Immunotherapy for squamous cell carcinoma of the head and neck Free

Abstract

Squamous cell carcinoma of the head and neck is characterized by an immunosuppressive environment and evades immune responses through multiple resistance mechanisms. A breakthrough in cancer immunotherapy employing immune checkpoint inhibitors has evolved into a number of clinical trials with antibodies against programmed cell death 1 (PD-1), its ligand PD-L1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) for patients with squamous cell carcinoma of the head and neck. CheckMate141 and KEYNOTE-048 were practice-changing randomized phase 3 trials for patients with platinum-refractory and platinum-sensitive recurrent or metastatic squamous cell carcinoma of the head and neck, respectively. Furthermore, many combination therapies using anti-CTLA-4 inhibitors, tyrosine kinase inhibitors and immune accelerators are currently under investigation. Thus, the treatment strategy of recurrent or metastatic squamous cell carcinoma of the head and neck is becoming more heterogeneous and complicated in the new era of individualized medicine. Ongoing trials are investigating immunotherapeutic approaches in the curative setting for locoregionally advanced disease. This review article summarizes knowledge of the role of the immune system in the development and progression of squamous cell carcinoma of the head and neck, and provides a comprehensive overview on the development of immunotherapeutic approaches in both recurrent/metastatic and locoregionally advanced diseases.

Introduction

Squamous cell carcinoma of the head and neck (SCCHN) includes malignancies in the oral cavity, nasopharynx, oropharynx, hypopharynx, larynx, nasal cavity and salivary gland. The multimodal strategies of surgery, radiotherapy and chemotherapy are performed for treating this condition. However, chemoradiotherapy (CRT) for locally advanced (LA) disease still has a rather poor success rate. Patients with recurrent or metastatic (RM)-SCCHN have a poor prognosis and few treatment options. Therefore, more effective and less toxic treatments are needed.

Immune checkpoint molecules, such as programmed cell death 1 (PD-1), its ligand PD-L1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), have a major role in maintaining self-tolerance and modulating immune response in normal immunoregulatory pathways of human peripheral tissues (1). Hence, immune checkpoint inhibitors (ICIs) targeting PD-1 (nivolumab, pembrolizumab), PD-L1 (atezolizumab, avelumab, durvalumab) and CTLA-4 (ipilimumab, tremelimumab) are able to block these inhibitory pathways, and consequently enhance immune surveillance against tumor cells. A number of clinical trials with these antibodies not only as monotherapy but also as combination therapy have been conducted, mainly focusing on patients with RM-SCCHN.

This review will focus on providing an overview of ICI drug development, presenting evidence that should aid the establishment of standard therapy for RM-SCCHN. Ongoing efforts to develop ICIs will also be presented, not only in RM-SCCHN but also in LA disease. Finally, we will discuss the future directions in this exciting and evolving era in immuno-oncology.

Rationale of using ICIs in head and neck cancer

HNSCC is an appropriate disease for immunotherapy, as immune escape plays a key role in its tumor initiation and progression. Several groups have examined the expression of PD-L1 in human SCCHN tissue samples across multiple primary sites, and these studies revealed high levels of PD-L1 expression, on 46–100% of tumors (2). Therefore, T-cell checkpoint inhibitors blocking the PD-L1:PD-1 association have been evaluated targeting RM-SCCHN.

The majority of SCCHN cases carry a high mutational burden, which is probably linked to heavy smoking, and the resultant tumor neoantigen may be a target of the host’s immune system. Subgroups of oropharyngeal cancer and nasopharyngeal cancer are associated with human papillomavirus (HPV) and Epstein–Barr virus (EBV), respectively. HPV-positive cancers might have mutations attributable to the expression of APOBEC cytidine deaminases (3–5). The expression of viral proteins, such as EBV nuclear antigen-1 or latent membrane proteins 1 and 2, can elicit a virus-specific immune response in patients with nasopharyngeal cancer (6).

