CRC accounts for 10-15% of all CRC. Recurrence rates for patients with stage III MSI-H/dMMR CRC are high, with 20-40% progressing to metastatic disease despite SOC chemotherapy. The NICHE-2 study investigated the use of neoadjuvant ICI to reduce the risk of disease relapse and progression in this high-risk population, and new data was presented by Dr. Myriam Chalabi, medical oncologist, Gastrointestinal Oncology bij Antoni van Leeuwenhoek, Amsterdam. In the non-randomised, multi-centre NICHE-2 study, 112 patients were enrolled to receive one cycle of BMS’ Opdivo (nivolumab) plus Yervoy, followed by a further cycle of Opdivo before undergoing surgical resection. Of the 107 evaluable patients, 98% of patients underwent timely surgery, meeting this critical safety endpoint.

Major pathological responses (MPRs, 10% or less residual viable tumour) and pathological complete responses (pCRs, 0% residual viable tumour) following surgery were secondary endpoints. The trial reported an MPR rate of 95% and a remarkable pCR rate of 67%. With a median follow-up of 13.1 months, there have been no disease recurrences. While no control arm was included in this study, these data far outperform any historical controls, and with three-year disease-free survival data expected next year, this study is expected to transform the SOC in this setting.

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ICI therapy requires pre-existing anti-tumour T cells to be in contact with the cancer cells. The administration of an ICI before surgery induces an anti-tumour immune response from a relatively large population of T cells residing within the primary tumour. These T cells can then induce a systemic anti-tumour response both at the primary site and any distant micro-metastatic sites, and can result in large numbers of tumour-reactive T cells following resection.

Circulation of tumour-reactive T cells following surgery has already been demonstrated to increase recurrence-free survival with use in the adjuvant setting, moreover, neoadjuvant treatment is expected to increase this effect. While the S1801 and NICHE studies demonstrate the significant potential of neoadjuvant ICI in non-metastatic disease, both melanoma and MSI-H/dMMR CRC are highly responsive to ICI. It remains to be seen whether neoadjuvant therapy will hold substantial promise in indications where ICIs are yet to demonstrate significant efficacy.

This article was updated with comment attributions to the presenters at ESMO 2022.