Efficacy and safety of necitumumab and pembrolizumab combination therapy in patients with Stage IV non-small cell lung cancer

Journal Pre-proof Efficacy and safety of necitumumab and pembrolizumab combination therapy in patients with Stage IV non-small cell lung cancer Benjamin Besse, Pilar Garrido, Alexis B. Cortot, Melissa Johnson, Haruyasu Murakami, Anas Gazzah, Maciej Gil, Jaafar Bennouna

PII:

S0169-5002(20)30299-3

DOI:

https://doi.org/10.1016/j.lungcan.2020.02.003

Reference:

LUNG 6259

To appear in:

Lung Cancer

Received Date:

18 July 2019

Revised Date:

5 February 2020

Accepted Date:

11 February 2020

Please cite this article as: Besse B, Garrido P, Cortot AB, Johnson M, Murakami H, Gazzah A, Gil M, Bennouna J, Efficacy and safety of necitumumab and pembrolizumab combination therapy in patients with Stage IV non-small cell lung cancer, Lung Cancer (2020), doi: https://doi.org/10.1016/j.lungcan.2020.02.003

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier.

Efficacy and safety of necitumumab and pembrolizumab combination therapy in patients with Stage IV non-small cell lung cancer

Benjamin Bessea,b,* Pilar Garridoc; Alexis B. Cortotd; Melissa Johnsone; Haruyasu Murakamif;

a

Department of Cancer Medicine, Gustave Roussy, Villejuif, France; Paris-Sud University, Orsay, France;

ro

b

of

Anas Gazzahg; Maciej Gilh; Jaafar Bennounai

c

Medical Oncology Department, Hospital Universitario Ramón y Cajal, IRYCIS and CIBERONC,

-p

Madrid, Spain; dThoracic Oncology Department, Lille University Hospital, University of Lille,

re

Lille, France; e

Sarah Cannon Research Institute, Nashville, USA;

Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan;

lP

f

Drug Development Department, Gustave Roussy, Villejuif, France;

h

Eli Lilly, Polska, Warsaw, Poland;

i

ur na

g

Thoracic Oncology Unit, University Hospital of Nantes, Nantes, France

*Corresponding Author: Benjamin Besse, Department of Medical Oncology, Gustave Roussy,

Jo

114 rue Edouard Vaillant, Villejuif 94805, France; Tel: +33142114157; Fax: +33142115219; Email: [email protected]

Running Title: Combination necitumumab and pembrolizumab in second-line NSCLC

Highlights 

Efficacy and safety of necitumumab combined with pembrolizumab was assessed in advanced NSCLC



Pretreated NSCLC population had relatively high proportion of PDL1 negative patients



Modest benefits of combined necitumumab and pembrolizumab seen in patients with

Safety corresponded to individual profiles of both drugs, with no additive toxicities

-p

ro



of

NSCLC

ABSTRACT1

re

Objectives: Efficacy and safety of necitumumab when combined with pembrolizumab was

lP

assessed in patients with Stage IV non-small cell lung cancer (NSCLC) of squamous and nonsquamous histology, who had progressed after treatment with a platinum-based doublet.

ur na

Materials and Methods: This single-arm, multicenter, phase Ib study had a dose-finding phase, in which escalating doses of necitumumab (600 mg and 800 mg IV) were administered on Day 1 and 8 every 3 weeks (Q3W) in combination with pembrolizumab (200 mg IV) on Day 1 Q3W,

Jo

and expansion cohorts. Patients were treated until progressive disease (PD), toxicity requiring cessation, protocol noncompliance, or withdrawal of consent. Efficacy was evaluated by overall response rate (ORR).

1

Results: In 64 treated patients (32 patients [50%] were programmed death-ligand 1 [PD-L1] negative), confirmed ORR was 23.4% (95% confidence interval [CI] 13.8%–35.7%). Two patients (3.1%) had complete response (CR), 13 patients (20.3%) had partial response (PR), 26 patients (40.6%) had stable disease, 17 patients (26.6%) had PD, and 6 patients (9.4%) were not evaluable. Regardless of histology or PD-L1 status, median PFS (mPFS) was 4.1 months (95% CI 2.4–6.9 months) and OS at 6 months was 74.7% (61.5% – 83.9%). Confirmed disease control rate was

of

64.1% (95% CI 51.5–75.7). Patients with programmed death-ligand 1 (PD-L1) ≥1% had

ro

numerically improved ORR and median progression-free survival when compared with patients with PD-L1 negative cancer. No dose-limiting toxicities were recorded and the combination of

re

-p

necitumumab 800 mg with pembrolizumab 200 mg was considered tolerable.

