Treatment Setting | ||||
---|---|---|---|---|
Trial | Description | Objective | Results | |
A. Recurrent/Metastatic | ||||
IO-Chemotherapy | Active8 (NCT01836029) | Phase 2. EXTREME + motolimod vs. EXTREME + placebo. | Combination of CT/cetuximab with an innate immune stimulator via toll-like receptor antagonism. | Adding motolimod to the EXTREME regimen did not improve PFS or OS in the intent-to-treat population [125]. |
KEYNOTE-048 (NCT02358031) | Phase 3. Pembrolizumab monotherapy vs. pembrolizumab + platinum-based CT (cisplatin or carboplatin) + 5-Fluorouracil (5-FU) vs. cetuximab + platinum-based CT (cisplatin or carboplatin) + 5-FU. | Pembrolizumab as first-line treatment of R/M HNSCC. | Pembrolizumab alone improved OS over SOC in the PD-L1 CPS ≥20 (p = 0.0007) and ≥ 1 (p = 0.0086) populations. Pembrolizumab + CT significantly improved OS in the total population (p = 0.0034) [126]. | |
IO-EGFR inhibitors | IPH2201–203 NCT02643550 | Phase 2. Monalizumab + cetuximab in patients with R/M HNSCC who progressed after platinum-based chemotherapy. | Dual targeting by reducing inhibitory signaling and unleashing NK and T Cell responses with monalizumab and enhancing cetuximab mediated ADCC. | Median PFS and OS: 5.0 and 10.3 months, respectively. ORR: 27.5%. Responses were observed in IO naïve (35%) and IO pretreated patients (18%). Median DOR: 5.6 months [127]. |
Dual Checkpoint Blockade | CheckMate-651 (NCT02741570) | Phase 3. Nivolumab + ipilimumab vs. SOC (Extreme Study Regimen) as first-line treatment in patients With R/M HNSCC. | Combination nivolumab + ipilimumab has shown significant promise in patients with NSCLC, advanced melanoma and advanced RCC [128]. | Results ongoing. Primary outcome measures include OS and PFS in patients with PD-L1 expressing tumors. |
CONDOR (NCT02207530) | Phase 2. Durvalumab + tremelimumab vs. durvalumab monotherapy vs. tremelimumab monotherapy in pts. with R/M HNSCC refractory to platinum-based therapy. | The PD-L1 and CTLA-4 pathways are non-redundant and preclinical data indicate targeting both may induce synergistic antitumor effects. | In combination, durvalumab monotherapy and tremelimumab monotherapy cohorts, median OS: 7.6, 6.0 and 5.5 months; median PFS: 2.0, 1.9, 1.9; and ORR*IRC: 7.8, 9.2 and 1.6% [129]. | |
KESTREL (NCT02551159) | Phase 3. Durvalumab + tremelimumab vs durvalumab monotherapy vs. SOC CT in treatment naïve R/M HNSCC patients. | First-line treatment for R/M HNSCC targeting both PD-L1 and CTLA-4 pathways has potential for synergistic antitumor effects. | Results ongoing [130]. | |
EAGLE (NCT02369874) | Phase 3. Durvalumab monotherapy vs. durvalumab + tremelimumab vs. SOC in R/M. Eligible patients are immunotherapy naïve but have progressed on a platinum-containing regimen or within 6 months of multimodality platinum therapy. | Second-line treatment for R/M HNSCC targeting both PD-1 and CTLA-4 pathways may induce synergistic antitumor effects. | Failed to meet primary endpoint of improved overall survival [131]. | |
IO-IO: Checkpoint + innate immune activation | MASTERKEY-232 (NCT02626000) | Phase 1b/3. Combination pembrolizumab + talimogene laherparepvec (T-VEC) as second-line therapy in R/M HNSCC patients. | T-VEC is the first FDA-approved oncolytic immunotherapy which works to systemically enhance the antitumor immune response [132] [133]. | Twenty-four (66.7%) patients experienced a grade 3 or higher TRAE, with 5 related to T-VEC and 3 related to Pembrolizumab. ORR*IR in 6 patients: 16.7%; 5 PD-L1-positive. Objective response/SD in 14 patients: 38.9%; 11 PD-L1-positive. 24/36 (66.7%) pts. had grade 3 or higher treatment-emergent adverse events [133]. |
KEYNOTE-184 (NCT02521870) | Phase 1b/2. Intratumoral Injections of SD-101 in Combination With Pembrolizumab in treatment-naïve R/M HNSCC patients. | SD-101 is a synthetic CpG-ODN agonist of TLR 9 that stimulates dendritic cells to release IFN-alpha and mature into antigen presenting cells to activate T cell anti-tumor responses. | Of the 10 evaluable patients, ORR*IR by radiographic images was 33%, compared to 15% by pembrolizumab therapy alone [134]. | |