Chronic viral infections often result in the exhaustion of virus-specific CD8⁺ T cells, in which multiple cell-surface inhibitory receptors, including PD-1, lymphocyte activation gene-3 (LAG-3), T-cell immunoglobulin mucin-3 (TIM-3) and T-cell immunoreceptor with Ig and ITIM domains (TIGIT), are overexpressed (7–9). Therefore, targeting these immune-inhibitory molecules in virus-associated cancer may restore the function of CD8⁺ cytotoxic T lymphocytes and lead to tumor regression. Furthermore, integration of virus into the PD-L1 locus causes the amplification of the virally interrupted PD-L1 allele and activates the transcription of a truncated PD-L1 mRNA, through which virally mediated cancers may escape from the anti-cancer mechanisms of the host’s immune system (10).

ICIs for recurrent and metastatic SCCHH

The treatment strategy for RM-SCCHN is determined according to the sensitivity to platinum agents. Platinum-naïve or progressive diseases more than 6 months after curatively intended platinum-based chemotherapy given for locoregionally advanced disease are designated as platinum-sensitive. On the other hand, progressive diseases during or within 6 months after platinum-based chemotherapy are designated as platinum-resistant.

The EXTREME trial showed that adding cetuximab, an anti-EGFR monoclonal antibody, to chemotherapy with carboplatin or cisplatin (CDDP) and 5-fluorouracil increased overall survival (OS) in patients with platinum-sensitive RM-HNSCC. Thus, platinum-based chemotherapy plus cetuximab was a standard of care for platinum-sensitive RM-SCCHN (11). Therapeutic options for platinum-resistant cases in clinical practice included taxane, methotrexate, S-1 and cetuximab monotherapy, if not chosen in the first line. The organizational framework for this review is structured around platinum sensitivity.

ICIs for platinum-sensitive RM-SCCHN

Anti-PD-1/PD-L1 antibodies have been evaluated in platinum-sensitive RM-SCCHN as monotherapies or in combination with chemotherapy. Furthermore, combination therapies of anti-CTLA-4 and anti-PD-1/PD-L1 antibodies have been investigated (Table 1).

KEYNOTE-048

KEYNOTE-048 was a practice-changing randomized phase 3 trial for platinum-sensitive RM-SCCHN, in which participants were allocated to pembrolizumab alone, pembrolizumab plus platinum and 5-fluorouracil, or cetuximab plus platinum and 5-fluorouracil (EXTREME regimen) (12). A key biomarker in this trial was PD-L1 combined positive score (CPS). CPS is different from tumor proportion score and defined as the total number of PD-L1-positive cells (tumor cells, lymphocytes and macrophages) divided by the total number of tumor cells. Pembrolizumab alone significantly improved OS compared with the EXTREME regimen in those with CPS ≥ 20 and CPS ≥ 1. However, superiority of pembrolizumab alone to the EXTREME regimen was not shown in the total population, although its non-inferiority was shown. Furthermore, pembrolizumab with chemotherapy significantly improved OS compared with the EXTREME regimen in the total population, those with CPS ≥ 20 and those with CPS ≥ 1. Taken together, the results of KEYNOTE-048 suggest that pembrolizumab monotherapy and pembrolizumab plus platinum-based chemotherapy are novel standards for platinum-sensitive diseases. In KEYNOTE-048, progression after the next line of therapy (PFS2) following pembrolizumab or pembrolizumab plus chemotherapy was also compared with EXTREME (13). For the pembrolizumab monotherapy versus EXTREME comparison, PFS2 was longer for the pembrolizumab arm in patients with CPS ≥ 20 and CPS ≥ 1. For the pembrolizumab plus chemotherapy versus EXTREME comparison, PFS2 was longer for pembrolizumab plus chemotherapy arm in patients with CPS ≥ 20, CPS ≥ 1 and the total population. These data further support the effect of the first line pembrolizumab or pembrolizumab plus chemotherapy, and subsequent salvage therapy on patient outcomes.