Conclusion: Results suggest modest benefits of second-line necitumumab and pembrolizumab

lP

combination therapy in patients with Stage IV NSCLC. Safety profiles were consistent with class effects typical of epidermal growth factor receptor inhibitors and immunotherapies with no

Keywords

ur na

additive toxicities.

EGFR inhibitor, immune checkpoint inhibitor, advanced non-small cell lung cancer,

Jo

necitumumab, pembrolizumab

Abbreviations: AE, adverse event; AESI, adverse events of special interest; ALK, anaplastic lymphoma kinase; CI, confidence interval; CR, complete response; DCR, disease control rate; DLT, dose-limiting toxicity; DoR, duration of response; ECOG = Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; FISH, fluorescence in situ hybridization; IgG1, immunoglobulin G, subclass 1; IgG4, immunoglobulin G, subclass 4; IHC, immunohistochemistry; IV, intravenous; mAb, monoclonal antibody; mPFS, median progressionfree survival; MTD, maximum tolerated dose; NSCLC, non-small cell lung cancer; ORR, overall response rate; OS, overall survival;

PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; PD-L2, programmed death-ligand 2; PFS, progressionfree survival; PR, partial response; Q3W, every 3 weeks; TEAE, treatment-emergent adverse event; TKI, tyrosine kinase inhibitor

Trial Registration: ClinicalTrials.gov identifier: NCT02451930

1. Introduction

of

Immunotherapies such as pembrolizumab, nivolumab or atezolizumab are currently secondline treatment options for patients with non-small cell lung cancer (NSCLC) who relapse or are

ro

resistant to first-line therapies. Pembrolizumab is a humanized immunoglobulin G, subclass 4

-p

(IgG4) monoclonal antibody (mAb) that binds to the programmed cell death protein 1 (PD-1) receptor and blocks its interaction with programmed death-ligand 1 (PD-L1) and PD-L2, resulting

re

in the activation of T-cell-mediated immune responses against tumor cells [1]. Between 20% and 60% of NSCLC tumors of both squamous and nonsquamous histology have been shown to express

lP

PD-L1 [2, 3]. Pembrolizumab is indicated for the treatment of a number of cancers including as a single agent for the treatment of patients with metastatic NSCLC whose tumors express PD-L1

ur na

≥1% and who have disease progression on or after platinum-containing chemotherapy [4]. Pembrolizumab is also approved as monotherapy in the first-line treatment of patients with NSCLC expressing PD-L1 ≥1%, as well as in combination with platinum doublet chemotherapy

Jo

in both squamous and nonsquamous NSCLC [4]. While immune checkpoint inhibitors have improved the treatment of NSCLC, the patients more likely to respond are not well-characterized and many questions remain unanswered [5]. Epidermal growth factor receptor (EGFR) expression is detectable in up to 85% of patients with advanced metastatic NSCLC [6], the activation of which results in cell proliferation and tumor progression. Thus, novel treatment strategies combining immune checkpoint inhibitors with other EGFR-targeted therapies are appealing. Necitumumab is

a recombinant human mAb of the humanized immunoglobulin G, subclass 1 (IgG1), which blocks the ligand-binding site of the EGFR [7]. Based on the findings of the phase III SQUIRE (SQUamous NSCLC treatment with the Inhibitor of EGF REceptor) trial, necitumumab was approved by the US Food and Drug Administration for the first-line treatment of patients with metastatic squamous NSCLC, when used in combination with gemcitabine and cisplatin [8]. The

of

European Medicines Agency has also approved necitumumab in combination with gemcitabine

ro

and cisplatin for the treatment of EGFR-positive NSCLC.

The rationale for combining necitumumab and pembrolizumab for the treatment of NSCLC

-p

is based on the single-agent activity of both agents, and preclinical data suggesting that the

re

antitumor activity of EGFR antibodies can be attributed, at least in part, to various immune effector mechanisms [9-12]. Importantly, EGFR signaling has been shown to upregulate PD-L1 expression

lP

in lung cancer cells, suppressing T-cell function and triggering immune escape [9]. Treatment of cancer cells with EGFR IgG1 antibodies activates natural killer cells, which promote dendritic cell

ur na

maturation and the development of tumor antigen-specific T-cell immunity [11, 12]. However, it appears that EGFR mAb-driven immune activity initiates a negative feedback loop of immunosuppression via immune checkpoints; thus, inhibition of these mechanisms through immuno-oncology treatment is a logical therapeutic strategy to use in combination with EGFR-

Jo

directed mAb [13].