(NCT01714739) | Phase 1/2. Lirilumab + Nivolumab in HNSCC. | Utilization of Lirilumab, a mAb that blocks inhibitory killer Ig-like receptors (KIRs) on NK cells, in patients with relapsed, advanced HNSCC. | ORR of 24% in combination compared to 13% by nivolumab alone, with 17% reductions in tumor burden ≥80%. However, Innate closed the trial due to a lack of efficacy on November 22, 2017 (press release). | |
STING (NCT02675439) | Phase 1. STING agonist MIW815 (ADU-S100) + ipilimumab vs. pembrolizumab in advanced solid tumors | The STING (stimulator of interferon genes) pathway is a critical component of the antitumor response. ADU-S100 is a cyclic dinucleotide that activates all known human STING alleles. | Despite data demonstrating stimulation of the immune system by STING, the role of the STING pathway in anti-tumor immunity is still unclear [135, 136]. | |
IO-IO: checkpoint + vaccine | (NCT02426892) | Phase 2. Nivolumab + ISA101 in patients with incurable oropharyngeal cancer. | To determine if nivolumab efficacy is amplified through treatment with ISA 101, a synthetic long-peptide HPV-16 vaccine inducing HPV-specific T cells, in patients with incurable HPV-16-positive cancer. | Median PFS: 2.7 months (95% CI, 2.5–9.4 months) and median OS: 17.5 months (95% CI, 17.5 months to inestimable). Response was positively correlated with tumor cell PD-L1 positivity (≥1%) [137]. 36% ORR in patients with oropharyngeal cancer compared to 16% by nivolumab alone [43]. |
(NCT03162224) | Phase 1b/2a. Safety and efficacy of MEDI0457 + durvalumab in patients with HPV+ R/M HNSCC. | Eligible patients include those with confirmed HPV+ HNSCC refractory to platinum-based CT. | Currently recruiting. [138]. | |
Adoptive T cell therapies | C-145-03 (NCT03083873) | Phase 2. Adoptive cell therapy with autologous TIL infusion (LN-145) followed by IL-2 after a non-myeloablative lymphodepletion R/M HNSCC patients. | Despite HNSCC tumor heterogeneity, many tumors are either virally-associated or carry high mutation loads that increase the potential antigens targeted by TIL ACT [139]. | Results ongoing. Preliminary safety and efficacy were reported. 3/8 patients treated with LN-145 achieved a PR as per RECIST 1.1 (press release). |
(NCT01818323) | Phase 1. Dose-escalation trial of T4-immunotherapy in patients with HNSCC without lymphodepletion [140]. | T4 immunotherapy includes patient T cells engineered to express a panErbB-targeted CAR, co-expressed with a chimeric cytokine receptor that allows interleukin-4-mediated CAR T cell proliferation [141]. | SD was observed in patients with ≥10 × 107 T4+ T-cells at 6-weeks post-intra-tumoral injection. An overall disease control rate of 69% was reported (RECIST 1.1) [140]. | |
(NCT02379520) | Treatment of metastatic HPV16+ epithelial cancers by a single intravenous infusion of engineered E6-targeting T cells [142]. | HPV-specific T-cells (HPVST) are derived from patients with HPV-related cancers to evaluate if these cells can survive in the blood and subsequently eliminate the HPV-associated tumor [143]. | 2/9 patients receiving the highest dose experienced tumor responses; one patient with a 6-month PR experienced complete regression of one lesion and partial regression of two lesions and no evidence of disease three years later [142]. | |
(NCT02858310) | Phase 1/2. Trial of T Cell Receptor gene therapy targeting HPV-16 E7 with or without PD-1 blockade for HPV+ cancers [144]. | To determine a safe dose and efficacy of E7 TCR cells and whether these cells will have efficacy in treating HPV+ patients. | Currently recruiting. T cells were successfully engineered to target HPV-16 E7 and were able to mediate regression of HPV-16+ human cancers in an animal model [145]. | |
