Multicenter phase I/II study of nivolumab combined with paclitaxel … · 2020. 12. 1. · Author Manuscript Published OnlineFirst on December 1, 2020; DOI: 10.1158/1078-0432.CCR-20-3559

1

Original Article 1

Multicenter phase I/II study of nivolumab combined with paclitaxel plus ramucirumab 2

as second-line treatment in patients with advanced gastric cancer 3

4

Takako Eguchi Nakajima1,2)

, Shigenori Kadowaki3)

, Keiko Minashi4)

, Tomohiro 5

Nishina5)

, Takeharu Yamanaka6)

, Yuichiro Hayashi7)

, Naoki Izawa1)

, Kei Muro3)

, 6

Shuichi Hironaka4,8)

, Takeshi Kajiwara5)

, Yutaka Kawakami9,10)

7

8

1Department of Clinical Oncology, St. Marianna University School of Medicine, 9

Kawasaki, Japan 10

2Kyoto Innovation Center for Next Generation Clinical Trials and iPS Cell Therapy, 11

Kyoto University Hospital, Kyoto, Japan 12

3Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan 13

4Clinical Trial Promotion Department, Chiba Cancer Center, Chiba, Japan. 14

5Department of Gastrointestinal Medical Oncology, National Hospital Organization 15

Shikoku Cancer Center, Matsuyama, Japan 16

6Department of Biostatistics, Yokohama City University School of Medicine, 17

Yokohama, Japan 18

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2

7Division of Pathology, Keio University School of Medicine, Tokyo, Japan 1

8Department of Medical Oncology and Hematology, Oita University Faculty of 2

Medicine, Oita, Japan 3

9Division of Cellular Signaling, Institute for Advanced Medical Research, Keio 4

University School of Medicine, Tokyo, Japan 5

10Department of Immunology, International University of Health and Welfare School of 6

Medicine, Narita, Japan 7

8

Running Title: Nivolumab/paclitaxel/ramucirumab for advanced gastric cancer 9

Key words: gastric cancer; nivolumab; paclitaxel; ramucirumab; phase II 10

Funding: This work was supported by Ono Pharmaceutical Co., Ltd. 11

12

Correspondence: 13

Prof. Takako Eguchi Nakajima, Kyoto Innovation Center for Next Generation Clinical 14

Trials and iPS Cell Therapy, Kyoto University Hospital, 54 Kawaharacho, Shogoin, 15

Sakyo-ku Kyoto, 606-8507, Japan. 16

Tel: +81-75-751-4756 17

Fax: +81-75-751-4732 18

E-mail: [email protected] 19



mailto:[email protected]://clincancerres.aacrjournals.org/

3

Disclosure 1

Dr. Nakajima reports grants from Ono Pharmaceutical Co. during the conduct of the 2

study; personal fees from Mochida Pharmaceutical, personal fees from Celltrion 3

Healthcare Japan, grants and personal fees from Taiho Pharmaceutical Co., personal 4

fees from Merck Serono Co., grants and personal fees from Chugai Pharmaceutical Co., 5

grants and personal fees from Takeda Pharmaceutical Co., grants and personal fees from 6

Sanofi K.K., grants and personal fees from Daiichi Sankyo Co., grants and personal fees 7

from Eli Lilly Japan K.K., grants and personal fees from Nippon Kayaku Co., grants 8

and personal fees from Ono Pharmaceutical Co., grants and personal fees from MSD 9

K.K., personal fees from Sawai Pharmaceutical Co., personal fees from Bayer Yakuhin, 10

personal fees from Bristol-Myers Squibb, personal fees from Teijin Pharma, personal 11

fees from Pfizer Japan Inc., personal fees from Novartis Japan, personal fees from 12

Yakult Honsha Co., personal fees from Nipro Co, grants from Astellas Pharma Inc., 13

grants from Sumitomo Dainippon Pharma Co., grants from Eisai Co, and grants from 14

Solasia Pharma K.K., outside the submitted work. 15

Dr. Kadowaki reports grants and personal fees from Ono Pharmaceutical Co. during the 16

conduct of the study; grants and personal fees from Lilly, grants and personal fees from 17

Chugai Pharmaceutical Co., personal fees from Bayer, personal fees from Daiichi 18




4

Sankyo, personal fees from Bristol-Myers Squibb, personal fees from Yakult, personal 1

fees from Eisai, personal fees from Merk KGaA, grants from MSD, grants from 2

Nobelpharma, and grants from Taiho Pharmaceutical Co., outside the submitted work. 3

Dr. Minashi reports grants from Ono Pharmaceutical Co. during the conduct of the 4

study. 5

Dr. Nishina reports grants and personal fees from Taiho Pharmaceutical Co., grants and 6

personal fees from Chugai Pharmaceutical Co., grants from Daiichi Sankyo, grants from 7