Considering their different, but potentially complimentary, mechanisms of action, the

combination of necitumumab and pembrolizumab was hypothesized to provide synergistic antitumor activity, without considerable additive toxicity. The purpose of this phase Ib study was

to assess the efficacy and safety of necitumumab when combined with pembrolizumab in patients with Stage IV NSCLC of squamous and nonsquamous histology, who had progressed after treatment with a platinum-based doublet. We also explored the potential relationship between EGFR- and PD-L1-expression, and treatment outcomes.

of

2. Methods 2.1 Design and patients

ro

This single-arm, multicenter, phase Ib study had a dose-finding phase (Part A) followed by an expansion cohort (Part B) and then dose confirmation in a Japanese cohort with the

-p

recommended dose from the part A (Part C; Fig. 1). The study was conducted at 16 investigative

re

sites in the United States, France, Japan (Part C), and Spain. Patients were at least 18 years old with histologically or cytologically confirmed Stage IV NSCLC, had measurable disease as

lP

defined by Response Evaluation Criteria In Solid Tumors (RECIST 1.1), and Eastern Cooperative Oncology Group (ECOG) performance status 0–1. Patients must have progressed after 1 platinum-

ur na

based chemotherapy regimen, and prior treatment with EGFR tyrosine kinase inhibitors (TKIs) and anaplastic lymphoma kinase (ALK) inhibitors was mandatory in patients with tumors that had EGFR-activating mutations or ALK translocations, respectively. Patients were also required to have archived tumor tissue for biomarker analysis. Key exclusion criteria were symptomatic brain

Jo

metastases, chest irradiation within 2 weeks of study drug administration, and history of thromboembolic events within 3 months of study enrollment.

The study was conducted in compliance with the Declaration of Helsinki, International Conference on Harmonisation Guidelines for Good Clinical Practice, and applicable local

regulations. The protocol was approved by the ethics committees of all participating centers and all patients provided written informed consent before study entry. 2.2 Treatments Part A followed a modified 3+3 design in which patients were treated in sequential cohorts of escalating doses of necitumumab in combination with a fixed dose of pembrolizumab 200 mg

of

administered as an intravenous (IV) infusion over 30 minutes on Day 1 every 3 weeks (Q3W), followed by necitumumab 600 mg or 800 mg IV over a minimum of 50 minutes on Day 1 and Day

ro

8 Q3W. The registered dose of necitumumab (800mg) was previously established in phase 1 studies. Based on principles of dose-finding studies with two novel agents, we used the full dose

-p

of the more active agent (pembrolizumab) and adjusted the dose of necitumumab based on the

re

safety considerations and started with dose level -1, which for necitumumab was 600mg (based on

lP

the original phase 1 study).

In Part B and Part C, the recommended necitumumab dose from Part A was given on Day

ur na

1 and Day 8 Q3W in combination with pembrolizumab 200 mg on Day 1 Q3W. At the time of study initiation, pembrolizumab was only approved at a mg/kg dosage. However, a 200 mg flat dose was used in this trial following advice that dosage was moving from mg/kg dosing to 200mg flat dose following discussions with the FDA. Patients were treated until progressive disease,

Jo

toxicity requiring cessation, protocol noncompliance, or withdrawal of consent.

2.3 Assessments

Dose-limiting toxicities (DLTs) were defined as treatment-related failure to administer ≥ 75% of the planned dose of necitumumab and pembrolizumab in Cycle 1 because of any toxicity, or delay >2 weeks in initiating Cycle 2 because of any treatment-related toxicity.

