Research ArticleClinical Studies

The Association Between Chemotherapy Immediately Before Nivolumab and Outcomes Thereafter

KENJI NAKAHAMA, SHUN-ICHI ISA, AKIHIRO TAMIYA, YOSHIHIKO TANIGUCHI, TAKAYUKI SHIROYAMA, HIDEKAZU SUZUKI, TAKAKO INOUE, MOTOHIRO TAMIYA, TOMONORI HIRASHIMA, FUMIO IMAMURA and SHINJI ATAGI
Anticancer Research October 2017, 37 (10) 5885-5891;

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Abstract

Background/Aim: We investigated whether the efficacy and type of pre-nivolumab chemotherapy influence outcomes in non-small cell lung cancer patients following nivolumab treatment. Patients and Methods: In this multicenter study, 199 patients treated with nivolumab were retrospectively reviewed. We analyzed the relationships between the clinical response to nivolumab and to chemotherapy administered immediately beforehand. Results: Patients who achieved objective responses to pretreatments showed higher disease control rates with nivolumab than patients who did not (64% vs. 47%, p=0.03), as did those who achieved disease control with pretreatments (62% vs. 35%, p<0.001). Bevacizumab-pretreated patients tended to show better objective response rates with nivolumab (27% vs. 13%, p=0.06); the objective response rate to nivolumab was significantly higher in bevacizumab-pretreated patients who showed clinical responses (42% vs. 9.1%, p=0.02). Conclusion: Achievement of a clinical response to chemotherapy immediately before nivolumab, particularly when combined with bevacizumab, increases the likelihood of disease control post-nivolumab.

The emergence of several immune checkpoint inhibitors (ICIs) has greatly influenced the clinical outcomes of patients with various cancers, including lung cancer (1). Nivolumab, a fully humanized immunoglobulin G4 ICI antibody, binds to programmed cell death-1 (PD-1) on activated immune cells and inhibits its interaction with its ligands PD-L1 and PD-L2. Although nivolumab is an ICI that shows significant efficacy compared to conventional cytotoxic drugs, only 20% of patients with non-small cell lung cancer (NSCLC) show clinical responses to this agent. In those achieving a clinical response, the duration of response to nivolumab has been much longer than that to other treatments (2, 3). Hence, there is a growing need for a method to identify patients who are predicted to respond to nivolumab and achieve good outcomes. Although PD-L1 expression and tumor mutation burden, which are reported to correlate with clinical effect, are used as biomarkers for patient selection, they remain inefficient identifiers (4, 5).

The immune and tumor microenvironments are critical to determining the efficacy of ICIs (6). Aside from being immunosuppressive, cytotoxic drugs also affect the immune system by contributing to tumor regression in various ways. For example, such drugs can deplete circulating regulatory T cells, leading to increased immunogenicity of the tumor and rendering it more susceptible to immune system response (7-11).

Such studies offer the possibility that the pretreatments administered before ICIs influence the outcomes of such inhibitors by modifying the immune microenvironment. In particular, vascular endothelial growth factor (VEGF) has been reported to be associated with the efficacy of ICIs, and antiangiogenic drugs have been reported to have synergistic effects with ICIs (12-16). Furthermore, significantly greater changes in the immune microenvironment were observed in patients who responded to anticancer treatments than in those who did not respond (11, 17).

Although these previous studies have suggested that the types and efficacies of agents administered prior to ICIs may be important for the usefulness of the latter, the relationship between pre-ICI treatments and the outcomes of patients post-ICIs has not been sufficiently investigated.

We hypothesized that the effects and types of treatments administered immediately before nivolumab influence the outcome of nivolumab, and performed this investigation to test our hypothesis.

Patients and Methods

This was a retrospective multicenter study of patients with advanced or recurrent NSCLC who were previously treated with nivolumab (3 mg/kg intravenously every 2 weeks) at the National Hospital Organization Kinki-chuo Chest Medical Center, Osaka Medical Center for Cancer and Cardiovascular Diseases, and Osaka Prefectural Medical Center for Respiratory and Allergic Diseases between December 2015 (the date that nivolumab was approved in Japan) and July 2016. Patients who received any other concurrent anticancer therapies were excluded, as were those who did not receive any treatments prior to nivolumab. Ultimately, 199 patients were reviewed; the protocol was conducted in accordance with the Declaration of Helsinki and Guidelines for Good Clinical Practices. All participants provided written informed consent. The study protocol was approved by the Institutional Review Boards of the three participating institutions. This study is registered with the University Hospital Medical Information Network in Japan (UMIN), Clinical Trials Registry number UMIN000025908.

