Background: Response rates to PD1 inhibitors are high in unresectable locally advanced or metastatic cSCC. However, the management of cSCC patients with LN-PNI is challenging given that standard measures of disease burden and treatment response are poorly suited to PNI. This study aims to quantify radiological and symptomatic PD1 inhibitor response in cSCC LN-PNI. Methods: Patients with biopsy or radiologically confirmed cSCC LN-PNI treated with PD1 inhibitors between September 2017 and April 2021 were enrolled in this retrospective observational study. Radiological disease control (RDC) was defined as non-progressive radiological changes (including absence of proximal extension of PNI) ± partial or complete resolution on MRI or CT. A detailed symptomatic assessment was performed at every clinic visit. Progression free survival (PFS) was calculated from the time of initiating treatment to radiological disease progression (RDP). Survival was calculated using the Kaplan-Meier method and Cox regression was used to determine the effect of early symptomatic response (≤6 wks) and RDC at first staging scan (≤12 wks) on PFS. Results: Four Australian hospitals enrolled 31 cSCC LN-PNI patients (median age 75 years; M: F = 3:1), of which 29 (93.5%) had trigeminal and 9 (29.0%) had facial nerve involvement. Symptoms were present in 29 (93.5%) patients at baseline, including neuropathic pain in 24 (77.4%) and motor weakness (facial palsy or ophthalmoplegia) in 10 (32%). 16 (51.6%) patients had prior surgery or radiotherapy, but none received prior systemic therapy for LN-PNI. RDC on first restaging (6-12 wks) was observed in 28 (90.3%) patients and symptomatic improvement was seen in 23 (79.3%) amongst the 29 symptomatic at presentation. At a median follow-up of 18.7 months, patients with RDC on first restaging scan had a 24-month PFS of 84.2% versus 25% with RDP (p < 0.001, HR = 0.086, 95% CI = 0.018 to 0.403). Symptomatic response at 6 wks was associated with superior 12-month PFS (94.7% versus 55.6%, p < 0.01, HR = 0.068; 95% CI 0.008 to 0.584). There was high concordance (89.6%) between symptomatic and radiological control (Cohen’s Κ = 0.61, χ² = 8.0023, p-value = 0.0047). Ocular toxicity was seen in 5 patients (16.1%), with corneal ulceration in 2 patients which was higher than expected but otherwise, toxicity profile was consistent with PD-1 inhibitors. Conclusions: These results demonstrate high response rates of PD1 inhibitors in patients with cSCC LN-PNI with acceptable toxicity and durability of response. Early symptomatic improvement within 6 wks and RDC on the first staging scan were significant markers of durable treatment response. PD1 inhibitors are active in patients with LN-PNI and should be considered for the treatment of cSCC with LN-PNI.