Tumor response was assessed radiographically according to RECIST 1.1, and an adaptation

ro

immunotherapeutic agents such as pembrolizumab (irRECIST) [14].

of

of RECIST that accounts for the unique tumor response characteristics seen with

Adverse events (AEs) were coded according to the Medical Dictionary for Regulatory

-p

Activities and graded with the National Cancer Institute Common Terminology Criteria for

re

Adverse Events version 4.0.

lP

Biomarker analysis was by immunohistochemistry (IHC) assay for EGFR and PD-L1 expression. PD-L1 was centrally assessed retrospectively using IHC 22C3 PharmDx assay

ur na

(Agilent, Santa Clara, California, USA) identifying patients with strongly positive (proportion score ≥50%), weak (proportion score 1-49%), or negative (proportion score ≤ 1%) PD-L1 expression. EGFR fluorescence in situ hybridization (FISH) testing was performed at the Lilly Clinical Diagnostics Laboratory (Indianapolis, USA). Categorization of tumors as EGFR FISH

Jo

positive or negative was based on the Colorado Classification [15].

2.4 Outcomes

The primary objective of Part A was to determine the maximum tolerated dose (MTD) of necitumumab at doses of 600 mg and 800 mg when combined with pembrolizumab 200 mg, as

measured by the number of patients with DLT in Cycle 1 (cycles were 21 days). The primary objective of Part B was to evaluate the efficacy of necitumumab in combination with pembrolizumab in terms of overall response rate (ORR), which was defined as the percentage of patients achieving partial response (PR) or complete response (CR) to therapy. In Part C, the safety

of

of necitumumab in combination with pembrolizumab was investigated in Japanese patients.

Secondary objectives were to determine disease control rate (DCR), duration of response

ro

(DoR), progression-free survival (PFS), and overall survival (OS). DCR was defined as the percentage of patients achieving a best overall response of stable disease, partial response (PR) or

-p

complete response (CR). DoR was defined as the time from the first documentation of CR or PR

re

to first radiographic documentation of objective progression or death from any cause. PFS was defined as the time from first dose date until the first radiographic documentation of objective

lP

progression. OS was defined as the time from first dose date until date of death from any cause.

ur na

Safety was assessed by clinical and laboratory significant events.

2.5 Statistical analyses

Approximately 66 patients were required to participate in Part A or Part B. A cohort of up to 12 treated patients (3–6 for Cohort 1 and 6 for Cohort 2) was considered adequate to evaluate

Jo

initial safety assessments supporting dose-escalation. Any patient who discontinued from the study before completing Cycle 1 was excluded from the DLT population, unless a DLT was observed. Patients who did not complete Cycle 1 for any reason other than DLT were replaced. The null hypothesis for the primary outcome of Part B was based on the assumption that the ORR is 20% and the alternative response rate of the combination treatment on ORR is 35%. The sample size of

54 evaluable patients in Part B provides statistical power of 83%, with a nominal one-sided alpha level of 0.10. For time-to-event variables, the Kaplan–Meier method was used. For DoR, data were censored at the date of the time of the last tumor assessment. For the analysis of PFS, data for patients who were alive and had no disease progression or who were lost to follow-up were censored at the time of the last tumor assessment. For the analysis of OS, data for patients who

of

were alive or who were lost to follow-up were censored at the time of the last contact.

ro

3. Results 3.1 Patients

-p

Between September 2015 and July 2016, 64 patients were enrolled in Parts A and B of the study. Part A completed without DLTs (9 patients; 2 with squamous and 7 with nonsquamous

re

histology). At the time of the data cut-off for Parts A and B (26 January 2017), 3 patients had been

lP

treated with necitumumab 600 mg and 61 were treated with necitumumab 800 mg (MTD from Part A), both in combination with pembrolizumab 200 mg. All 64 patients (9 in Part A and 55 in

ur na

Part B) received at least 1 dose of each drug and had a complete radiographic assessment at baseline. At data cut-off, 15 patients receiving necitumumab 800 mg with pembrolizumab 200 mg were still on study treatment. The most common reason for treatment discontinuation in the whole cohort was progressive disease (n=30, 46.9%), followed by death (n=8, 12.5%), AE (n=6, 9.4%),

Jo

patient decision (n=3, 4.7%), and physician decision (n=2, 3.1%).