Data collection. We collected clinical medical records, including age and Eastern Cooperative Oncology Group Performance Status (ECOG PS) at the time of initiating nivolumab, sex, smoking history, histology, molecular profiling of EGFR and ALK, chemotherapy regimens administered immediately before nivolumab administration and resultant patient outcomes, the response to nivolumab, date of progression (or last follow-up), and date of death or last follow-up. Tumor responses were assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (18).

We analyzed overall response rates (ORRs) and disease control rates (DCRs) based on the response to the pretreatments administered immediately before nivolumab as well as the types of these pretreatment regimens. We categorized the pretreatment chemotherapy regimens into five groups (each with or without bevacizumab): platinum-based (cisplatin and carboplatin), taxanes (docetaxel, paclitaxel, and nab-paclitaxel), antimetabolites (pemetrexed, S-1, and gemcitabine) and tyrosine kinase inhibitors (TKIs). We also performed a sub-analysis of ORRs and DCRs in response to pretreatment regimens only in patients who showed a partial response (PR) or complete response (CR) to the chemotherapy administered immediately before nivolumab. All patients were followed until September 30, 2016.

Statistical analyses. Fisher's exact test was used to compare nonparametric variables such as ORR and DCR. p-Values less than 0.05 were considered statistically significant. All statistical analyses were conducted using the JMP statistical software program for Windows, version 13.0 (SAS Institute Inc., Cary, NC, USA).

Results

Patients' characteristics. The clinical characteristics of the 199 patients are summarized in Table I. The median age was 68 years old, 68% of the patients were men, and most (78%) had a smoking history. The ECOG PS of 92% of the patients was ≤2. The most common histology was adenocarcinoma (70%); 18% of patients had EGFR mutations and only one had an ALK mutation. Seventy-five patients (38%) were administrated nivolumab as second-line therapy, 48 (24%) as third-line, and 76 (38%) as fourth or subsequent lines.

ORR and DCR following nivolumab treatment based on the pretreatment response. Among the patients who achieved CR or PR following pre-nivolumab chemotherapy, ORR and DCR rates after nivolumab were 16% and 64%, respectively. In contrast, patients who did not achieve CR or PR (including those with stable disease [SD], progressive disease [PD], or were not evaluable [NE]) following previous treatments experienced a post-nivolumab ORR and DCR of 15% and 47%, respectively (Table II). There was no significant difference in terms of good response to nivolumab between patients who achieved good response to pretreatment chemotherapy and those who did not (p=0.83); however, the DCR following nivolumab was significantly higher in patients who achieved clinical response in previous treatments (p=0.03). Among patients who achieved disease control with pre-nivolumab chemotherapy, the ORR and DCR following nivolumab were 16% and 62%, respectively (Table III). On the other hand, patients who showed PD or were NE following previous treatments had a post-nivolumab ORR and DCR of 13% and 35%, respectively.

The DCR following nivolumab was significantly higher in patients who achieved disease control with pre-nivolumab chemotherapy than in the patients who showed PD or were NE after such treatments (p<0.001).

ORR and DCR following nivolumab according to pretreatment chemotherapy regimens. We analyzed the outcomes of nivolumab based on the types of chemotherapy regimens administered immediately before nivolumab (Table IV). Patients whose pretreatment regimens included bevacizumab tended to show better ORRs following nivolumab than those whose pretreatment regimens did not include bevacizumab (p=0.06); however, including bevacizumab in pretreatment regimens did not influence the DCRs achieved following nivolumab treatment. There was no significant difference in ORR and DCR with respect to other types of anticancer drugs used for pre-nivolumab chemotherapy other than bevacizumab.

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Table I.

Patient characteristics.