How the choice of pembrolizumab monotherapy or pembrolizumab plus platinum-based chemotherapy is made in individual cases is important. Pembrolizumab monotherapy may be an appropriate treatment for CPS-positive cases. However, the response rate of pembrolizumab monotherapy was less than that of the EXTREME regimen even at a high CPS level. Furthermore, Kaplan–Meier curves in PFS raised the possibility of early disease progression in some populations in the pembrolizumab monotherapy arm compared with the EXTREME regimen. Although data on time to response in each arm are insufficient in KEYNOTE-048, the combination of chemotherapy with pembrolizumab may be a better option for patients with a high tumor burden, rapid tumor growth and tumor-related symptoms who require rapid tumor shrinkage.

Specifically, the post hoc exploratory analysis in European Medicines Agency (EMA) (14) demonstrated that hazard ratio (HR) of OS in pembrolizumab versus EXTREME was 0.86 (95% confidence interval [CI]: 0.66–1.12) for 1 ≤ CPS < 20 population, and that in pembrolizumab plus chemotherapy versus EXTREME was 0.71 (0.54–0.94) for 1 ≤ CPS < 20 population. This result suggests that pembrolizumab plus chemotherapy might be better option than pembrolizumab monotherapy for symptomatic patients with 1 ≤ CPS < 20. For CPS < 1 population, it is noteworthy that HR of OS in pembrolizumab versus EXTREME was 1.51 (0.96–2.37), and that in pembrolizumab plus chemotherapy versus EXTREME was 1.21 (0.76–1.94). Therefore, chemotherapeutic backbone may be required for CPS negative patients with or without symptom, instead of pembrolizumab monotherapy.

Issues remain regarding the positioning of cetuximab, selection of salvage chemotherapy after the failure of pembrolizumab, optimization of the chemotherapeutic backbone, and predictive biomarkers for pembrolizumab, on which further debate is needed.

Combination of anti-PD-1 antibody and IDO1 inhibitor

Although the response to anti-PD-1 or PD-L1 monotherapy is characterized by durability, only a limited number of patients may obtain a response to single-agent immunotherapies. Against this background, focus has been placed on combinatorial immunotherapy approaches with other molecules in the tumor microenvironment.

Indoleamine 2,3-dioxygenase (IDO) is an enzyme involved in the degradation of the amino acid tryptophan into kynurenine (15). Because tryptophan is critical for lymphocyte functions, IDO plays a role in immunosuppression, such as inhibition of T-cell activation. The results of multiple phase 1/2 trials encouraged the idea that the combination of a small-molecule inhibitor of IDO1 (epacadostat) may improve the outcomes of anti-PD-1 monotherapy. However, the failure of epacadostat to improve PFS in combination with pembrolizumab in a subsequent phase 3 trial of melanoma (16) influenced the development of IDO1 inhibitors in HNSCC, leading to the withdrawal of two phase 3 trials investigating pembrolizumab plus epacadostat and nivolumab plus BMS-986205 in platinum-sensitive HNSCC.

Ongoing clinical trials and future perspectives in platinum-sensitive RM-SCCHN

Combinations of checkpoint inhibitors targeting CTLA-4 and PD-1/PD-L1 are being tested in the front-line setting of palliative therapy for RM-SCCHN. The accrual of patients for the phase III KESTREL study was terminated, in which durvalumab alone or durvalumab plus tremelimumab was compared with the EXTREME regimen for the first-line treatment of RM-SCCHN (17). Nivolumab in combination with ipilimumab was also compared with the EXTREME regimen in the CheckMate651 study. Notably, adverse events (AEs) of anti-CTLA-4 therapy are generally more severe than those of anti-PD-1/PD-L1 therapies (18–20). Colitis, diarrhea, hypophysitis and adrenal insufficiency were closely associated with anti-CTLA-4. Furthermore, the signal strength of AEs increased when anti-CTLA-4 therapy was combined with anti-PD-1/PD-L1 therapies (21). Therefore, management against such immune-related AEs is critical if this combination is to be practically applicable in the future.