Of the 64 treated patients, the majority were male (71.9%), white (78.1%), and had ECOG

performance status of 1 (71.9%) (Table 1). Most patients were current or former smokers (85.9%). In the cohort of patients with nonsquamous histology (n=34), 20.6% were never smokers, and 3 were previously treated with an EGFR TKI. Overall, half of patients were PD-L1 negative

(50.0%), with similar distribution across squamous and nonsquamous histology. Seven Japanese patients were treated in Part C: 5 (71.4%) were male; 5 (71.4%) were current or former smokers; 5 (71.4%) had ECOG performance status of 1; 2 patients (28.6%) each had weak positive or strong positive PD-L1 status, and 3 (42.9%) had negative status. The median age of the Japanese patients was 67 years (range: 48–71 years).

of

The median number of cycles of necitumumab (600 mg or 800 mg) and pembrolizumab 200

ro

mg received per patient was 6 (range: 1–22). The median duration of necitumumab was 18.5 weeks (range: 2–65) and for pembrolizumab was 18.5 weeks (range: 3–66). The median relative dose

-p

intensity for necitumumab was 97.3% (range: 48.8–102.4) and for pembrolizumab was 100%

re

(range: 64.3–102.4).

lP

3.2 Efficacy

For all evaluable patients (any patient who received at least 1 dose of each drug and had a

ur na

complete radiographic assessment at baseline), confirmed ORR was 23.4% (95% confidence interval [CI] 13.8% – 35.7%). Two patients (3.1%) had a CR, 13 patients (20.3%) had a PR, 26 patients (40.6%) had stable disease, 17 patients (26.6%) had progressive disease, and 6 patients (9.4%) were not evaluable (Fig. 2). ORR was similar in squamous and nonsquamous histology

Jo

(20.0% vs 26.5%, respectively; Table 2). Median duration of response was 10.9 months (95% CI 4.2 – not reached), and confirmed DCR was 64.1% (95% CI 51.5–75.7). In all evaluable patients, regardless of histology or PD-L1 status, median PFS (mPFS) was 4.1 months (95% CI 2.4–6.9 months) and OS at 6 months was 74.7% (61.5% – 83.9%). Median PFS was numerically better in the nonsquamous than squamous cohort (mPFS 6.9 months vs 2.8 months, respectively; Table 2).

Exploratory evaluation of efficacy data by biomarker revealed that patients with PD-L1 positive status had numerically improved ORR (40.0% for strong positive status vs 25.0% for weak positive status vs 12.5% for negative status) and mPFS (7.6 months for strong positive status vs 5.4 months for weak positive status vs 2.7 months for negative status) when compared with

of

patients with PD-L1 negative cancer (Table 2; Fig. 3). Similarly, in patients evaluable for EGFR status by FISH, there was an improved response to the treatment in the EGFR FISH-positive group

ro

with respect to both ORR (33.3% in EGFR positive patients vs 21.7% in EGFR negative patients) and mPFS (9.4 months in EGFR positive patients vs 6.8 months in EGFR negative patients).

-p

Interestingly, patients in whom EGFR protein expression was present by IHC appeared to respond

re

to the therapy in a greater proportion that those without, but this did not translate to any difference

lP

in mPFS.

3.3 Safety

ur na

Part A completed without DLTs and the combination of necitumumab 800 mg with pembrolizumab 200 mg was considered tolerable. The most common any-grade treatmentemergent AEs (TEAEs) were dermatitis acneiform (67%), asthenia (38%), dry skin (36%), hypomagnesemia (33%), and fatigue (31%) (Supplementary Table S1). All other TEAEs

Jo

occurred in fewer than 30% of patients. Grade ≥3 TEAEs occurred in fewer than 10% of patients, the most common being dyspnea (9%), hypomagnesemia, and fatigue (6% each).

Although the majority of patients (94%) experienced treatment-related AEs (TRAE) of any grade, less than a third of patients experienced at least 1 Grade 3–4 TRAE (Table 3). Treatment-

emergent SAEs occurred in 42% of patients; the most commonly reported events (occurring at an incidence of ≥5%) were in the System Organ Class of Respiratory, Thoracic and Mediastinal Disorders (n=9, 14%); Gastrointestinal Disorders (n=4, 6.3%); Infections and Infestations (n=4, 6%); and Nervous System Disorders (n=4 patients, 6%). The most commonly reported individual SAEs (occurring in ≥3 patients) were dyspnea (n=3) and pulmonary embolism (n=3). Eleven

of

patients (17%) experienced an SAE at least possibly related to study treatment per investigator assessment. Of the related SAEs, no individual AEs occurred in more than 1 patient. Of the 8

ro

patients that died while on treatment, 6 deaths were the result of progressive disease and 2 were the result of respiratory tract infections, 1 of which was considered treatment-related. Four more

re

-p

patients died as a result of progressive disease in the 30 days following treatment discontinuation.