ORR and DCR following nivolumab based on pretreatment regimens in patients who achieved clinical responses. We analyzed the outcomes of nivolumab treatment based on the chemotherapy regimens used immediately before nivolumab in the subset of patients who showed clinical responses (CR or PR) following pre-nivolumab chemotherapy (Table V). Fifty-five patients showed CR or PR to pre-nivolumab treatment; patients pretreated with bevacizumab before nivolumab showed a significantly higher ORR (42%) than those pretreated without bevacizumab (9.1%) (p=0.02). However, the DCR in patients who received bevacizumab was not different from those who did not. Other pre-nivolumab chemotherapy regimens did not significantly influence ORRs and DCRs after nivolumab among patients who achieved CR or PR.

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Table II.

Comparison of ORRs and DCRs following nivolumab treatment among patients who achieved pre-nivolumab treatment responses vs. those who did not.

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Table III.

Comparison of ORRs and DCRs following nivolumab treatment among patients who achieved pre-nivolumab disease control vs. those who did not.

Discussion

In this study, a higher DCR to treatments administered immediately before nivolumab was significantly associated with a higher DCR to nivolumab, and patients treated with bevacizumab as part of the pre-nivolumab regimen tended to exhibit better ORRs to nivolumab. Furthermore, among patients who showed clinical responses to the pre-nivolumab treatments, those whose pretreatments included bevacizumab demonstrated a significantly higher ORR to nivolumab than those whose treatments did not include bevacizumab. The type of anti-lung cancer agents administered pre-nivolumab, including platinum, taxane, antimetabolites, and TKIs, did not significantly influence nivolumab treatment outcome.

The tumor microenvironment is considered important for ICI efficacy. Immunotherapy, cytotoxic drugs, and TKIs can all alter the microenvironment and immune system response (19); examples of such effects are shown in Table VI (20-27).

Antiangiogenic therapy in particular has been reported to have a synergistic effect with immunotherapy. In fact, the combination of bevacizumab and ICI has been reported to increase tumor antigen recognition, tumor-associated endothelial activation, and infiltration of T cells (28, 29). The vascular endothelium plays an important role in activating immune responses by increasing the expression of adhesion molecules that interact with various immune cells. VEGF mediates the down-regulation of these adhesion molecules and inhibits dendritic cell maturation (20). Moreover, some antiangiogenic molecules alleviate the immunosuppression associated with cancer by down-regulating immunosuppressive cells, immunosuppressive cytokines, and T cell inhibitory molecules (14, 16). Furthermore, VEGF reportedly increased PD-1 expression on T cells (30). Our finding that bevacizumab inclusion in pre-nivolumab treatments was associated with better post-nivolumab outcomes was consistent with studies suggesting synergy between antiangiogenic treatments and ICIs.

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Table IV.

ORR and DCR based on the type of pretreatment.

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Table V.

ORRs and DCRs in patients who achieved clinical responses to pre-nivolumab chemotherapy by type of agent.

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Table VI.

Examples of the various effects of anticancer agents in the tumor microenvironment.

On the other hand, none of the pre-nivolumab drugs other than bevacizumab showed any significant difference in patient outcomes post-nivolumab regardless of their types, although these drugs are also reported to sensitize the tumor microenvironment to therapy. Previous studies have shown that the degree of immune microenvironment alteration was greater in patients who responded to chemotherapy than in those who did not (11, 17). In our study, the DCR to pre-nivolumab treatments was associated with the DCR to nivolumab, suggesting that the effect of nivolumab might be enhanced by immune microenvironment sensitization. Moreover, patients who were treated with bevacizumab and showed clinical responses to pre-nivolumab treatments demonstrated a high ORR (42%) to nivolumab; bevacizumab use was a significant factor associated with a higher ORR to nivolumab. This result suggests that the synergistic effect between bevacizumab and nivolumab is stronger when clinical response is first obtained by bevacizumab.

Our study had some limitations, including its retrospective nature and the lack of assessment of the non-conventional responses of nivolumab. Although a better pre-nivolumab treatment DCR was associated with a better DCR to nivolumab, this result may be attributed to the slowly progressing nature of the tumor itself rather than the effect of pretreatment. There was also the possibility of selection bias towards patients treated with bevacizumab. Finally, the numbers of patients in each pre-nivolumab treatment regimen group were relatively small, which might affect statistical accuracy.

In summary, the DCRs of patients following initial-line treatments were associated with DCRs following nivolumab administration, and the use of bevacizumab in pre-nivolumab chemotherapy was associated with better outcomes post-nivolumab. Further prospective and large-cohort studies are warranted to determine whether better early treatment responses truly predict the outcome of nivolumab, and if the use of antiangiogenic drugs such as bevacizumab improves outcomes post-nivolumab.