MSD, grants and personal fees from Ono Pharmaceutical Co., grants and personal fees 8

from Bristol-Myers Squibb, grants and personal fees from Lilly Pharma, and grants 9

from Sumitomo Dainippon Pharma Co., outside the submitted work. 10

Dr. Yamanaka reports grants and personal fees from Takeda Pharmaceutical, grants and 11

personal fees from Chugai Pharmaceutical Co., grants and personal fees from 12

Boehringer Ingelheim, grants and personal fees from Taiho Pharmaceutical Co., grants 13

and personal fees from Daiichi Sankyo, grants from Ono Pharmaceutical Co., grants and 14

personal fees from Bayer, grants from Merck Serono, grants from Astellas, grants from 15

Eli Lilly, personal fees from Pfizer, personal fees from Sysmex, personal fees from 16

Huya Biosciences, and personal fees from Gilead Sciences, outside the submitted work. 17




5

Dr. Hayashi reports grants from Ono Pharmaceutical Co. during the conduct of the 1

study. 2

Dr. Izawa reports grants from Ono Pharmaceutical Co. during the conduct of the study 3

and outside the submitted work. 4

Dr. Muro reports grants from Ono Pharmaceutical Co. during the conduct of the study; 5

grants and personal fees from Ono Pharmaceutical Co., grants and personal fees from 6

Sanofi, grants from Daiichi Sankyo, grants from Parexel International, grants from 7

Shionogi Pharma, grants from Sumitomo Dainippon Pharma Co., grants from MSD, 8

grants from Pfizer, grants from Mediscience Planning, grants from Solasia Pharma, 9

personal fees from Eli Lilly, personal fees from Chugai Pharmaceutical Co., personal 10

fees from Takeda Pharmaceutical, personal fees from Taiho Pharmaceutical Co., 11

personal fees from Bristol-Myers Squibb, and personal fees from Bayer, outside the 12

submitted work. 13

Dr. Hironaka reports personal fees from Bristol-Myers Squibb Japan, personal fees from 14

Ono Pharma, personal fees from Taiho Pharmaceutical, personal fees from Yakult 15

Honsha, personal fees from Daiichi Sankyo, personal fees from Lilly, personal fees 16

from Chugai Pharmaceutical Co., personal fees from Nippon Kayaku, personal fees 17




6

from Tsumura & Co, personal fees from Sanofi, personal fees from Merck, personal 1

fees from AstraZeneca, and personal fees from MSD K.K., outside the submitted work. 2

Dr. Kajiwara reports grants from Ono Pharmaceutical Co. during the conduct of the 3

study; personal fees from Chugai Pharmaceutical Co., personal fees from Taiho 4

Pharmaceutical Co.,, personal fees from Bristol-Myers Squibb, personal fees from 5

Merck Biopharma Co., Ltd., and personal fees from Kyowa Hakko Kirin Co., Ltd., 6

outside the submitted work. 7

Dr. Yutaka Kawakami reports grants from Ono Pharmaceutical Co. during the conduct 8

of the study. 9

10

Word count excluding references, tables, and figure legends: 4665 11

Number of figures: 4 12

Number of tables: 2 13

Supplemental Materials: 4 14

15

16




7

Translational relevance 1

Here we report the first study (phase I/II; 43 patients) showing promising efficacy of 2

nivolumab combined with paclitaxel plus ramucirumab as second-line treatment for 3

advanced gastric cancer: 12- and 18-month overall survival rates of 55.8% and 32.1% 4

were observed, higher than a previous trial of paclitaxel plus ramucirumab. The most 5

common adverse events were hematotoxicities, and the frequency and grade of 6

immune-related adverse events were manageable. Combined with the recently reported 7

phase III studies comparing nivolumab plus chemotherapy vs chemotherapy alone in 8

first-line treatment for advanced gastric cancer, CheckMate-649 and ATTRACTION-4 9

(ONO-4538-37), this study will determine the future therapeutic direction of 10

immune-checkpoint inhibitors for advanced gastric cancer. 11

12




8

ABSTRACT 1

Purpose: We conducted a phase I/II study to investigate the safety and efficacy of 2

nivolumab (NIVO) with paclitaxel (PTX) plus ramucirumab (RAM). 3

Experimental Design: Patients with advanced gastric cancer (AGC) refractory to 4

first-line chemotherapy were included. Patients received NIVO (3 mg/kg on days 1 and 5

