Discordant Responses Between Primary Head and Neck Tumors and Nodal Metastases Treated With Neoadjuvant Nivolumab: Correlation of Radiographic and Pathologic Treatment Effect

Abstract

PD-1 blockade represents a promising treatment in patients with head and neck squamous cell carcinoma (HNSCC). We analyzed results of a neoadjuvant randomized window-of-opportunity trial of nivolumab plus/minus tadalafil to investigate whether immunotherapy-mediated treatment effects vary by site of involvement (primary tumor, lymph nodes) and determine how radiographic tumor shrinkage correlates with pathologic treatment effect.Patients and MethodsForty-four patients enrolled in trial NCT03238365 were treated with nivolumab 240 mg intravenously on days 1 and 15 with or without oral tadalafil, as determined by random assignment, followed by surgery on day 31. Radiographic volumetric response (RVR) was defined as percent change in tumor volume from pretreatment to posttreatment CT scan. Responders were defined as those with a 10% reduction in the volume of the primary tumor or lymph nodes (LN). Pathologic treatment effect (PTE) was defined as the area showing fibrosis or lymphohistiocytic inflammation divided by total tumor area.ResultsSixteen of 32 patients (50%) with pathologic evidence of LN involvement exhibited discordant PTE between primary sites and LN. In four patients with widely discordant adjacent LN, increased PTE was associated with increased infiltration of tumor CD8+ T cells and CD163+ macrophages, whereas stromal regulatory T cells were associated with low nodal PTE. RVR correlated with PTE at both primary tumor (slope = 0.55, p < 0.001) and in LN (slope = 0.62, p < 0.05). 89% (16/18) of radiographic non-responders with T1–T3 primary sites had no (n = 7) or minimal PTE (n = 9), whereas 15/17 (88%) of radiographic responders had moderate (n = 12) or complete (n = 3) PTE.ConclusionNivolumab often induces discordant treatment effects between primary tumor sites and metastatic lymph nodes within subjects. This treatment discordance was also demonstrated in adjacent lymph nodes, which may correlate with local immune cell makeup. Finally, although these data were generated by a relatively small population size, our data support the use of early radiographic response to assess immunotherapy treatment effect in HNSCC.

Multimodal genomic markers predict immunotherapy response in the head and neck squamous cell carcinoma

“…The RNA-seq data of pre-therapeutic tumors from phase-II neoadjuvant trial of nivolumab (PD1inhibitor) was obtained as raw count matrix from Squamous cell carcinoma (SCC) group in Sidney Kimmel Cancer Center, Thomas Jefferson University, PA, USA. Response was characterized as pathologic treatment effect where by each tumor was graded by two pathologists to the degree of treatment effect within the primary tumor [34]. Overall, we had sequencing data from n=13 patients, where, n=5 were responders, and n=8 were non-responders.…”

Preoperative Immunotherapy in the Multidisciplinary Management of Oral Cavity Cancer

“…After treatment, a radiographically detected mass can include both tumor cells and inflammatory cells/debris. Our recent publication correlating imaging with pathologic treatment effect in the context of a 4 week WOT supports the use of volumetric image analysis as it relates to evidence of pathologic response (62). The difficulty related to assessing tumor response has led to the advent of metabolic imaging studies (72).…”

“…The difference in tumor molecular landscape between patients provides the rationale behind the differences in treatment response. Recently, response to immunotherapy has been found to be discordant between primary tumor and lymph node metastasis in certain patients, illustrating the complexity of the immune landscape in OCSCC (62). A study by Merlino et al compared treatment effect and radiographic volumetric response between primary tumor and lymph node metastasis within the same patient after receiving preoperative nivolumab prior to definitive surgery (62).…”

“…Clinical trials have shown that the range of pathologic response to immunotherapy is wide and correlates with recurrence rates between patients ( 61 ). Interestingly, studies have shown that even within the same patient, immunotherapy can have a different effect on the primary tumor bed and regional metastasis, highlighting the complexity of the tumor immune landscape and its implication on treatment response and prognosis ( 60 , 62 ).…”

Identification of Immune-Related LncRNA Pairs for Predicting Prognosis and Immunotherapeutic Response in Head and Neck Squamous Cell Carcinoma

“…The reversal of immune rejection mediated by tadalafil and antitumor vaccines also resulted in the up-regulation of PD-L1 in recurrent HNSCC, indicating that immune checkpoint therapy may be equally effective in patients with recurrent HNSCC ( 8 ). Relevant research on HNSCC patients is also in full swing, which is expected to improve the survival of HNSCC patients ( 9 , 10 ). Although these findings support the importance of HNSCC immunology, its molecular mechanism is still unclear, especially for immune-related gnomic effects.…”