Impact of Neoadjuvant Durvalumab with or without Tremelimumab on CD8+ Tumor Lymphocyte Density, Safety, and Efficacy in Patients with Oropharynx Cancer: CIAO Trial Results

Ferrarotto, Renata; Bell, Diana; Rubin, Maria Laura; Hutcheson, Katherine A.; Johnson, Jason M.; Goepfert, Ryan P.; Phan, Jack; Elamin, Yasir Y.; Torman, Danice K.; Warneke, Carla L.; Hessel, Amy C.; Garden, Adam S.; Myers, Jeffrey N.; Johnson, Faye M.; Lee, J. Jack; Sikora, Andrew G.; Gillison, Maura L.; Glisson, Bonnie S.; Gross, Neil D.

doi:10.1158/1078-0432.ccr-19-3977

Cited by 88 publications

(78 citation statements)

References 41 publications

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“…In the CIAO trial, 28 patients received two cycles of neoadjuvant durvalumab either alone or in combination with tremelimumab. 26 Two of 25 patients (8%) developed a pCR. Interestingly, three patients who received subsequent induction chemotherapy all developed pCR of their primary tumor, which favors induction treatments of combined chemoimmunotherapy.…”

Section: Discussionmentioning

confidence: 97%

“…In the CIAO trial, CD8 density also increased, but only by a factor of 1.3 for durvalumab monotherapy and a factor of 1.2 for durvalumab combined with tremelimumab. 26 The reason for this more intense immune activation in the CheckRad-CD8 trial is probably the combination with chemotherapy as especially docetaxel is expected to have immune-modulating properties. 34 A limitation of the CD8 measurement and PD-L1 analyses is that intratumoral heterogeneity cannot be evaluated as only biopsies were analyzed in the CheckRad-CD8 trial.…”

Section: Discussionmentioning

confidence: 99%

“… 14 However, in the CIAO trial using immunotherapy without chemotherapy, no predictive value of intratumoral CD8+ cell density was reported. 26 Tumor-infiltrating immune cells also have a prognostic value in chemoradiotherapy of HNSCC, whereas their role in chemotherapy alone is not clear. 32 33 In the CheckRad-CD8 trial, patients with residual tumor had a median increase of intratumoral CD8+ cell density by a factor of 3.0.…”

Section: Discussionmentioning

confidence: 99%

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Safety and efficacy of single cycle induction treatment with cisplatin/docetaxel/ durvalumab/tremelimumab in locally advanced HNSCC: first results of CheckRad-CD8

Hecht

Gostian

Eckstein

et al. 2020

J Immunother Cancer

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BackgroundTo determine safety and efficacy of single cycle induction treatment with cisplatin/docetaxel and durvalumab/tremelimumab in stage III-IVB head and neck cancer.MethodsPatients received a single cycle of cisplatin 30 mg/m² on days 1–3 and docetaxel 75 mg/m² on day 1 combined with durvalumab 1500 mg fix dose on day 5 and tremelimumab 75 mg fix dose on day 5. Patients with pathologic complete response (pCR) in the rebiopsy after induction treatment or at least 20% increase of intratumoral CD8+ cell density in the rebiopsy compared with baseline entered radioimmunotherapy with concomitant durvalumab/tremelimumab. The objective of this interim analysis was to analyze safety and efficacy of the chemoimmunotherapy-induction treatment before radioimmunotherapy.ResultsA total of 57 patients were enrolled, 56 were treated. Median pretreatment intratumoral CD8+ cell density was 342 cells/mm². After induction treatment, 27 patients (48%) had a pCR in the rebiopsy and further 25 patients (45%) had a relevant increase of intratumoral CD8+ cells (median increase by a factor of 3.0). Adverse event (AE) grade 3–4 appeared in 38 patients (68%) and mainly consisted of leukopenia (43%) and infections (29%). Six patients (11%) developed grade 3–4 immune-related AE. Univariate analysis computed p16 positivity, programmed death ligand 1 immune cell area and intratumoral CD8+ cell density as predictors of pCR. On multivariable analysis, intratumoral CD8+ cell density predicted pCR independently (OR 1.0012 per cell/mm², 95% CI 1.0001 to 1.0022, p=0.016). In peripheral blood CD8+ cells, the coexpression of programmed death protein 1 significantly increased especially in patients with pCR.ConclusionsSingle cycle induction treatment with cisplatin/docetaxel and durvalumab/tremelimumab is feasible and achieves a high biopsy-proven pCR rate.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Safety and efficacy of single cycle induction treatment with cisplatin/docetaxel/ durvalumab/tremelimumab in locally advanced HNSCC: first results of CheckRad-CD8