15) combined with PTX (80 mg/m2 on days 1, 8, and 15) and RAM (8 mg/kg on days 1 6

and 15) every 4 weeks. After feasibility evaluation in 6 patients (phase I), 37 additional 7

patients were enrolled to the phase II with the primary endpoint of 6-month 8

progression-free survival (PFS) rate with two-sided 80% CI. The combined positive 9

score (CPS) was defined as the number of programmed death-ligand 1-positive cells 10

divided by the total number of viable tumor cells, multiplied by 100. 11

Results: Forty-three patients were enrolled. Of these, 60.5% had CPS≥1. Dose-limiting 12

toxicities were observed in 2 patients, and the recommended dose was determined as 13

level 1. Thirty-nine (90.7%) patients experienced treatment-related adverse events ≥ 14

grade 3 and 14 (32.6%) patients experienced immune-related adverse events ≥ grade 3. 15

The overall response rate was 37.2% (95%CI, 23.0%–53.5%) and the 6-month PFS rate 16

was 46.5% (80% CI, 36.4%–55.8%) (P=0.067). Median survival time was 13.1 months 17




9

(95%CI, 8.0–16.6 months): 13.8 months (95%CI, 8.0–19.5 months) in CPS≥1 patients 1

and 8.0 months (95%CI, 4.8–24.1 months) in CPS

10

Introduction 1

Gastric cancer (GC) reportedly harbors the fifth highest rate of somatic mutations 2

among major cancer types.1 Programmed death-ligand 1 (PD-L1) and its receptor, 3

programmed cell death-1 (PD-1), are overexpressed in GC,2,3

and on T-cells in GC, 4

respectively.4 However, the efficacy of anti-PD-1/PD-L1 antibodies in treating 5

advanced GC (AGC) is limited. Although nivolumab (NIVO), a human monoclonal 6

IgG4 antibody targeting PD-1, confers a survival benefit as salvage therapy for AGC 7

patients and is established standard treatment, the overall response rate (ORR) was only 8

11% in the ATTRACTION-2 trial.5 Even as second-line treatment, pembrolizumab 9

targeting PD-1 was not more efficacious than paclitaxel (PTX) alone in the 10

KEYNOTE-061 trial6 – median progression-free survival (PFS) was 1.5 months 11

(95%CI, 1.4–2.0) for pembrolizumab and 4.1 months (95%CI, 3.1–4.2) for PTX (hazard 12

ratio 1.27, 95%CI, 1.03–1.57). The standard second-line regimen is PTX plus 13

ramucirumab (RAM), an IgG1 anti-vascular endothelial growth factor receptor 2 14

(VEGFR-2) antibody that demonstrated superiority to PTX alone in PFS and overall 15

survival (OS) in the RAINBOW trial.7 16

As first-line treatment, pembrolizumab showed noninferiority in OS to 17

chemotherapy of cisplatin and fluoropyrimidines for combined positive score (CPS) ≥1 18




11

AGC tumors in the KEYNOTE-062 trial.8 However, survival in the pembrolizumab arm 1

was lower that in the chemotherapy-only arm at approximately 1 year from the start of 2

treatment, indicating that pembrolizumab is not optimal first-line treatment for all 3

patients. However, the survival curve of the combination of pembrolizumab and 4

chemotherapy in the KEYNOTE-062 trial almost overlapped in the early period and 5

was superior in the later period to that in the pembrolizumab arm for CPS ≥1 tumors, 6

although statistical superiority was not demonstrated. Conversely, NIVO combined with 7

chemotherapy in the first-line setting recently showed significant superiority to 8

chemotherapy alone in both OS and PFS in patients with CPS ≥5 tumors (CheckMate 9

649 study).9 However, in the ATTRACTION-4 (ONO-4538-37) trial conducted in 10

Japan, South Korea, and Taiwan, NIVO combined with chemotherapy in the first-line 11

could not show superiority to chemotherapy alone in OS in all patients.10

These findings 12

suggest that chemotherapy might overcome resistance to pembrolizumab or only add 13

patients who respond to chemotherapy but not to pembrolizumab. 14

A synergistic anti-tumor effect of simultaneous blockade of PD-1 and taxanes such 15

as PTX has been reported. Low-dose PTX promotes Toll-like receptor 4-dependent 16

maturation of dendritic cells (DCs) and enhances antigen-specific, 17

interferon-gamma-secreting CD8(+) T-cells in vivo.11

On the other hand, simultaneous 18




12

blockade of PD-1 and VEGFR-2 enhanced T-cell recruitment, activated local immune 1

status, and induced synergistic anti-tumor effects.12

These findings support the 2

development of a combination regimen of NIVO and PTX plus RAM, the standard 3

second-line treatment for AGC.7 4

We conducted a multicenter phase I/II study of NIVO and PTX plus RAM, 5

registered as UMIN-CTR (UMIN000025947). 6

7

Materials and Methods 8

Patients 9

Eligibility criteria included age ≥20 years; Eastern Cooperative Oncology Group 10