Acknowledgements

The Authors wish to thank all the participating patients. This study was supported by Ono Pharmaceutical Co., Ltd and Bristol-Myers Squibb Co., Ltd.

Footnotes

  • Conflicts of Interest

    Dr. Y. Taniguchi, Dr. A. Tamiya, Dr. S. Isa, Dr. K. Nakahama, Dr. T. Shiroyama, Dr. H. Suzuki, Dr. T. Inoue, Dr. M. Tamiya, Dr. T. Hirashima, Dr. F. Imamura, and Dr. S. Atagi report grants from Ono Pharmaceutical and Bristol-Myers Squibb. Dr. Y. Taniguchi, Dr. A. Tamiya, Dr. T. Shiroyama, Dr. H. Suzuki, Dr. M. Tamiya, Dr. T. Hirashima, Dr. F. Imamura, and Dr. S. Atagi report personal fees from Ono Pharmaceutical. Dr. Y. Taniguchi, Dr. A. Tamiya, Dr. M. Tamiya, Dr. T. Hirashima, Dr. F. Imamura, and Dr. S. Atagi report personal fees from Bristol-Myers Squibb during the conduct of the study. Dr. Y. Taniguchi reports personal fees from Chugai Pharmaceutical outside the submitted work. Dr. A. Tamiya reports personal fees from Chugai Pharmaceutical, AstraZeneca, Eli Lilly, and Boehringer Ingelheim outside the submitted work. Dr. K. Okishio reports personal fees from Ono Pharmaceutical outside the submitted work. Dr. T. Shiroyama reports personal fees from Taiho Pharmaceutical, Boehringer Ingelheim, and AstraZeneca outside the submitted work. Dr. H. Suzuki reports personal fees from Taiho Pharmaceutical, Boehringer Ingelheim, Pfizer, and Eli-Lilly outside the submitted work. Dr. M. Tamiya reports personal fees from Chugai Pharmaceutical, Pfizer, AstraZeneca, Taiho Pharmaceutical, Eli Lilly, Asahi Kasei Pharmaceutical, Daichi Sankyo CO. LTD. Alere Medical and Boehringer Ingelheim outside the submitted work. Dr. K. Nishino reports personal fees from Chyugai, Boehringer Ingelheim, Eli Lilly, and AstraZeneca outside the submitted work. Dr. T. Kumagai reports personal fees from Ono Pharmaceutical, Astra Zeneca, and Boehringer Ingelheim outside the submitted work. Dr. T. Hirashima reports grants and personal fees from MSD Oncology, Lilly Japan, AstraZeneca, Chugai Pharma, and Boehringer Ingelheim, grants from Eisai, Daiichi Sankyo, Merck Serono, Taiho Pharmaceutical, Kyowa Hakko Kirin, and Takeda, and personal fees from Bayer outside the submitted work. Dr. F. Imamura reports personal fees from Pfizer Inc., AstraZeneca K.K., Novartis Pharma K.K., Kyowa Hakko Kirin Co. Ltd., Boehringer Ingelheim GmbH, Taiho Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., Chugai Pharmaceutical Co. Ltd. outside the submitted work. Dr. S. Atagi reports grants from Pfizer, Chugai Pharmaceutical, AstraZeneca, MSD, Taiho Pharmaceutical, Yakult Pharmaceutical Industry, Eli Lilly, and Boehringer Ingelheim, and personal fees from Taiho Pharmaceutical, Chugai Pharmaceutical, AstraZeneca, Eli Lilly, and Boehringer Ingelheim outside the submitted work.

  • Received September 3, 2017.
  • Revision received September 20, 2017.
  • Accepted September 21, 2017.

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The Association Between Chemotherapy Immediately Before Nivolumab and Outcomes Thereafter
KENJI NAKAHAMA, SHUN-ICHI ISA, AKIHIRO TAMIYA, YOSHIHIKO TANIGUCHI, TAKAYUKI SHIROYAMA, HIDEKAZU SUZUKI, TAKAKO INOUE, MOTOHIRO TAMIYA, TOMONORI HIRASHIMA, FUMIO IMAMURA, SHINJI ATAGI
Anticancer Research Oct 2017, 37 (10) 5885-5891;
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