The recent trend in cancer immunotherapy has expanded to the combination of ICIs with tyrosine kinase inhibitors (TKIs) and immune accelerators. Lenvatinib is an oral, multitargeted TKI of VEGFRs 1, 2 and 3, FGFRs 1 through 4, PDGFRα, RET and KIT signaling networks (22,23). A phase Ib/II study of lenvatinib plus pembrolizumab demonstrated a manageable safety profile and highly promising antitumor activity in patients with selected solid tumor types, including renal cell carcinoma, endometrial cancer, melanoma and SCCHN (24). The ORR in SCCHN was 36% (8/22; 95% CI: 17.2–59.3%). This combination is designated as a breakthrough therapy by the FDA. A randomized double-blind phase 3 study of pembrolizumab with or without lenvatinib is ongoing as first-line treatment of PD-L1-positive RM-HNSCC (25).

Besides the inhibition of the PD-1/PD-L1 pathway, stimulation of immune accelerator is also actively under development. Inducible T-cell co-stimulator (ICOS) is an immune checkpoint protein that is stimulated by both the T-cell receptor and CD28 signals (26). Co-stimulation by ICOS and ICOS ligand confers an anticancer response. The approaches combining anti-PD-1 antibody with ICOS agonists appear to be promising and may help to overcome resistance to PD-1/PD-L1 inhibitors. A randomized double-blind phase 3 study comparing GSK3359609 (ICOS agonist) plus pembrolizumab versus placebo plus pembrolizumab is ongoing as first-line treatment of PD-L1-positive RM-HNSCC (27).

ICIs for platinum-resistant RM-SCCHN

The development of ICIs in SCCHN was initiated by targeting platinum-resistant RM-SCCHN. The main focus of ICIs was anti-PD-1/PD-L1 antibody, and its monotherapy significantly prolonged OS compared with conventional chemotherapy (Table 1).

CheckMate141

CheckMate141 was a randomized phase 3 trial for patients with RM-SCCHN whose disease had progressed within 6 months after platinum-based chemotherapy (28,29). Patients were randomly assigned to receive nivolumab or single-agent therapy of the investigator’s choice (IC arm). The results showed that treatment with nivolumab significantly improved OS. With 2-year long-term follow-up, median OS was 7.7 months in the nivolumab arm and 5.1 months in the IC arm (HR = 0.68) (29). Although methotrexate, weekly docetaxel or cetuximab as single-agent therapy in the IC arm did not fully reflect the previous clinical practice for platinum-resistant RM-SCCHN in Asian countries, the use of nivolumab is clinically approved for the treatment of platinum-refractory RM-HNSCC. Asian subgroup analysis also demonstrated that nivolumab conferred a survival advantage compared with conventional treatments in Asian patients and was well tolerated (30). Importantly, OS benefit with nivolumab was also noted among patients who received nivolumab as first-line treatment for RM-SCCHN after progressing on or after platinum-based adjuvant or definitive CRT setting for LA disease (31).

KEYNOTE-012/KEYNOTE-055

Pembrolizumab is an anti-PD-1 monoclonal antibody. A phase 1b multi-cohort study (KEYNOTE-012) demonstrated a durable objective response rate by treatment with pembrolizumab monotherapy in a subgroup of platinum-refractory SCCHN (32). Based on this study, pembrolizumab was approved by the US FDA for the treatment of platinum-refractory recurrent and/or metastatic HNSCC in August 2016 (33). Asian subset analyses of 26 patients with HNSCC from KEYNOTE-012 also revealed that pembrolizumab was well tolerated and had durable antitumor activity (34). Furthermore, pembrolizumab exhibited clinically meaningful antitumor activity of an overall response rate of 16%, with a median duration of response of 8 months in platinum- and cetuximab-refractory RM-SCCHN (KEYNOTE-055) (35).