(ECOG) performance status (PS) of 0 or 1; histologically verified gastric 11

adenocarcinoma (papillary, tubular, or poorly differentiated), signet-ring cell carcinoma, 12

mucinous adenocarcinoma, or hepatoid adenocarcinoma; recurrence more than 6 13

months after completion of postoperative adjuvant chemotherapy or patients with stage 14

IV disease who received one prior systemic chemotherapy of platinum and 15

fluoropyrimidine doublet chemotherapy (patients with recurrence within 6 months after 16

completion of postoperative adjuvant chemotherapy of platinum and fluoropyrimidine 17

doublet chemotherapy were eligible); at least one measurable lesion; preserved organ 18




13

function, including neutrophil count ≥1500/mm3, platelet count ≥100000/mm

3, 1

hemoglobin ≥8.0 g/dL, aspartate aminotransferase (AST) and alanine aminotransferase 2

(ALT) ≤100 U/L, total bilirubin ≤1.5 mg/dL and serum creatinine ≤1.5 mg/dL, and 3

prothrombin time-international normalized ratio (PT-INR) ≤1.5; one of the following 4

conditions: (i) urinary protein with a negative (−) or 1+ result or (ii) where urinary 5

protein is 2+ or higher, 24-hour urine protein must be ≤1 g/24 hours; and adequate 6

blood pressure control ( two antihypertensive agents and systolic and diastolic blood 7

pressures ≤150 and 90 mmHg, respectively). Exclusion criteria included previous 8

administration of anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-CTLA-4 antibodies, 9

or other T-cell suppression therapy; anti-cancer treatment such as chemotherapy, 10

molecular-targeted therapy, immunotherapy, and radiotherapy, administered within 14 11

days before enrollment; systemic corticosteroids at prednisolone-equivalent doses of 12

>10 mg/day (except when administered temporarily) or immunosuppressive agents 13

administered within 14 days before enrollment; active multiple cancers; active infection; 14

uncontrolled complications such as heart disease, pulmonary fibrosis, or active 15

pneumonitis; and pregnancy or lactation. Written informed consent was obtained from 16

each patient before the initiation of study procedures. The institutional review boards of 17

all participating institutions approved the study protocol, which was conducted 18




14

according to the Declaration of Helsinki and Japanese Good Clinical Practice 1

guidelines. 2

3

Study design and treatment 4

This was a multicenter, open-label, nonrandomized phase I/II study with dose 5

de-escalation in the phase I part and cohort expansion in the phase II part. In the phase I 6

part, we assessed dose-limiting toxicity (DLT) and determined the recommended dose 7

(RD) of NIVO combined with PTX plus RAM. The phase I part, starting from level 1, 8

followed a modified 3 + 3 design and included two dose level cohorts (Figure 1). 9

Toxicity profiles of NIVO and PTX plus RAM did not generally overlap. We therefore 10

selected a dose de-escalation design starting from a standard dose and schedule 11

described previously for NIVO,5 combined with the clinically established fixed dose 12

and schedule of PTX plus RAM10

(Figure 1). If DLT was observed in 0–2 patients in 13

level 1, it was determined as the RD for phase II. If DLTs were observed in ≥3 patients 14

of a total of 6 patients in level 1, level 0 would be evaluated. If DLTs were observed in 15

0–2 patients of the total 6 patients in level 0, it was determined as the RD for phase II. If 16

DLTs were observed in ≥3 patients in level 0, the study would be discontinued. Dose 17

de-escalation decisions were made by the primary investigator and an Independent Data 18




15

Monitoring Committee, based on safety and other parameters in phase I. Eligible 1

patients received protocol treatment on day 1 of a 28-day cycle and continued until 2

disease progression or unacceptable toxicity. 3

DLTs were assessed in cycle 1 with the following definitions: (i) Grade 4 4

neutropenia, maintained for at least 8 days; (ii) febrile neutropenia; (iii) Grade 4 5

thrombocytopenia; (iv) Grade 2 or higher pneumonitis; (v) uncontrolled, Grade 2 or 6

higher uveitis, eye pain, or optic nerve disorder; (vi) Grade 3 or higher nausea, vomiting, 7

anorexia or diarrhea, uncontrolled by supporting treatment; (vii) Grade 3 8

non-hematotoxicity other than (v), (vi), or electrolyte abnormalities; (viii) one or more 9

of the drugs included in combination therapy not meeting the cycle initiation criteria, 10

and 28 days elapsed since the scheduled initiation date for the second cycle without 11

initiation being possible; (xi) per-protocol treatment discontinued due to adverse 12

reactions other than (i) to (viii), above. 13

The primary objective of the second stage was to assess the clinical efficacy of 14

