Neoadjuvant IO response suggesting long-term benefit in HPV – HNSCC

Ravindra Uppaluri, MD, PhD, noted during the presentation that ongoing trials are examining the use of neoadjuvant OI in all types of head and neck cancer, as this approach can help induce an immune response. to provide lasting benefit long after surgery and potentially reduce the need to add adjuvant therapies.

For patients with HNSCC in particular, relapse is still a major concern after surgery, so researchers hope that neoadjuvant therapy for these patients would improve outcomes.

Uppaluri, head of the otolaryngology division at Brigham and Women’s Hospital in Boston, Mass., Explained that neoadjuvant inhibition of immune checkpoints would activate the immune response against the primary tumor as well as the lymph nodes. regional. Since patients receiving neoadjuvant therapy have an intact immune system since they have not yet been treated, they would likely be more sensitive to treatment, and the immune system would then be primed for a greater anti-tumor lymphocyte response. T.2 This can be best seen, Uppaluri said, in terms of the pathological tumor response after neoadjuvant therapy, which is an indication of an activated immune response.

Currently, only a limited number of patients with HNSCC achieve a partial molecular response or a pathologic complete response to neoadjuvant OI as monotherapy compared to what has been observed in other types of tumors, such as melanoma. Yet, up to 70% of patients with HNSCC show some degree of pathological response.1

New data suggests that even with any degree of pathologic response, there is still a benefit in patients in terms of delaying relapse. In a meta-analysis of neoadjuvant melanoma trials, any pathologic response resulted in a higher recurrence-free survival rate (SSR). In patients with a pathologic complete response (pCR), the rate of RFS was 100% at 2 years; in those with a close pCR, the rate of RFS was 89%, and it was 61% for those with a pathologic partial response (pPR). With particular immunotherapy treatment, the rate of RFS at 2 years was 96% for any patient with pCR, near-pCR or pPR.3

“We see it now in the head and neck [cancer]”said Uppaluri.

In a study (NCT02641093) presented at the 2021 American Society of Clinical Oncology annual meeting on neoadjuvant pembrolizumab (Keytruda) in patients with HPV-negative, resectable and locally advanced HNSCC, 8% of patients had exhibited a partial molecular response and 38% exhibited a pathological response. At 1 year, the disease-free survival rate was 100% in patients with a pathologic response and 73% in non-responders (RR: 0.23; 95% CI: 0.06-0.81; P = .013). The 2-year overall survival rate was 95% in patients who achieved a partial response and 61% in patients who did not respond (P = .00078).4

The study authors concluded that the pathological response could be a promising surrogate for long-term disease control.

Uppaluri suggested that differential gene expression can be found between patients who respond pathologically and those who do not. In a phase 2 trial (NCT02296684) of neoadjuvant and adjuvant pembrolizumab in patients with resectable, locally advanced, HPV-unrelated HNSCC, researchers examined the immunologic correlates of tumor response to neoadjuvant therapy and found increased expression of immune and inflammatory gene signatures in baseline responders. Compared to patients who did not show a pathological response, responders showed increased baseline expression of the IFNG, CXCL9, CXCL10 and C XC L11 genes (P 5

“In patients who have answers … there is a very strong signature of interferon-γ. It is a well-known signature which …[can] predict pathological responses, ”Uppaluri said.

Going forward, although encouraging data has been observed, Uppaluri noted that many unanswered questions need to be answered and that more research is needed in larger randomized trials. Among these remaining questions, Uppaluri asked what the clinical impact will be for patients and how the appropriate patients who will derive the most benefit can be selected to receive neoadjuvant therapy.

The ongoing KEYNOTE-689 Phase 3 trial (NCT03765918) is one that Uppaluri says will help answer some of these questions. The trial examines the use of neoadjuvant and adjuvant pembrolizumab in patients with locally advanced resectable HNSCC. In the study, patients will be randomized 1: 1 to receive pembrolizumab as a neoadjuvant or no treatment, followed by surgery, then pembrolizumab plus radiotherapy with or without added cisplatin (depending on risk category) or radiotherapy with or without cisplatin alone. The trial is expected to enroll around 300 patients.

1. Uppaluri R. Neoadjuvant immunotherapy before surgery for HPV-negative head and neck cancer. Presented at the 10th American Head & Neck Society International Conference on Head and Neck Cancer; July 22-25, 2021; virtual.
2. Topalian SL, Taube JM, Pardoll DM. Blockade of neoadjuvant checkpoints for cancer immunotherapy. Science. 2020; 367 (6477): eaax0182. doi: 10.1126 / science.aax0182
3. Menzies AM, Amaria RN, Rozeman EA, et al. Pathological response and survival with neoadjuvant therapy in melanoma: a pooled review by the International Neoadjuvant Melanoma Consortium (INMC). Nat Med. 2021; 27 (2): 301-309. doi: 10.1038 / s41591-020-01188-3
4. Wise-Draper TM, Takiar V, Mierzwa ML, et al. Association of pathological response to neoadjuvant pembrolizumab with tumor expression of PD-L1 and high disease-free survival (DFS) in patients with resectable, locally-regionally advanced squamous cell carcinoma of the head and neck (HNSCC) . J Clin Oncol. 2021; 39 (suppl 15): 6006. doi: 10.1200 / JCO.2021.39.15_suppl.6006
5. Uppaluri R, Campbell KM, Egloff AM, et al. Neoadjuvant and adjuvant pembrolizumab in locally advanced resectable head and neck cancer unrelated to human papillomavirus: a multicenter phase II trial. Clin Cancer Res. 2020; 26 (19): 5140-5152. doi: 10.1158 / 1078-0432.CCR-20-1695

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