IO-targeted therapy | (NCT02501096) | Phase 1b/2. Lenvatinib + pembrolizumab combination therapy. | First systemic combination of a TKI and immunotherapy for patients with HNSCC. | ORR*IR at 24 weeks: 36.4% (95% CI: 17.2–59.3). Grade 3/4 AEs occurred in 91% of patients, with 4 patients (18%) having to discontinue study treatment due to AEs [146]. |
Bispecific antibodies, fusion proteins | (NCT02517398) | Phase 1. M7824 given once every 2 weeks at different dose levels in metastatic or locally advanced solid tumors. | Genome wide association studies point to transforming growth factor-β (TGF-β) which is overexpressed in HPV+ cancers [147]. | ORR*IRC of 45.5% in patients with known HPV+ disease and an overall disease reduction in 56% (9/16) of patients [147]. |
IO-IO: checkpoint + microenvironment/ immunometabolism | (NCT02499328) | Phase 1b/2. Durvalumab + AZD9150 (STATi) or AZD5069 (CX2i) in HNSCC patients. | Metabolic competition exists between tumor and immune cells and there is evolving evidence that combining therapies that directly dampen tumor metabolism with immunotherapy could be a promising therapeutic strategy. | A 25% ORR (5PR) was observed in patients with anti-PD-L1 treatment naïve R/M HNSCC patients, with responses observed in PD-L1+/− patients as well as HPV- patients [148]. |
Photoimmunotherapy | (NCT02422979) | Phase 2a. Non-thermal red light was applied to tumors 24 h after intravenous infusion of RM1929. Light was applied by surface illumination for superficial disease or interstitial illumination via intratumoral placement of fiber optic diffusers for deep tumors. | Photoimmunotherapy is an emerging therapeutic strategy that combines photodynamic therapy with immunotherapy, i.e. RM-1929, a novel light-activated drug [149]. | Median PFS for 28 evaluable patients was 173 days (5.7 months). Median OS for entire 30 patient cohort was 278 days (9.1 months). ORR*IRC of 28% (8/28), CR of 14% (4/28) [149]. Therapeutic response was calculated using CT RECIST 1.1. |
IO-radiotherapy (SBRT) | (NCT02684253) | Phase 2. Nivolumab + SBRT vs. nivolumab monotherapy in metastatic HNSCC patients, including nasopharynx [150]. | Radiation may act as an in situ vaccine, which propagates via epitope spreading to enhance anti-tumor immunity beyond the radiated lesion and enhance immune control of distant disease (abscopal effect) [150]. | OS at 1 year for Nivolumab monotherapy versus nivolumab + SBRT: 64% (95% CI: 47, 88%) compared to 53% (95% CI: 36, 79%) (p = 0.79), respectively. ORR*IR for nivolumab monotherapy: 26.9% (95% CI: 13.7, 46.1%), while nivolumab plus SBRT: 22.2% (95% CI: 10.6, 40.8%) [150]. |
B. Adjuvant | ||||
PATHWay Study (NCT02841748) | Phase 2. Pembrolizumab vs. placebo in advanced HNSCC. | To test pembrolizumab in pts. with head and neck cancers at high risk for recurrence or low-volume residual disease [151]. | Currently recruiting. Eligible patients must have HNSCC, completed therapy with definitive intent, and have an estimated risk of recurrence ≥40–50% [151]. | |
NRG HN-003 (NCT02775812) | Phase 1. Adjuvant pembrolizumab + cisplatin and IMRT in patients with high-risk, HPV-, stage III-IV HNSCC. | Giving pembrolizumab with cisplatin and IMRT to boost immune response. | Active. Primary outcome is to determine the recommended phase II dose for the combination of pembrolizumab and cisplatin-radiotherapy in patients with high-risk, HPV- HNSCC, based upon dose-limiting toxicity. | |
ECOG ACRIN EA3161 | Phase 2/3. Definitive chemoradiation followed by nivolumab or observation for intermediate risk patients with locally advanced, HPV+ SCC of the oropharynx. | Importance of focusing specifically on HPV-related locally advanced OPSCC as a unique disease entity. | Will determine whether a maintenance approach with a single agent ICI following definitive therapy would alter PF or OS for high-risk HPV+ disease. | |
WO40242 (NCT03452137) | Phase 3. Atezolizumab vs. placebo for high risk stage IV HPV- or stage III HPV+ HNSCC after definitive local therapy. | To evaluate efficacy and safety of atezolizumab as adjuvant therapy. | Currently recruiting. Primary outcomes will include Independent Review Facility assessed Event Free Survival (IRF assessed EFS) and OS. | |