KEYNOTE-040

KEYNOTE-040 was a mirror study of CheckMate141, in which pembrolizumab was compared to single-agent therapy in the investigator’s choice treatment (IC arm) in platinum-refractory RM-SCCHN (36). Unlike CheckMate141, however, pembrolizumab failed to show superior OS compared with the investigator’s choice. Although KEYNOTE-040 and CheckMate141 used the same comparator treatments of methotrexate, cetuximab and docetaxel, the higher doses of docetaxel administered once every 3 weeks in KEYNOTE-040 may have had more efficacy than the lower weekly doses in CheckMate141. KEYNOTE-040 excluded the cases of platinum-refractory disease that had progressed for less than 3 months, suggesting that the patients in KEYNOTE-040 might have had a better prognosis than those in CheckMate141. Furthermore, salvage ICI treatment may have influenced the outcomes in the IC arm. Indeed, one or more subsequent ICIs were received by 13% of patients in the IC arm. Taken together, these findings may explain why the IC arm in KEYNOTE-040 had longer survival than expected.

Durvalumab and its combination with tremelimumab

The HAWK study investigated durvalumab monotherapy in patients with tumors highly expressing PD-L1 who had progressed on platinum-based chemotherapy (37). In contrast, the experimental strategies of the CONDOR study were durvalumab or tremelimumab monotherapy, and durvalumab in combination with tremelimumab targeting tumors with low or no PD-L1 (38). Although no improvement of treatment outcome was seen in combination therapy, these trials suggested that durvalumab monotherapy had a clinical benefit irrespective of the level of PD-L1 expression in the tumors.

However, the EAGLE study did not demonstrate a statistically significant survival benefit for durvalumab alone or durvalumab plus tremelimumab over single-agent standard of care (SoC) as second-line treatment for patients with RM-HNSCC (39). SoC therapy included not only cetuximab, docetaxel and methotrexate, but also paclitaxel, 5-fluorouracil, S-1 or capecitabine, which reflects Asian clinical practice for platinum-refractory disease in contrast to the SoC arm in the CheckMate141 and KEYNOTE-040 trials. Furthermore, a higher percentage of patients in the SoC arm received subsequent immunotherapy. Thus, the choice of SoC therapy and subsequent immunotherapy may have contributed to the unexpectedly longer OS of the SoC arm and its negative results.

Novel combination approaches and future perspectives in platinum-resistant RM-SCCHN

Monalizumab is a first-in-class humanized IgG4 targeting NKG2A receptors expressed on both tumor-infiltrating cytotoxic NK and CD8⁺ T lymphocytes (40). NKG2A blockade, either alone or together with other ICIs (anti-PD-1/PD-L1 Ab), might improve the anti-tumor efficacy of NK and CD8⁺ TILs in cancer patients. The EORTC 1559-HNCG study is investigating monalizumab monotherapy or monalizumab plus durvalumab in immunotherapy patient cohorts (41). Furthermore, monalizumab enhances NK cell-mediated antibody-dependent cellular cytotoxicity and anti-tumor activity induced by cetuximab in SCCHN. A phase 2 trial of monalizumab plus cetuximab in SCCHN demonstrated a promising response rate (31%) in patients with HNSCC regardless of the prior use of ICIs (40,42). Based on this finding, a global phase 3 randomized clinical trial evaluating monalizumab in combination with cetuximab will be initiated for patients with platinum-resistant RM-SCCHN who were previously treated with anti-PD-1/PD-L1 Ab.

