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Table 2 Incorporation of immunotherapy within novel combination therapy strategies for HNSCC

From: The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of squamous cell carcinoma of the head and neck (HNSCC)

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
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.
  1. 1. *IRC: Response evaluation by an independent review committee
  2. 2. *IR: Response evaluation by investigator review