Immune checkpoint inhibitors directed against programmed death protein 1 (PD-1) have become standard treatment in patients with recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC).1 2 A first phase Ib trial proved the feasibility of the PD-1 inhibitor pembrolizumab in combination with radiochemotherapy with weekly administration of cisplatin in locally advanced tumors.3 The ongoing phase III trials Keynote-412 and Javelin head and neck 100 add anti-PD(L)1 agents to standard radiochemotherapy with three administrations of high-dose cisplatin in locally advanced tumors. However, recently it was reported in a press release that Javelin head and neck 100 will not meet its primary endpoint.

Beside primary radiochemotherapy, the strategy of induction chemotherapy followed by radio(chemo)therapy has become a treatment option for laryngeal cancer.4 However, when this strategy was expanded to other locations in the head and neck, randomized trials failed to prove a survival benefit compared with radiochemotherapy alone.5 In more recent trials using induction chemotherapy, excellent responders were identified after three cycles and subsequently treated with dose and volume-reduced radiotherapy in order to minimize late toxicity.6 7

The CheckRad-CD8 study was conducted to develop an efficient single cycle induction therapy, which allows patient selection for a further chemotherapy-free treatment based on pathologic response evaluation. Induction treatment consisted of cisplatin, docetaxel, durvalumab and tremelimumab. Patients with pathologic response entered definitive radiation therapy combined with durvalumab and tremelimumab followed by durvalumab maintenance, here called radioimmunotheapy.

The combination of durvalumab with platinum-based chemotherapy was studied in the phase III CASPIAN trial in extensive-stage small cell lung cancer. In this trial, the addition of durvalumab increased overall survival (OS) without relevant increase in toxicity.8 The combination of durvalumab and tremelimumab with chemotherapy was studied in the Canadian phase IB IND226 trial mainly in patients with lung cancer. This was the first trial that proved the feasibility of a quadruple combination consisting of durvalumab and tremelimumab in combination with platinum-doublet chemotherapy and provided first dose recommendations.9

In this interim analysis of the CheckRad-CD8 trial the safety, antitumor activity and biological response of this single cycle induction treatment were studied in locally advanced HNSCC. To our knowledge, this is the first report on safety and antitumor activity of a combination scheme consisting of chemotherapy, programmed cell death ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antagonists.

The results of the CheckRad-CD8 trial support the feasibility of the combination of docetaxel/cisplatin with durvalumab/tremelimumab as single cycle induction treatment in locally advanced HNSCC. The feasibility of radiotherapy combined with durvalumab/tremelimumab, including the whole safety of all the treatment, will be studied in a future analysis. Grade 3–4 AE mainly consisted of leukocytopenia and infections. This may be prevented by prophylactic use of G-CSF, which was not part of the study protocol. However, prophylactic G-CSF has to be discussed critically, as it may also increase myeloid-derived suppressor cells leading to impaired tumor control.16 The incidence of irAE grade 3–4 in 11% of the patients was in the expected range and the events were treated effectively by immune-suppressive treatment. The first study that established data on feasibility of durvalumab and tremelimumab in combination with platinum-doublet chemotherapy was the Canadian IND226 trial.9 In this trial, patients with different tumors, mainly non–small cell lung cancer, received durvalumab and tremelimumab at different dose levels in combination with chemotherapy. The studied chemotherapy regimens included pemetrexed/platinum, gemcitabine/platinum, etoposide/platinum and nab-paclitaxel/carboplatin, but not the scheme of the CheckRad-CD8 trial docetaxel/platinum. Treatment was feasible up to the highest dose level of 1500 mg durvalumab q3w (every three weeks) and 75 mg tremelimumab q3w (up to four doses of tremelimumab). The frequency of irAE ≥grade 3 was 21% compared with 11% in the CheckRad-CD8 trial. As this analysis of the CheckRad-CD8 trial focuses on the period until the end of the restaging assessments, additional late irAE might increase the rate of irAE. In the IND226 study, irAE ≥grade 3 mainly consisted of diarrhea (9%), which also appeared in the CheckRad-CD8 trial (4%). The most frequent irAE ≥grade 3 in CheckRad-CD8 was hepatitis (5%), which also appeared in 3% in IND226. The studied induction treatment resulted in a high rate of biopsy-proven pCR in 48% of the patients after only a singe cycle of induction chemoimmunotherapy. In further 45% of the patients, intratumoral CD8+ cells increased, which has previously been described as predictor of treatment response to PD-1 antagonists.14 Patient selection was based on biopsies and not imaging, as the time period of a single cycle induction treatment is too short to allow sufficient tumor shrinkage. The pathologic response assessment in a rebiopsy opens the opportunity to study new pathologic parameters besides pCR as possible predictive values. A similar approach was performed in a study with neoadjuvant pembrolizumab using tumor necrosis, giant cells and histiocytic reaction as response criteria.17

The rate of clinical complete responses after three cycles of docetaxel, cisplatin and 5-fluorouracil 5FU (TPF) ranges from 17% to 43% in phase III trials with unselected patients.18–22 However, data about biopsy-proven pCR rates after induction chemotherapy are limited. In a Spanish phase III trial, biopsies were performed in a quarter of the 382 randomized patients, and a biopsy-proven pCR was found in 42% of the patients after three cycles of paclitaxel/cisplatin/5FU arm compared with 23% in the cisplatin/5FU arm.19 In a GORTEC trial, biopsies were performed in half of the 213 randomized patients, and a biopsy-proven pCR was found in 64% of the patients after three cycles TPF compared with 36% in the cisplatin/5FU arm.20 In a phase II trial with three cycles of TPF induction before planned surgery, the pCR rate of the primary tumor was 33%.23 A limitation of the CheckRad-CD8 trial is that only biopsies and not complete surgical specimens were available, which probably has a reduced sensitivity in the detection of residual TCs and may lead to an overestimation of the pCR rate. Taken together, the efficacy of only a single cycle induction treatment with cisplatin/docetaxel and durvalumab/tremelimumab seems to be at least comparable with three cycles of TPF induction.