Adverse events of special interest (AESI), occurring in >5% of patients, were skin reactions

lP

(any grade: 84%; Grade ≥3: 13%), rash (any grade: 83%; Grade ≥3: 9%), hypomagnesemia (any grade: 33%; Grade ≥3: 6%), conjunctivitis (any grade: 17%; Grade ≥3: 0%), and venous

ur na

thromboembolic events (any grade: 8%; Grade ≥3: 5%). There were 2 cases of interstitial lung disease (pneumonitis), one of which was Grade ≥3.

In Part C, 1 Japanese patient died on study therapy as the result of an AE (cardiac arrest),

Jo

which was not considered related to study treatment. No other serious TEAEs occurred among the Part C safety population. The TEAEs in part C categorized by preferred term are summarized in the Supplementary Table S2.

4. Discussion The results of the current phase Ib study suggest activity of the necitumumab and pembrolizumab combination in a previously treated advanced NSCLC patient population with a relatively high proportion of PD-L1 negative patients. The observed ORR of 23.4% was numerically higher than that reported in previous studies evaluating the effects of PD-1 inhibitors as monotherapy in

of

second-line treatment of NSCLC, despite there being a relatively high proportion of PD-L1 negative patients in the current study. In the KEYNOTE-010 trial, which compared

ro

pembrolizumab versus docetaxel in previously treated advanced NSCLC with PD-L1 expression on ≥1% of tumor cells, among the total study cohort, 18% of patients receiving pembrolizumab

-p

exhibited a response (although ORR was higher in those patients with a tumor proportion score

re

≥50%) [16]. Of note, in the current study, median PFS appeared better in nonsquamous compared with squamous patients, while the effect on PFS did not differ by tumor histology with

lP

pembrolizumab historical data. Median OS was not able to be calculated in the current study at the time of data cut-off, so no comparisons with previous studies can be made. In contrast to

ur na

KEYNOTE-010, the current study did not restrict enrolment to patients with PD-L1-positive tumors, since we wanted to assess whether a combination of necitumumab and pembrolizumab could be active in PD-L1 low positive or even PD-L1 negative disease. For the same reason, the

Jo

study population was not limited to squamous histology only.

Two other studies with nivolumab, another immune checkpoint inhibitor that targets PD-

1, reported similar results [17, 18]. In the CheckMate 017 and CheckMate 057 studies, the effects of second-line nivolumab were evaluated compared with docetaxel in patients with squamous and nonsquamous NSCLC, respectively. The rate of confirmed objective response was 20% with

nivolumab in CheckMate 017 and 19% in CheckMate 057. Median PFS with nivolumab was 3.5 months in squamous NSCLC and 2.3 months in nonsquamous NSCLC patients.

PD-L1 protein expression in tumor samples, as measured by immunohistochemistry analysis, has emerged as the main predictive biomarker for response to immunotherapy. Among

of

advanced NSCLC patients receiving necitumumab and pembrolizumab in the current analyses, efficacy also appeared related to PD-L1 status, with ORR and mPFS benefits being greatest in

ro

patients with PD-L1 ≥50% and least in patients with PD-L1 <1%. While outcomes in patients with PD-L1 expression ≥50% is comparable to the historical pembrolizumab monotherapy data, our

-p

data suggest an improved outcome in those patients with PD-L1 <50% expression. Moreover, in

re

line with historical data suggesting improved efficacy of EGFR-directed mAbs in lung cancer shown to be positive for EGFR by FISH, there seems to be improved outcome as measured by

lP

ORR and mPFS in this current study. In the SWOG SO819 study, although EGFR FISH was not a predictive marker for the overall patient population, EGFR FISH-positivity predicted a beneficial

ur na

response to treatment with cetuximab in a subpopulation with squamous cell histology [19]. Similar results were observed in the EGFR FISH-positive cohort in the SQUIRE trial that compared necitumumab plus gemcitabine and cisplatin with gemcitabine and cisplatin alone [20]. These data suggest a role for EGFR FISH as a predictive biomarker for therapy with EGFR

Jo

antibodies in distinct biological subgroups of patients.

Pre-clinical evidence has demonstrated that activation of the EGFR pathway up-regulates

expression of PD-L1 and other immunosuppressive factors, which in turn contributes to immune evasion [9, 21]. Data generated with first-generation EGFR-directed antibody cetuximab suggest

that EGFR mAb-induced immunostimulation is also associated with counterregulatory mechanisms, which may lead to immunosuppressive feedback loops including an increased expression of checkpoint molecules such as PD-1, PD-L1, and CTLA-4 [13].