NIVO combined with PTX plus RAM as second-line treatment for AGC. Key 15

secondary objectives included safety assessment at the RD level. 16

17




16

Assessments 1

Adverse events (AEs) were classified according to Common Terminology Criteria for 2

Adverse Events (CTCAE) version 4.0. The AE reporting period was from day 1 of 3

cycle 1 until 30 days after the last dose of any protocol drugs. CT scans with 4

≤5-mm-thick sections were performed for tumor assessment every 4 weeks for 12 5

weeks from day 1 of cycle 1 and every 8 weeks thereafter, evaluated based on Response 6

Evaluation Criteria in Solid Tumors (RECIST) version 1.1.13

Physical examinations and 7

laboratory tests were performed on days 1, 8, and 15. Serious AEs were death; 8

life-threatening AEs; AEs requiring hospitalization or prolongation of hospitalization 9

for treatment; AEs leading to permanent or major disability or dysfunction; AEs leading 10

to congenital abnormalities for later generations; and AEs judged as the result of 11

another medically important condition. 12

For biomarker analyses, tumor tissues were obtained before treatment initiation 13

(either the archival or taken immediately just before the study enrollment) for 14

immunohistochemical analysis of human epidermal growth factor receptor 2 (HER2), 15

Mismatch repair (MMR) proteins of MutS Homolog 6 (MSH6) and PMS1 Homolog 2 16

(PMS2), and PD-L1. PD-L1 tumor expression was examined with the Dako PD-L1 17

immunohistochemistry (IHC) 22C3 pharmDx. The tumor proportion score (TPS) was 18




17

the percentage of viable tumor cells showing partial or complete membrane staining, 1

and positivity was defined as staining in 1% of tumor cells. CPS was the number of 2

PD-L1 positive cells (tumor cells, macrophages, and lymphocytes) divided by the total 3

number of viable tumor cells, multiplied by 100. EB-virus encoded small RNAs 4

(EBER) were analyzed using in situ hybridization. 5

6

Statistical analysis 7

The primary endpoint of the phase I part was RD determination based on DLT 8

evaluation. The DLT analysis population included all patients in phase I who completed 9

the DLT evaluation period of 28 days after study treatment initiation. The secondary 10

endpoint of phase I was AE rate. The safety population included all patients who 11

received any dose of protocol drugs. The primary endpoint of the phase II part was 12

6-month PFS rate with two-sided 80% CI, which was estimated for the efficacy analysis 13

populations (full analysis set [FAS] and per-protocol set) by the Kaplan–Meier method. 14

Greenwood's formula for variance was used to establish the CI. In addition, an 15

appropriate test statistical value was established, and the P-value was calculated for a 16

test relating to the null hypothesis, which was that the 6-month PFS rate was 35%: it 17

had been reported 36% in PTX+RAM arm in the RAINBOW trial.7 18




18

Secondary endpoints in the phase II part were ORR, disease control rate (DCR), 1

PFS, OS, and AE rate. DCR was the proportion of patients who experienced complete 2

response (CR), partial response (PR), or stable disease (SD). An accurate CI based on 3

the binomial distribution was used for the two-sided 95%CI of ORR and DCR. PFS and 4

OS were estimated for the efficacy analysis populations by the Kaplan–Meier method. 5

PFS was the time from enrollment to the first documentation of disease progression or 6

death. For surviving patients without documented disease progression, data on PFS 7

were censored on the date that the absence of progression was confirmed. PFS in 8

patients who discontinued protocol treatment due to toxicity was the time to disease 9

progression in subsequent therapies or to death. OS was the duration from enrollment to 10

death from any cause. All statistical analyses were performed using SAS software 11

version 9.4 (TS1M3; SAS Institute Inc., Cary, NC, USA). 12

13

Results 14

Patient characteristics and treatment 15

A total of 43 patients (6 patients in phase I and 37 patients in phase II) were enrolled 16

between February 2017 and July 2018, and all patients were included in the FAS. Table 17

1 summarizes the baseline characteristics in the FAS. The majority of patients were 18




19

male, with an age range of 38–78 years. Twenty-two patients (51.2%) had PS of 0; TPS 1

was positive in 6 patients (14.0%); and CPS was ≥1 in 26 patients (60.5%) and ≥10 in 7 2

patients (16.3%). MMR and EBER were positive in 0 and 4 patients (9.3%), 3

respectively. 4

Median treatment duration was 4.6 months (95%CI, 2.8–6.2). Median number of 5

administrations of PTX, RAM, and NIVO was 7 (range: 1–58), 9 (range: 1–49), and 9 6

