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

ABSTRACT: 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.

SUBMITTER: Vos JL

PROVIDER: S-EPMC8695578 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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

Vos Joris L JL Elbers Joris B W JBW Krijgsman Oscar O Traets Joleen J H JJH Qiao Xiaohang X van der Leun Anne M AM Lubeck Yoni Y Seignette Iris M IM Smit Laura A LA Willems Stefan M SM van den Brekel Michiel W M MWM Dirven Richard R Baris Karakullukcu M M Karssemakers Luc L Klop W Martin C WMC Lohuis Peter J F M PJFM Schreuder Willem H WH Smeele Ludi E LE van der Velden Lilly-Ann LA Bing Tan I I Onderwater Suzanne S Jasperse Bas B Vogel Wouter V WV Al-Mamgani Abrahim A Keijser Astrid A van der Noort Vincent V Broeks Annegien A Hooijberg Erik E Peeper Daniel S DS Schumacher Ton N TN Blank Christian U CU de Boer Jan Paul JP Haanen John B A G JBAG Zuur Charlotte L CL

Nature communications 20211222 1

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 ...[more]

PMID: 34937871

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Project description:BackgroundPatients with colorectal carcinoma and high-grade microsatellite instability (MSI-H) or deficiency in mismatch repair (dMMR) exceptionally respond to immune checkpoint inhibitors (ICIs). ICIs are more active in treatment-naïve patients than in patients with refractory MSI-H/dMMR metastatic colorectal cancer and even more active in patients with locally advanced tumors.Material and methodsA 33-year-old male patient with Lynch syndrome was diagnosed with a locally advanced rectal cancer and refused standard neoadjuvant chemoradiation because of the potential harm of sexual dysfunction. MMR and microsatellite instability status were analyzed by immunohistochemistry and fragment length polymerase chain reaction followed by capillary electrophoresis.ResultsAfter MSI-H/dMMR was confirmed, the patient was treated with ICIs (1 mg/kg ipilimumab at day 1 and 3 mg/kg nivolumab at day 1 and 15). A complete clinical response was documented at day 21 after start of treatment. The patient underwent a total mesorectal excision at day 30. In the extirpated tissue, a complete pathological response was confirmed.ConclusionIn MSI-H/dMMR locally advanced rectal cancer short-course ICI treatment is highly effective and may be discussed in patients with dMMR locally advanced rectal cancer.Key pointsImmune checkpoint inhibitors are more active in treatment-naïve patients than in patients with refractory high-grade microsatellite instability (MSI-H)/deficiency in mismatch repair (dMMR) colorectal cancer. Standard neoadjuvant chemoradiation is less effective in MSI-H/dMMR rectal cancer patients than in patients with proficient mismatch repair. A young patient with Lynch syndrome and MSI-H/dMMR locally advanced rectal cancer refused chemoradiation in order to preserve his fertility. After neoadjuvant treatment with one dose of ipilimumab and two doses of nivolumab a complete clinical and pathological response was documented. Clinical trials are needed to first establish neoadjuvant treatment with immune checkpoint inhibitors in patients with locally advanced MSI-H/dMMR rectal cancer and thereafter to evaluate organ-preservation strategies.

Project description:In the CheckMate 651 study, nivolumab plus ipilimumab versus EXTREME (cisplatin/carboplatin + cetuximab + fluorouracil) regimen was compared for effectiveness. It is not known whether these immunotherapy agents are cost-effective for recurrent or metastatic squamous cell carcinomas of the head and neck (R/M SCCHN). The purpose of this study was to compare the cost-effectiveness of nivolumab plus ipilimumab with EXTREME in the first-line setting from the standpoint of third-party payers in the United States. The projecting of costs and outcomes over 15 years was done using a three-state partitioned survival model discounted by 3% per year. Long-term extrapolation of CheckMate 651 was used to model progression-free survival and overall survival (OS). The incremental net health benefit (INHB), incremental net monetary benefit (INMB), quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER) were calculated. The uncertainty and stability of the model were accounted for via one-way and probabilistic sensitivity analyses. As compared with nivolumab plus ipilimumab, EXTREME was associated with an increase of 0.154 life-years and 0.076 QALYs, as well as a cost increase of $572 per patient. The corresponding ICERs were $7545/QALY along with the values of INMB and INHB were $113,267 and 0.076 QALYs, respectively, at a willingness to pay (WTP) threshold of $150,000/QALY. The probability of nivolumab plus ipilimumab being cost-effective was > 99% in patients with combined positive score (CPS) ≥ 1, CPS 1-19, or CPS ≥ 20. Moreover, hazard ratio for OS and body weight were the most sensitive parameters for the model. According to sensitivity analyses, these results were generally robust. In overall populations with R/M SCCHN, the EXTREME regimen is cost-effective compared with nivolumab plus ipilimumab. Given a WTP threshold of $150,000 per QALY, the probability of the EXTREME regiment being cost-effective compared with nivolumab and ipilimumab, was 64%. Importantly, there was heterogeneity in the cost-effectiveness probabilities, based on primary sites and expression levels of PD-L1. Therefore, tailored treatment based on individual patient and clinical characteristics, remains important, and may impact the cost-effectiveness of the regimens under study.