Hecht

Gostian

Eckstein

et al. 2020

J Immunother Cancer

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“…PD‐1/PD‐L1 inhibitors like atezolizumab and pembrolizumab showed superior efficacy in clinical utilization 12,14–19 . Some studies try to uncover the clinical value of the utilization of PD‐1/PD‐L1 inhibitors in neoadjuvant therapy 20–39 . To evaluate the efficacy and safety of the therapy, this meta‐analysis pooled and analyzed the data of these trials.…”

Section: Introductionmentioning

confidence: 99%

Clinical benefit of neoadjuvant anti‐PD‐1/PD‐L1 utilization among different tumors

Zhao

et al. 2021

MedComm

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PD‐1/PD‐L1 (programmed cell death‐1 and programmed death‐ligand 1) inhibitors utilization in neoadjuvant therapy has been assessed in tumors. This study focused on the clinical benefits of neoadjuvant anti‐PD‐1/PD‐L1 therapy. A comprehensive search was conducted in electronic databases to identify eligible studies. Major response rate (MRR) and complete response rate (CRR) were pooled in this analysis to assess the efficacy of neoadjuvant anti‐PD‐1/PD‐L1 utilization, all grades and high‐grade adverse events (AEs) were pooled to evaluate its safety. Twenty studies were included in this meta‐analysis, with 828 patients suffering from different tumors. The pooled CRR of triple‐negative breast cancer was 0.569 (95% CI 0.514, 0.624, I2 = 0%) and the pooled MRR of lung cancer was 0.471 (95% CI 0.267, 0.575, I2 = 0%). The most frequent adverse event was fatigue (0.272 95% CI 0.171, 0.402, I2 = 87%), and the most common high‐grade adverse event was febrile neutropenia (0.084 95% CI 0.063, 0.112, I2 = 85%). In conclusion, neoadjuvant anti‐PD‐1/PD‐L1 therapy received satisfactory clinical results in these tumors included.

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“…For example, combinations of doxorubicin and anti-PD1 drugs can be delivered by synthetic high-density lipoprotein (sHDL) nanodiscs which can not only reduce the off-target toxicity of chemo-drugs, but also amplify antitumor CD8 + T cell responses [74]. This may be important because as seen in a recent study, there were no significant changes of posttreatment to pretreatment median CD8+TIL density ratio in OPC patients who received durvalumab (PD-L1 inhibitor) ordurvalumab plus tremelimumab (CTLA-4 inhibitor) [75]. Yang et al developed a nanovesicle platform which includes pH-responsive nanovesicles (pRNVs) self-assembled from block copolymer polyethylene glycol-b-cationic polypeptide (PEG-b-cPPT) [76].…”

Section: Combination Therapymentioning

confidence: 99%

Insights into Nanomedicine for Immunotherapeutics in Squamous Cell Carcinoma of the head and neck

Fang

Zhu

et al. 2020

Int. J. Biol. Sci.

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Immunotherapies such as immune checkpoint blockade benefit only a portion of patients with head and neck squamous cell carcinoma. The multidisciplinary field of nanomedicine is emerging as a promising strategy to achieve maximal anti-tumor effect in cancer immunotherapy and to turn non-responders into responders. Various methods have been developed to deliver therapeutic agents that can overcome bio-barriers, improve therapeutic delivery into the tumor and lymphoid tissues and reduce adverse effects in normal tissues. Additional modification strategies also have been employed to improve targeting and boost cytotoxic T cell-based immune responses. Here, we review the state-of-the-art use of nanotechnologies in the laboratory, in advanced preclinical phases as well as those running through clinical trials assessing their advantages and challenges.

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Impact of Neoadjuvant Durvalumab with or without Tremelimumab on CD8+ Tumor Lymphocyte Density, Safety, and Efficacy in Patients with Oropharynx Cancer: CIAO Trial Results

Cited by 88 publications

References 41 publications

Safety and efficacy of single cycle induction treatment with cisplatin/docetaxel/ durvalumab/tremelimumab in locally advanced HNSCC: first results of CheckRad-CD8

Safety and efficacy of single cycle induction treatment with cisplatin/docetaxel/ durvalumab/tremelimumab in locally advanced HNSCC: first results of CheckRad-CD8

Clinical benefit of neoadjuvant anti‐PD‐1/PD‐L1 utilization among different tumors

Insights into Nanomedicine for Immunotherapeutics in Squamous Cell Carcinoma of the head and neck

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