(range: 1–44), respectively. Five patients (11.6%) discontinued protocol treatment due 7

to toxicities: two PTX-related toxicities and four NIVO-related toxicities (1 patient had 8

both PTX- and NIVO-related toxicities). By final data cutoff of Jan 2019, the median 9

follow-up was 16.8 months and protocol treatment was ongoing in 1 patient. 10

Post-protocol treatment was administered to 31 patients (72.1%). Regimens containing 11

irinotecan were administered to 26 patients (60.5%) (Supplementary Table S1). 12

13

Dose-limiting toxicities, recommended dose, and safety 14

All 6 patients in the phase I part completed the DLT evaluation period of 28 days after 15

study treatment initiation. DLTs (febrile neutropenia and neutropenia over a period of 8 16

days) were observed in 2 of 6 patients in level 1, and the RD was determined at level 1. 17

No patients were enrolled at level 0, and all patients included in the phase II part were 18




20

treated at the RD. Thirty-nine (90.7%) patients experienced grade ≥3 treatment-related 1

AEs (Table 2). The most common grade ≥3 AE was neutrophil count decrease (33 2

patients, 76.7%), while febrile neutropenia was observed in 7 patients (16.3%). 3

Fourteen (32.6%) patients experienced grade ≥3 immune-related AEs, with all 4

frequencies 5%. There was one treatment-related death from thrombocytopenia. 5

6

Efficacy 7

Clinical courses of all patients are shown in Figure 2. At the primary analysis (January 8

2019, median follow-up time of 8.2 months), 23 PFS events (53.5%) had occurred. 9

Six-month PFS was 46.5% (80% CI, 36.4–55.8; P=0.067), which means primary 10

endpoint was met (Figure 3A). At final analysis with a median follow-up time of 23.2 11

months (95%CI, 17.4–28.0), OS at 12 and 18 months was 55.8% (95%CI, 39.8–69.1) 12

and 32.1% (95%CI, 18.2–46.8), respectively (Figure 3B). Median PFS was 5.1 months 13

(95%CI, 4.5–6.5 months): 6.4 months (95%CI, 4.2–7.9 months) in CPS≥1 patients and 14

5.1 months (95%CI, 2.6–6.7 months) in CPS

21

(Supplementary Figure S1(B)); and 5.8 months (95%CI, 4.2–7.9 months) in PS 0 1

patients and 4.9 months (95%CI, 3.2–6.4 months) in PS 1 patients (Figure 4B). 2

Thirty-two OS events (74.4%) occurred and median survival time (MST) was 13.1 3

months (95%CI, 8.0–16.6 months): 13.8 months (95%CI, 8.0–19.5 months) in CPS≥1 4

patients and 8.0 months (95%CI, 4.8–24.1 months) in CPS

22

prognosis with the study treatment regimen. Prognostic and predictive effects of PD-L1 1

expression by CPS and TPS were not identified. 2

3

Discussion 4

Here we report the first study showing promising efficacy of NIVO combined with PTX 5

plus RAM as second-line treatment for AGC, in which the primary endpoint was met. 6

RD was determined at the standard doses and schedules of PTX plus RAM and NIVO. 7

The most common AEs were hematotoxicities, and the frequency and grade of 8

immune-related AEs were manageable. 9

VEGF-A impairs DC maturation to induce PD-L1 expression on DCs and activate 10

regulatory T-cells (Tregs) via neuropilin-1 (NRP-1).14

Moreover, VEGF-A induces the 11

accumulation of myeloid-derived suppressor cells, immature DCs, Tregs, and 12

tumor-associated macrophages,15

which are potential mechanisms for treatment failure 13

of PD-1 blockade.16-21

Immunosuppressive cell-related markers, such as forkhead box 14

P3 (Foxp3) or colony-stimulating factor 1 receptor (CSF1R), are more highly expressed 15

in the PD-L1-positive than the PD-L1-negative population.22

Therefore, synergistic 16

anti-tumor effects induced by simultaneous blockade of VEGF-A and PD-1 have been 17

investigated. Concomitant administration of a VEGF-A inhibitor and an anti-PD-1 18




23

antibody produced strong synergistic anti-tumor activity against tumors showing high 1

VEGF-A production.23

Additionally, when VEGF was inhibited in renal cell carcinoma 2

using a tyrosine kinase inhibitor, intra-tumor PD-L1 and Foxp3 expression were 3

markedly reduced.24

Combination therapy of anti-angiogenesis treatment and 4

PD-1/PD-L1 blockade have subsequently become standard therapy in non-small cell 5

and renal cell carcinoma.25-28

6

RAM has been shown to reduce Tregs in local tumors of patients with GC,29

and 7

showed promising activity in combination with pembrolizumab in patients with gastric 8

or gastro-esophageal junction adenocarcinoma whose disease had progressed on one or 9

two lines of previous therapy (N=41); MST was 5.9 months, 18-month survival was 10