Project description:BackgroundPatients with recurrent or metastatic squamous-cell carcinoma of the head and neck after platinum chemotherapy have a very poor prognosis and limited therapeutic options. Nivolumab, an anti-programmed death 1 (PD-1) monoclonal antibody, was assessed as treatment for this condition.MethodsIn this randomized, open-label, phase 3 trial, we assigned, in a 2:1 ratio, 361 patients with recurrent squamous-cell carcinoma of the head and neck whose disease had progressed within 6 months after platinum-based chemotherapy to receive nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks or standard, single-agent systemic therapy (methotrexate, docetaxel, or cetuximab). The primary end point was overall survival. Additional end points included progression-free survival, rate of objective response, safety, and patient-reported quality of life.ResultsThe median overall survival was 7.5 months (95% confidence interval [CI], 5.5 to 9.1) in the nivolumab group versus 5.1 months (95% CI, 4.0 to 6.0) in the group that received standard therapy. Overall survival was significantly longer with nivolumab than with standard therapy (hazard ratio for death, 0.70; 97.73% CI, 0.51 to 0.96; P=0.01), and the estimates of the 1-year survival rate were approximately 19 percentage points higher with nivolumab than with standard therapy (36.0% vs. 16.6%). The median progression-free survival was 2.0 months (95% CI, 1.9 to 2.1) with nivolumab versus 2.3 months (95% CI, 1.9 to 3.1) with standard therapy (hazard ratio for disease progression or death, 0.89; 95% CI, 0.70 to 1.13; P=0.32). The rate of progression-free survival at 6 months was 19.7% with nivolumab versus 9.9% with standard therapy. The response rate was 13.3% in the nivolumab group versus 5.8% in the standard-therapy group. Treatment-related adverse events of grade 3 or 4 occurred in 13.1% of the patients in the nivolumab group versus 35.1% of those in the standard-therapy group. Physical, role, and social functioning was stable in the nivolumab group, whereas it was meaningfully worse in the standard-therapy group.ConclusionsAmong patients with platinum-refractory, recurrent squamous-cell carcinoma of the head and neck, treatment with nivolumab resulted in longer overall survival than treatment with standard, single-agent therapy. (Funded by Bristol-Myers Squibb; CheckMate 141 ClinicalTrials.gov number, NCT02105636 .).

Project description:ImportanceNovel approaches are needed to improve outcomes in patients with squamous cell carcinoma of the oral cavity. Neoadjuvant immunotherapy given prior to surgery and combining programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) immune checkpoint inhibitors are 2 strategies to enhance antitumor immune responses that could be of benefit.Design, setting, and participantsIn this randomized phase 2 clinical trial conducted at 1 academic center, 29 patients with untreated squamous cell carcinoma of the oral cavity (≥T2, or clinically node positive) were enrolled between 2016 to 2019.InterventionsTreatment was administered with nivolumab, 3 mg/kg, weeks 1 and 3, or nivolumab and ipilimumab (ipilimumab, 1 mg/kg, given week 1 only). Patients had surgery 3 to 7 days following cycle 2.Main outcomes and measuresSafety and volumetric response determined using bidirectional measurements. Secondary end points included pathologic and objective response, progression-free survival (PFS), and overall survival. Multiplex immunofluorescence was used to evaluate primary tumor immune markers.ResultsFourteen patients were randomized to nivolumab (N) and 15 patients to nivolumab/ipilimumab (N+I) (mean [SD] age, 62 [12] years; 18 men [62%] and 11 women [38%]). The most common subsite was oral tongue (n = 16). Baseline clinical staging included patients with T2 (n = 20) or greater (n = 9) T stage and 17 patients (59%) with node-positive disease. Median time from cycle 1 to surgery was 19 days (range, 7-21 days); there were no surgical delays. There were toxic effects at least possibly related to study treatment in 21 patients, including grade 3 to 4 events in 2 (N), and 5 (N+I) patients. One patient died of conditions thought unrelated to study treatment (postoperative flap failure, stroke). There was evidence of response in both the N and N+I arms (volumetric response 50%, 53%; pathologic downstaging 53%, 69%; RECIST response 13%, 38%; and pathologic response 54%, 73%, respectively). Four patients had major/complete pathologic response greater than 90% (N, n = 1; N+I, n = 3). With 14.2 months median follow-up, 1-year progression-free survival was 85% and overall survival was 89%.Conclusions and relevanceTreatment with N and N+I was feasible prior to surgical resection. We observed promising rates of response in both arms, supporting further neoadjuvant studies with these agents.Trial registrationClinicalTrials.gov Identifier: NCT02919683.

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

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

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