ICIs for LA SCCHH

Rationale for using the combination of ICIs with RT

CRT with concurrent high-dose CDDP is the gold standard of care as a non-surgical approach for patients with LA-SCCHN (43–45). Radiation modulates the immune system, such as antigen presentation, recruitment of CD8⁺ T cells and induction of the expression of immune checkpoint receptors, in cooperation with CDDP (46–49). Therefore, combined therapy with RT and ICIs works synergistically to improve treatment outcomes. Interestingly, RT enhances host tumor immunity through yielding a vaccination effect against treated cancer cells. The combination of ICIs with RT can treat not only irradiated local tumors but also distant metastatic tumors outside the irradiated fields, which is known as the abscopal effect (50–52). Although no evidence that changes the current standard of care has yet become available, the recent development of ICIs has expanded their indication as definitive treatments in LA-SCCHN. In particular, combinations of anti-PD-1/PD-L1 antibodies with RT/CRT have been vigorously investigated.

Combination of ICIs with definitive CRT

Selected ongoing clinical trials examining ICIs in combination with RT for LA disease are shown in Table 2. Pembrolizumab in combination with weekly CDDP-based CRT was shown to be safe and does not significantly impair radiation or chemotherapy dosing (53). The efficacy of this combination is being further explored through larger phase 3 clinical trials (54).

JAVELIN Head and Neck 100 is a phase 3, randomized, double-blind, placebo-controlled, parallel-arm study investigating treatment with avelumab plus CRT followed by avelumab maintenance versus CRT alone in patients with LA-SCCHN (55). However, a preplanned interim analysis suggested that the study is unlikely to show a statistically significant improvement in the primary endpoint of PFS.

Combination of ICIs with RT for patients ineligible for standard CRT

There are no standard non-surgical treatments for patients ineligible for high-dose CDDP. Therefore, the development of alternative treatments is an unmet need for patients ineligible for standard treatment using high-dose CDDP. Combinations of anti-PD-1 or anti-PD-L1 antibody with RT alone have been compared with cetuximab plus RT (BioRT) for these populations in randomized trials. A phase 3 trial is evaluating whether the addition of avelumab to BioRT significantly improves the survival outcome compared with BioRT in the specific cohort of patients ineligible for standard treatment using high-dose CDDP (56) (Table 2).

ICIs in neoadjuvant, post-operative and post-CRT settings

ICIs as post-CRT or in a perioperative setting have been investigated for locoregionally advanced disease in a number of clinical trials. For instance, atezolizumab is currently being investigated in an adjuvant therapy setting after definitive local therapy in patients with high-risk LA-SCCHN in a phase 3 trial (Table 2).

Many of the recent trials have used ICIs not only concurrently with RT but also in the neoadjuvant, adjuvant and maintenance phases. However, the optimal sequence of RT and immunotherapy remains a subject of debate. Furthermore, the role of maintenance ICIs and their duration after local therapy are also unclear. Understanding the biology of immune responses to radiotherapy is crucial for estimating the best timing of RT and ICIs. RT initiates the following multiple steps involving innate and adaptive immune cells in the tumor microenvironment: a wave of cell death, recruitment of antigen-presenting macrophages to sample the bolus of tumor debris released in the microenvironment, trafficking it to lymph nodes to present antigens, and systemic priming of tumor-specific T lymphocytes (57). For instance, neoadjuvant anti-PD-1 blockade induces systemic priming of tumor-specific CD8⁺ T lymphocytes and an interferon response within the tumor microenvironment, before the occurrence of a cytotoxic effect of CRT on lymphocytes (58). Pre-surgical checkpoint inhibition also enables selective, primary tumor-specific T-cell clonal modulation, driving its systemic expansion.

Conclusions

The introduction of PD-1 monoclonal antibodies into clinical practice has improved the prognosis without compromising quality of life in RM-SCCHN. Pembrolizumab either as a single agent or in combination with platinum-based chemotherapy has become a novel standard of care in platinum-sensitive RM-SCCHN. Nivolumab monotherapy is also a standard of care for platinum-refractory disease. Although no definitive biomarkers are available for predicting the outcome by ICIs, CPS and tumor-related symptoms may be used for deciding on the first-line treatment. Combination therapies using PD-1/PD-L1 inhibitors and CTLA-4 inhibitors, and different immune modulating approaches are under investigation. Thus, the strategy for treating RM-SCCHN is becoming more heterogeneous and complicated in the new era of individualized medicine. Although no practice-changing data are currently available for LA diseases, ongoing trials are investigating immunotherapeutic approaches in the concurrent CRT, neoadjuvant, adjuvant and perioperative settings.