22%, median PFS was 2.5 months, and ORR was 7%.30

The combination of regorafenib 11

80 mg plus NIVO had a manageable safety profile and encouraging anti-tumor activity 12

in patients with GC who had received ≥2 previous lines of chemotherapy (N=25); 13

median PFS was 5.6 months and ORR was 44%.31

14

The survival data in the pembrolizumab arm of the KEYNOTE-062 trial of 15

first-line treatment for AGC showed that the anti-tumor effect of cytotoxic agents 16

remains important even in CPS≥1 AGC.7 Most previous reports on concomitant 17

treatment with cytotoxic anti-cancer agents and NIVO have been in lung cancer. In the 18




24

Impower150 trial,25

addition of atezolizumab, an anti-PD-L1 antibody, to carboplatin 1

plus PTX and bevacizumab as first-line treatment for metastatic non-squamous 2

non-small cell lung cancer resulted in significant improvements in PFS and OS 3

regardless of PD-L1 expression, indicating an favorable association of PTX and 4

VEGF-A inhibition with anti-PD-L1 blockade. Of note, Kaplan–Meier curves of PFS 5

and OS in the arms with concomitant chemotherapy and PD-1/PD-L1 antibodies in the 6

KEYNOTE-062 and Impower150 trials showed that treatment benefits were delayed 7

and increased substantially after the median was reached. In our study, MST was 13.1 8

months, comparable with 11.4 months in Japanese patients receiving PTX plus RAM in 9

the RAINBOW trial.32

Although cross-trial comparisons require careful interpretation, 10

12- and 18-month OS in our trial were 55.8% (95%CI, 39.8–69.1) and 32.1% (95%CI, 11

18.2–46.8), respectively, which was better than that among Japanese patients receiving 12

PTX plus RAM in the RAINBOW trial. “The numbers of patients were small in the 13

CPS subgroups, PD-L1 expression may have had some influence on clinical outcome in 14

this combination regimen. 15

Very recently, NIVO combined with chemotherapy in the first-line showed 16

significant superiority to chemotherapy alone in OS both in CPS ≥5 AGC and in CPS 17

≥1 AGC patients (CheckMate 649 study).9 Although the treatment benefit of the 18




25

combination arm compared with the chemotherapy-alone arm increased gradually in 1

both CPS ≥5 AGC and CPS ≥1 AGC, the Kaplan–Meier curves were more 2

differentiated in CPS ≥5 AGC than in CPS ≥1 AGC. Furthermore, the HR was lower in 3

CPS ≥5 AGC (0.71 [98.4% CI, 0.59–0.86]) than in CPS ≥1 AGC (0.77 [98%.4% CI, 4

0.64–0.92]). These data may indicate that CPS has some impact on clinical outcome in 5

AGC. However, in the ATTRACTION-4 (ONO-4538-37) trial conducted in Asia, the 6

Kaplan–Meier curves of OS in both arms including CPS

26

patients were included (Figure 2), and efficacy of the regimen thus requires further 1

investigation in this subgroup. Although HER2-positive patients receiving NIVO in the 2

ATTRACTION-2 trial33

and HER2-positive patients receiving cabazitaxel, a novel 3

next-generation taxane, in the phase II study recently reported34

tended to have better 4

prognosis, HER2 positivity was not a prognostic marker in subset analyses of OS in the 5

present study (Supplementary Table S2 and Figure S2). 6

NIVO with PTX plus RAM demonstrated promising anti-tumor activity with 7

manageable toxicities as second-line treatment for AGC patients. Further biomarker 8

results from this study will be reported at a later date and may clarify the characteristics 9

of patients suitable for NIVO with PTX plus R 10

11

12

Acknowledgments 13

We thank the participants and their families and our collaborators who contributed to 14

the study: Dr. Toshiyuki Misumi for assistance with data analysis; the members of the 15

Independent Data Monitoring Committee: Dr. Ichinosuke Hyodo, Dr. Chigusa 16

Morizane, and Dr. Kan Yonemori; the members of St. Marianna University Data 17

Center; and ASCA Corporation for editing a draft of this manuscript. 18

19

20




27

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35

Tables 1

Table 1. Patient characteristics 2

N=43 (%)

Sex Male 36 (83.7)

Age (years) Median (range) 66 (38–78)

ECOG PS 0 22 (51.2)

1 21 (48.8)

Histology pap/tub1/tub2 21 (48.8)

por1/por2/sig 19 (44.2)

Other 3 (7.0)

Primary tumor Gastric 38 (88.4)

Esophago-gastric junction 15 (11.6)

Disease status Stage IV 32 (74.4)

Recurrence 11 (25.6)




36

Gastrectomy Total gastrectomy 5 (11.6)

Partial gastrectomy 7 (16.2)

Remnant gastrectomy 2 (4.6)

None 29 (67.4)

Metastatic site 1 9 (20.9)

2 22 (51.2)