C. Definitive | ||||
RTOG-3504 (NCT02764593) | Phase 2. Adding nivolumab to standard cetuximab-RT for patients with newly diagnosed intermediate/high-risk loco-regionally advanced HNSCC [152]. | Immunotherapy is added to enhance other conventional therapies such as surgery, CT and RT. | Nivo is safe and reasonable to administer in combination with a cetuximab-RT regimen for patients with newly diagnosed IR/HR HNSCC [152]. | |
GORTEC 2015–01 (NCT02707588) | Phase 2. Pembrolizumab or cetuximab + RT in LA HNSCC patients. | To determine synergistic effects when combining ICI with RT compared to SOC cetuximab plus RT. | Decrease in serious AEs in pembrolizumab arm (78% pts) vs. cetuximab arm (94% pts) [153]. | |
GORTEC 2017–01 (REACH) (NCT02999087) | Phase 3. Avelumab + cetuximab and RT vs. SOC in LA HNSCC. | Expansion of GORTEC 2015–01. Based on the hypothesis of a synergistic effect upon combination of avelumab with cetuximab + RT. | This trial achieved an acceptable safety profile and was granted approval to continue by the Data and Safety Monitoring Committee [154]. | |
(NCT02609503) | Phase 2. Pembrolizumab with concurrent RT in cisplatin-ineligible LA HNSCC patients. | Immunotherapy is added to intensity-modulated RT (IMRT) for synergistic effects. | All patients completed 70Gy radiation and demonstrated low levels of toxicity [155]. | |
NRG HN-004 (NCT03258554) | Phase 2/3. Standard IMRT + durvalumab vs. cetuximab in cisplatin-ineligible patients with stage III-IV HNSCC. | Immunotherapy compared to targeted therapy in addition to RT to compare synergistic effects. | Recruitment currently suspended. | |
(NCT02586207) | Phase 1. Pembrolizumab plus weekly cisplatin-based chemoradiation (CRT). | Immunotherapy is added to CRT for synergistic effects. | 78% of enrolled pts. completed all planned pembrolizumab doses. All pts. completed the full 70 Gy radiation dose and 85% received the target dose of cisplatin (≥200 mg/m2) [156]. | |
(NCT02777385) | Phase 2. Pembrolizumab + cisplatin and IMRT was compared by sequencing of PD-1 blockade during and after CRT. | Immunotherapy is added to CT and RT at different sequences to determine synergistic effects. | Currently recruiting. | |
JAVELIN (NCT02952586) | Phase 3. Avelumab + SOC CRT vs. SOC CRT in LA HNSCC patients. | Combining avelumab + CRT may synergistically activate multiple immune-mediated mechanisms and improve long-term disease control [157]. | Currently recruiting. | |
KEYNOTE-412 (NCT03040999) | Phase 3. Pembrolizumab or placebo + CRT in LA HNSCC patients. | CRT has immunomodulatory effects; preclinical data suggest efficacy can be improved by adding pembrolizumab [158]. | Currently recruiting. Adult pts. with newly diagnosed, pathologically proven, treatment-naive LA-HNSCC will be enrolled [158]. | |
(NCT03349710) | Phase 3. Nivolumab monotherapy vs. nivolumab + cisplatin, in combination with RT in cisplatin-ineligible or eligible will be assessed in LA HNSCC patients. | To determine whether nivolumab in combination with RT is more effective than cetuximab in combination with RT. | Active, not recruiting. Largest trial of its kind with a planned participant count of 1046. | |
KEYCHAIN (NCT03383094) | Phase 2. Pembrolizumab + RT vs. Bolus cisplatin + RT for intermediate risk P16-positive HNSCC. | To compare PFS for head-to-head comparison of immunotherapy vs. chemotherapy for intermediate risk previously untreated HNSCC. | Currently recruiting. | |
D. Neoadjuvant | ||||
Checkmate-358 (NCT02488759) | Phase 1/2. Neoadjuvant nivolumab in patients with resectable HPV+ or HPV− HNSCC and EBV-associated NPC. | Treatment options for patients with R/M NPC are limited to palliative chemotherapy. | As of database lock, pre-surgery tumor reduction per CT scan was observed in 11 of 23 (48%) evaluable pts. (5/10 HPV+ and 6/13 HPV−); 3 pts. had tumor reduction ≥40% (largest reduction, 75%) [159]. | |
