Neoadjuvant immunotherapy can induce pathological responses and immunological memory in different malignancies, being a potential therapy for hepatocellular carcinoma
A multi-cohort, phase II study (NCT03916627) of neoadjuvant cemiplimab (an anti-PD-1 antibody) for the treatment of non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC) and head and neck squamous cell carcinoma (all resectable) was highlighted during the American Association for Cancer Research (AACR) Annual Meeting 2021. The data presented were from cohort B, i.e., HCC patients.
The trial recruited 21 patients to receive two cycles of neoadjuvant cemiplimab (350mg every three weeks) followed by surgical resection and then eight more cycles of anti-PD-1 in the adjuvant setting. The primary endpoint was significant tumor necrosis, defined as > 70% of necrosis in the resected specimen. Secondary endpoints included delayed surgery, overall response rate, adverse events (AEs), and lymphocyte infiltration. Patients underwent pre-treatment biopsies and periodic blood collection throughout treatment to allow exploratory analyses, including multiplex immunohistochemistry and single–cell proteomic and transcriptomic analysis.
All patients received two cycles of preoperative cemiplimab and all but one patient underwent successful resection. One patient was diagnosed with metastatic disease at the time of surgery and resection was aborted.
Cemiplimab demonstrated an acceptable risk-benefit profile: 90.5% of patients experienced some treatment-emergent adverse events (TEAE) of any degree during the neoadjuvant treatment period up to the perioperative period; 28.6% experienced any grade 3 TEAE. One patient presented grade 3 pneumonitis during neoadjuvant therapy and surgery was postponed two weeks after the protocol-defined surgical window.
Out of the 20 patients with resected tumors, four (20%) met the predefined endpoint of > 70% of tumor necrosis and seven (35%) had ≥ 50% tumor necrosis. Three (15%) of the four patients with > 70% of tumor necrosis had a complete pathological response, defined as 100% tumor necrosis.
Similar patterns of change in the degree of necrosis were observed in the pathological evaluation and 3D magnetic resonance imaging (MRI) from the beginning to the completion of immunotherapy. The initial pathological evaluation suggests an association between immune cell infiltration and tumor response.
This is the largest trial to date of neoadjuvant anti-PD-1 monotherapy targeting HCC. According to the authors, pathological response data support the development of larger studies to identify optimal clinical endpoints that correlate with improvement in survival, establishing the utility and safety of perioperative PD-1 blockade.
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