≥3 12 (27.9)

Peritoneal metastasis Positive 26 (60.5)

Negative 17 (39.5)

HER2 Negative 32 (74.4)

Positive 11 (25.6)

TPSb Positive 6 (14.0)

Negative 33 (76.7)

Unknowna 4 (9.3)




37

CPSc

38

dDNA MMR protein (MutS Homolog 6 and PMS1 Homolog 2) expression was 1

analyzed by immunohistochemistry. 2

eEBER was analyzed using in situ hybridization. 3

Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance 4

status; HER2, human epidermal growth factor receptor 2; TPS, tumor proportion score; 5

CPS, combined positive score; MMR, mismatch repair; EBER, EB-virus encoded small 6

RNAs. 7

8

9




39

Table 2. Treatment-related adverse events (≥ 15% frequency and additional 1

immune-related adverse events) 2

Grade

1 2 3 4 5 All (%) 3–5 (%)

Neutrophil count decreased 0 6 18 15 0 39 (90.7) 33 (76.7)

White blood cell decreased 1 5 17 3 0 26 (60.5) 20 (46.5)

Epistaxis 18 0 1 0 0 19 (44.2) 1 (2.3)

Anorexia 8 8 2 0 0 18 (41.9) 2 (4.7)

Peripheral sensory neuropathy 6 11 1 0 0 18 (41.9) 1 (2.3)

Myalgia 15 1 1 0 0 17 (39.5) 1 (2.3)

Malaise 12 4 1 0 0 17 (39.5) 1 (2.3)

Alopecia 19 7 0 0 0 26 (60.5) 0 (0.0)

Anemia 1 8 6 0 0 15 (34.9) 6 (14.0)

Diarrhea 8 4 3 0 0 15 (34.9) 3 (7.0)

Mucositis oral 12 2 1 0 0 15 (34.9) 1 (2.3)

Fatigue 5 7 2 0 0 14 (32.6) 2 (4.7)

Rash maculo-papular 9 4 0 0 0 13 (30.2) 0 (0.0)

Lymphocyte count decreased 0 4 7 1 0 12 (27.9) 8 (18.6)




40

Platelet count decreased 3 6 2 0 1 12 (27.9) 3 (7.0)

Proteinuria 0 11 0 0 0 11 (25.6) 0 (0.0)

Vomiting 8 2 1 0 0 11 (25.6) 1 (2.3)

Arthritis 8 1 1 0 0 10 (23.3) 1 (2.3)

Hypertension 3 9 2 0 0 9 (20.9) 2 (4.4)

Dysgeusia 8 0 0 0 0 8 (18.6) 0 (0.0)

Nausea 7 2 0 0 0 7 (16.3) 0 (0.0)

Febrile neutropenia 0 0 6 1 0 7 (16.3) 7 (16.3)

Skin disorders 6 1 0 0 0 7 (16.3) 0 (0.0)

Additional immune-related adverse events

Hypothyroidism 2 4 0 0 0 6 (14.0) 0 (0.0)

Hyperthyroidism 5 0 0 0 0 5 (11.6) 0 (0.0)

Adrenal insufficiency 1 0 1 0 0 2 (4.7) 1 (2.3)

Endocrine disorders

Isolated adrenocorticotropic hormone

deficiency

0 1 2 0 0 3 (7.0) 2 (4.7)

Panhypopituitarism 0 1 0 0 0 1 (2.3) 0 (0.0)




41

Thyroid stimulating hormone decreased 1 0 0 0 0 1 (2.3) 0 (0.0)

Thyroiditis 1 0 0 0 0 1 (2.3) 0 (0.0)

Metabolism disorder: Type 1 diabetes

mellitus

0 1 0 0 0 1 (2.3) 0 (0.0)

Pneumonitis 2 3 0 0 0 5 (11.6) 0 (0.0)

Thrombotic thrombocytopenic purpura 0 0 1 0 0 1 (2.3) 1 (2.3)

1

2




42

Figure Legends 1

Figure 1. Study design and dose levels. 2

Figure 2. Swimmer plots by combined positive score. 3

Figure 3. Kaplan–Meier plots of (A) progression-free survival at the primary analysis 4

and (B) overall survival at the final analysis. 5

Figure 4. Kaplan–Meier plots at the final analysis of (A) progression-free survival by 6

combined positive score, (B) progression-free survival by performance status, (C) 7

overall survival by combined positive score, and (D) overall survival by performance 8

status. 9

10




Published OnlineFirst December 1, 2020.Clin Cancer Res Takako Eguchi Nakajima, Shigenori Kadowaki, Keiko Minashi, et al. patients with advanced gastric cancerpaclitaxel plus ramucirumab as second-line treatment in Multicenter phase I/II study of nivolumab combined with

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