(NCT02296684) | Phase 2. Neoadjuvant pembrolizumab prior to surgical resection in HPV- LA HNSCC. | A “preoperative window,” study underway in HNSCC. | Preliminary analyses revealed no serious TRAEs resulting in surgical delays or complications. Data supported an anti-tumor effect following a single dose of pembrolizumab [160]. | |
(NCT02641093) | Phase 2. Pembrolizumab in combination with SOC surgery followed by RT +/− cisplatin. | To test the ability of pembrolizumab to improve locoregional recurrence and distant metastatic rates in high-risk patients with LA HNSCC treated with current SOC surgical approaches. | 47% of patients demonstrated a pathological response – high immune cell infiltration and amplified PD-L1 (> 10% tumor effect) and 32% achieved a major response (> 70% tumor effect). 1 patient had CR [161]. | |
(NCT02274155) | Phase 1. Anti-OX40 antibody, MEDI6469, given prior to surgery in patients with advanced HNSCC. | Immunotherapy given prior to surgery to enhance immune response. | This pre-surgery therapy proved both safe and effective, inducing activation and proliferation of T cells as well as expansion of tumor reactive T cells within the tumor after infusion [162]. | |
LCC 1621 (NCT03174275) | Phase 2. Induction CT with carboplatin, nab-paclitaxel, and durvalumab prior to surgery in previously untreated stage III-IV HNSCC. | To test combination CT + immunotherapy to increase response to therapy and decrease side effects associated with RT. | Recruiting. Primary outcome measure will determine the pathologic complete response rate (pCRR) after induction CT. | |
OPTIMA-II (NCT03107182) | Phase 2. Combination carboplatin, nab-paclitaxel, and nivolumab followed by TransOral Robotic Surgery or RT/CRT after induction CT in HPV+ OSCC patients. | To determine radiologic response to induction CT with nivolumab. | Results ongoing. Primary outcome measure will evaluate tumor shrinkage (%) to measure the deep response rate (DRR). DRR is defined as ≥50% tumor shrinkage by RECIST 1.1. | |
KEO (NCT03325465) | Phase 2. Neoadjuvant pembrolizumab + epacadostat prior to surgery in HNSCC patients. | To define the rate of major treatment effect to neoadjuvant pembrolizumab plus epacadostat immunotherapy in HNSCC compared to data from neoadjuvant pembrolizumab treatment alone. | Not yet recruiting. Primary outcome will measure the rate of major treatment effect (50% resolution of tumor with active immune response). | |
NIRT (NCT03247712) | Phase 1/2. Nivolumab administration + RT prior to restaging and surgical resection, followed by nivolumab. | Integrating nivolumab and hypofractionated RT to down-stage prior to definitive surgery in HNSCC. | Recruiting. Primary outcome measure is the number of patients with an unplanned delay to surgery. | |
ADXS (NCT02002182) | Phase 2. Vaccination prior to robotic surgery in HPV+ oropharyngeal cancer. | A neoadjuvant study to determine if ADXS11–001 vaccine will stimulate the body’s defense system before transoral surgery. | Results ongoing. The primary outcome is HPV E6/E7-specific CD8+ cytotoxic lymphocyte responses at different time points. Secondary outcomes include toxicity. | |
(NCT02827838) | Phase 2. Durvalumab treatment prior to surgery for patients with oral cavity or oropharynx cancer. | To investigate the effect of durvalumab on local and systemic immune activation by HPV status in patients with oral cavity and oropharynx HNSCC. | Recruiting. Primary outcome measures include assessment of immune effectors, immune-regulatory miR responses, and systemic responses to HPV and systemic immune response to tumor associated antigens. | |
(NCT02812524) | Phase 1. Intratumoral injections of ipilimumab before surgical resection in HNSCC patients. | To test the feasibility of the administration of intratumoral injections of ipilimumab prior to surgical resection, and immune system response to treatment. | Recruiting. The primary objective is to assess safety, as determined by the number of delayed surgeries. |