It has also been established that the benefit of ICIs is limited to only a subset of patients. Therefore, an effort to elucidate the mechanisms of the dynamic tumor microenvironment under the treatment of immunotherapy, and to identify predictive markers of response and resistance, is crucial to develop rational trial designs in the next era of head and neck immuno-oncology.

Funding

None declared.

Conflict of interest statement

Dr Yokota serves in an advisory role in Merck Biopharma and MSD, and has received lecture fees from Merck Biopharma, Ono Pharmaceutical Co., Ltd., Bristol-Myers Squibb, AstraZeneca, Chugai, MSD, and Eisai. Dr Kiyota reports grants from research funding from Ono Pharmaceutical Co., Ltd., Bristol-Meyers Squibb, Astra Zeneca Co., Ltd, Pfizer Co., Ltd, Chugai Pharmaceutical Co., Ltd, Rakuten Medical, during the conduct of the study; and honoraria from Ono Pharmaceutical Co., Ltd., Bristol-Meyers Squibb, Merck Biopharma, Astra-Zeneca Co., Ltd, Merck Sharp & Dohme, Eisai and Bayer. Dr Takahashi reports grants and personal fees from MSD, AstraZeneca, Chugai, BAYER, Ono Pharmaceutical Co., Ltd., Bristol-Myers Squib, outside the submitted work. Dr. Homma reports personal fees from Bristol-Myers Squibb K.K., grants and personal fees from ONO Pharmaceutical Co., Ltd., during the conduct of the study. Dr. Tahara reports grants and personal fees from Pfizer, grants and personal fees from MSD, grants and personal fees from BMS, grants and personal fees from Ono Pharmaceutical, grants and personal fees from AstraZeneca, during the conduct of the study; grants and personal fees from Bayer, grants and personal fees from Eisai, grants and personal fees from Merck serono, personal fees from LOXO, grants and personal fees from Rakuten Medical, personal fees from Celgene, personal fees from Amgen, grants and personal fees from Novartis, outside the submitted work. Dr. Hanai reports grants from research funding from Chugai Pharmaceutical Co., Ltd, grants from research funding from Rakuten Medical, grants from research funding from Merck Sharp and Dohme K.K., grants from research funding from ONO PHARMACEUTICAL Co.,Ltd, during the conduct of the study; and honoraria from Bristol-Meyers Squibb, Merck Biopharma, Eisai Co., Ltd, Merck Sharp & Dohme K.K. and ONO PHARMACEUTICAL Co.,Ltd,. Dr. Asakage reports personal fees from ONO PHARMACEUTICAL outside the submitted work. Dr. Kodaira reports grants from Ministry of Health, Labour and Welfare, Japan, grants from National Cancer Center, Japan, during conduct of the study; personal fees from Merck Serono. Co., Hitachi Co., Bayer Co., Kyowa Kirin Co., Elekta Co., Otsuka Pharmaceutical Co., outside the submitted work. Dr. Tanaka reports personal fees from Astrazeneca, personal fees from Merck Serono, personal fees from Eisai, personal fees from Bristol-Myers Squibb, personal fees from ONO PHARMACEUTICAL, personal fees from MSD, outside the submitted work. Dr. Onoe reports honoraria from Bristol-Myers Squibb. Dr. Okano reports personal fees from Merck Serono, personal fees from Ono Pharmaceutical, personal fees from Bristol-Myers Squibb Japan, personal fees from Eisai, personal fees from Taiho Pharmaceutical, personal fees from AstraZeneca, personal fees from Kirin Pharmaceuticals, outside the submitted work.

References