Neoadjuvant immunotherapy with nivolumab and ipilimumab induces major pathological responses in patients with head and neck squamous cell carcinoma

Surgery for locoregionally advanced head and neck squamous cell carcinoma (HNSCC) results in 30‒50% five-year overall survival. In IMCISION (NCT03003637), a non-randomized phase Ib/IIa trial, 32 HNSCC patients are treated with 2 doses (in weeks 1 and 3) of immune checkpoint blockade (ICB) using nivolumab (NIVO MONO, n = 6, phase Ib arm A) or nivolumab plus a single dose of ipilimumab (COMBO, n = 26, 6 in phase Ib arm B, and 20 in phase IIa) prior to surgery. Primary endpoints are feasibility to resect no later than week 6 (phase Ib) and primary tumor pathological response (phase IIa). Surgery is not delayed or suspended for any patient in phase Ib, meeting the primary endpoint. Grade 3‒4 immune-related adverse events are seen in 2 of 6 (33%) NIVO MONO and 10 of 26 (38%) total COMBO patients. Pathological response, defined as the %-change in primary tumor viable tumor cell percentage from baseline biopsy to on-treatment resection, is evaluable in 17/20 phase IIa patients and 29/32 total trial patients (6/6 NIVO MONO, 23/26 COMBO). We observe a major pathological response (MPR, 90‒100% response) in 35% of patients after COMBO ICB, both in phase IIa (6/17) and in the whole trial (8/23), meeting the phase IIa primary endpoint threshold of 10%. NIVO MONO’s MPR rate is 17% (1/6). None of the MPR patients develop recurrent HSNCC during 24.0 months median postsurgical follow-up. FDG-PET-based total lesion glycolysis identifies MPR patients prior to surgery. A baseline AID/APOBEC-associated mutational profile and an on-treatment decrease in hypoxia RNA signature are observed in MPR patients. Our data indicate that neoadjuvant COMBO ICB is feasible and encouragingly efficacious in HNSCC

Defining oligometastatic non-small cell lung cancer: Concept versus biology, a literature review

Objective: In this review, the concept of (synchronous) oligometastatic disease in patients with non-oncogene-driven non-small cell lung cancer (NSCLC) will be placed in the context of tumor biology and metastatic growth patterns. We will also provide considerations for clinical practice and future perspectives, which will ultimately lead to better patient selection and oligometastatic disease outcome. Background: The treatment landscape of metastasized NSCLC has moved from “one-size fits all” to a personalized approach. Prognosis has traditionally been poor but new treatment options, such as immunotherapy and targeted therapy, brighten future perspectives. Another emerging development is the recognition of patients with so-called “oligometastatic” state of disease. Oligometastatic disease has been recognized as a distinct clinical presentation in which the tumor is stated to be early in its evolution of metastatic potential. It is suggested that this stage of disease has an indolent course, comes with a better prognosis and therefore could be considered for radical multimodality treatment. Methods: Narrative overview of the literature synthesizing the findings of literature retrieved from searches of computerized databases, hand searches, and authoritative texts. Conclusions: Oligometastatic NSCLC is a broad spectrum disease, with a variable prognosis. Although the biology and behavior of “intermediate state” of metastatic disease are not fully understood, there is evidence that a subgroup of patients can benefit from local radical treatment when integrated into a multimodality regime. The consensus definition of oligometastatic NSCLC, including accurate staging, may help to uniform future trials. The preferable treatment strategy seems to sequential systemic treatment with subsequent local radical treatment in patients with a partial response or stable disease. Prognostic factors such as N-stage, number and site of distant metastases, tumor volume, performance status, age, and tumor type should be considered. The local radical treatment strategy has to be discussed in a multidisciplinary team meeting, taking into account patient characteristics and invasiveness of the procedure. However, many aspects remain to be explored and learned about the cancer biology and characteristics of intermediate state tumors

HYpofractionated, dose-redistributed RAdiotherapy with protons and photons to combat radiation-induced immunosuppression in head and neck squamous cell carcinoma: study protocol of the phase I HYDRA trial

Background: Radiotherapy (RT) is the standard of care for most advanced head and neck squamous cell carcinoma (HNSCC) and results in an unfavorable 5-year overall survival of 40%. Despite strong biological rationale, combining RT with immune checkpoint inhibitors does not result in a survival benefit. Our hypothesis is that the combination of these individually effective treatments fails because of radiation-induced immunosuppression and lymphodepletion. By integrating modern radiobiology and innovative radiotherapy concepts, the patient’s immune system could be maximally retained by (1) increasing the dose per fraction so that the total dose and number of fractions can be reduced (HYpofractionation), (2) redistributing the radiation dose towards a higher peak dose within the tumor center and a lowered elective lymphatic field dose (Dose-redistribution), and (3) using RAdiotherapy with protons instead of photons (HYDRA). Methods: The primary aim of this multicenter study is to determine the safety of HYDRA proton- and photon radiotherapy by conducting two parallel phase I trials. Both HYDRA arms are randomized with the standard of care for longitudinal immune profiling. There will be a specific focus on actionable immune targets and their temporal patterns that can be tested in future hypofractionated immunoradiotherapy trials. The HYDRA dose prescriptions (in 20 fractions) are 40 Gy elective dose and 55 Gy simultaneous integrated boost on the clinical target volume with a 59 Gy focal boost on the tumor center. A total of 100 patients (25 per treatment group) will be recruited, and the final analysis will be performed one year after the last patient has been included. Discussion: In the context of HNSCC, hypofractionation has historically only been reserved for small tumors out of fear for late normal tissue toxicity. To date, hypofractionated radiotherapy may also be safe for larger tumors, as both the radiation dose and volume can be reduced by the combination of advanced imaging for better target definition, novel accelerated repopulation models and high-precision radiation treatment planning and dose delivery. HYDRA’s expected immune-sparing effect may lead to improved outcomes by allowing for future effective combination treatment with immunotherapy. Trial registration: The trial is registered at ClinicalTrials.gov; NCT05364411 (registered on May 6th, 2022)