Two phase II trials containing 21 and 28 patients, respectively, studied a single dose of pembrolizumab before planned surgery in locally advanced HNSCC.17 24 A limitation of the comparison of these trials with the CheckRad-CD8 trial is that in these trials complete surgical specimens were available compared with biopsies in CheckRad-CD8. However, as altogether only one pCR appeared in these two trials, the single agent induction seems to be less effective in inducing pCR compared with the combined induction therapy of the CheckRad-CD8 trial. In the IMCISION trial containing 12 patients, treatment consisted of two doses of nivolumab alone or in combination with a single dose of ipilimumab in a neoadjuvant setting.25 Their findings of one ‘near complete response’ in the monotherapy arm and two ‘near complete responses’ in the combined arm, together with an increased immune-related gene expression in the combined arm, favor a combined approach. 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. Similar approaches were also studied in non–small cell lung cancer. Two preoperative doses of nivolumab induced pCR of the primary tumor in 3e of 20 resected tumors (15%).27

In the phase III EAGLE trial, both durvalumab alone and durvalumab with tremelimumab failed to prove a significant improvement of OS compared with second line chemotherapy in recurrent and/or metastatic HNSCC.13 However, the 1-year survival rate of durvalumab with 37% was comparable to second line trials with nivolumab with 36% or pembrolizumab with 37%, whereas the 1-year survival rate of durvalumab with tremelimumab was only 30%.2 13 28 The results of the phase III KESTREL trial with a durvalumab/tremelimumab combination in first-line treatment are still outstanding. As tremelimumab enhances T-cell priming in an early phase, the combination with single PD-(L)1 agents that only can release a pre-existing immune reaction may not be efficient. Nevertheless, the combination with cell death inducing agents as chemotherapy or radiotherapy may release a real benefit of tremelimumab.29 30

The median pretreatment intratumoral CD8+ cell density of 342 cells/mm² in the CheckRad-CD8 trial is in line with previous reports with ranges between median cell densities of 220/mm² in the tumor center and 545/mm² in the invasive margin.31 The presented results of the CheckRad-CD8 trial emphasize the value of the baseline intratumoral CD8+ cell density as independent predictor for pCR after induction chemoimmunotherapy. These findings are in line with previous reports on the predictive role of intratumoral CD8+ cells in PD-1 inhibitor monotherapy.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. 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. Regarding the staining method and subsequent pathologic evaluation, CD8+ cells have already been validated for colon cancer.35

Recent phase III trials with PD-1 inhibitors in HNSCC typically use PD-L1 on tumor cells or combined on TCs and ICs as predictive marker.1 2 28 In the CheckRad-CD8 trial, only PD-L1 on ICs and not on TCs was a predictor of pCR in the univariate analysis. Interestingly, this finding of a better predictive value of PD-L1 on immune cells compared with TCs has also been described before for PD-1 inhibitor monotherapy.36

HPV-positive tumors are typically identified via p16 immunohistochemistry and have superior prognosis, especially if treated with radiochemotherapy or induction treatment followed by radiochemotherapy,37 38 which has been attributed to significantly higher immune responses especially to HPV-positive oropharyngeal HNSCC.39 This effect was also found in a recent phase IB trial when radiochemotherapy was combined with pembrolizumab in locally advanced HNSCC.3 In the CheckRad-CD8 trial, p16 positive tumors had a higher CD8+ cell density and higher PD-L1 immune cell area compared with p16 negative tumors. Increased densities of tumor-infiltrating immune cells in p16-positive tumors have also been reported previously.40 Despite this increased immune cell infiltration in p16-positive tumors, the immune cell composition of T-cell subsets is similar to p16-negative tumors, but B-cells seem to differ in both tumor types.41 In a recent meta-analysis, patients with p16-positive HNSCC treated with immune checkpoint inhibitors had a favorable OS.42 This is in line with the CheckRad-CD8 trial, as p16 positivity had a positive predictive value for pCR after induction chemoimmunotherapy.

Another new finding of this trial is that, especially in patients with pCR, the coexpression of PD-1 increases on peripheral blood CD8+ cytotoxic T cells. This is probably not a sign of cell exhaustion, but indicates the expansion of cell subpopulations with high capacity for tumor recognition.43

In conclusion, single cycle of induction treatment with cisplatin/docetaxel and durvalumab/tremelimumab is feasible. This treatment achieves a high rate of biopsy-proven pCR of 48%. The pre-therapeutic intratumoral CD8+ cell density is the most valuable predictive factor for pCR. These results encourage the clinical development of induction treatments with combined chemoimmunotherapy in HNSCC.