The modest benefits with the addition of necitumumab to pembrolizumab support the

of

hypothesis that the combination of EGFR inhibition with PD-1 blockade may be a therapeutic strategy that could lead to a stronger response, particularly in tumors with PD-L1 expression

ro

<50%. The seemingly improved outcomes compared with previous data in patients with PD-L1 expression <50% could be the consequence of the combination of potentially increased PD-L1

-p

expression following EGFR blockade and increased tumor antigen release resulting from the direct

re

cytotoxic effect of necitumumab on EGFR-expressing cells.

lP

There were no new safety issues identified with necitumumab and pembrolizumab relative to either drug given as monotherapy and, compared with other immunotherapy combinations, the

ur na

safety profile is favorable. Results from previous early-phase studies have demonstrated unexpectedly high incidence of AEs with the combination of other drugs against EGFR and immunotherapy, albeit in patients with oncogene-addicted NSCLC rather than in a wild-type population. In the phase Ib TATTON study, the rate of interstitial lung disease (38%) reported for

Jo

the combination of osimertinib and durvalumab was much greater than observed with either drug alone, and as a result, further enrolment in the osimertinib plus durvalumab combination arm of the study was terminated [22]. Analysis of over 20,000 NSCLC cases in the FDA Adverse Event Reporting System (FAERS) database, found a higher proportion of reports of interstitial pneumonitis for nivolumab in combination with an EGFR TKI compared with either treatment

alone [23]. In another phase I trial, a higher than expected incidence of Grade 3/4 liver enzyme elevation (40–70%) was observed in treatment-naïve NSCLC patients receiving gefitinib in combination with durvalumab [24]. Despite the relatively high incidence of treatment-related toxicities associated with the combination of EGFR TKIs and immunotherapy described, preliminary results from other early

of

studies have demonstrated encouraging efficacy coupled with an acceptable safety profile [25, 26]. In the current study, no DLTs were observed during the first cycle of treatment, thus establishing

ro

800 mg necitumumab and 200 mg pembrolizumab as the MTD. Previous evidence suggests a nonoverlapping toxicity profile of pembrolizumab and necitumumab and other EGFR-targeted agents.

-p

TEAEs observed with the combination of necitumumab and pembrolizumab in the current study

re

were consistent with class effects typical of EGFR mAbs and immunotherapies, and no new safety

lP

signals were observed with the use of this combination therapy.

One potential limitation of our analyses is the relatively small sample size, coupled with

ur na

the fact that the group of patients included were not selected on the basis of biomarker status, making the population more heterogeneous. In addition, there was no parallel group for comparison.

Jo

5. Conclusion

The results of this study suggest modest benefits of second-line necitumumab and

pembrolizumab combination therapy in patients with Stage IV NSCLC. The MTD was identified as 800 mg necitumumab and 200 mg pembrolizumab. No unexpected safety signals were observed with the use of combination therapy.

Author contributions All authors were involved in the study design, and analysis and interpretation of data, and critically revising the manuscript. All authors agree to be responsible for all aspects of the work and read and approved the final manuscript to be published.

of

Funding

ro

This study was sponsored by Eli Lilly and Company.

-p

Author contributions

re

All authors were involved in the study design, and analysis and interpretation of data, and critically revising the manuscript. All authors agree to be responsible for all aspects of the work and read

ur na

Acknowledgements

lP

and approved the final manuscript to be published.

Medical writing assistance was provided by John Bilbruck of Envision Pharma and was funded by Eli Lilly. Envision Pharma’s services complied with international guidelines for Good Publication

Jo

Practice (GPP3).

References

[1] P. Fessas, H. Lee, S. Ikemizu, T. Janowitz, A molecular and preclinical comparison of the PD1-targeted T-cell checkpoint inhibitors nivolumab and pembrolizumab, Semin. Oncol. 44(2) (2017) 136–140. http://doi.org/10.1053/j.seminoncol.2017.06.002. [2] A. Calles, X. Liao, L.M. Sholl, et al., Expression of PD-1 and Its Ligands, PD-L1 and PD-L2,

of

in Smokers and Never Smokers with KRAS-Mutant Lung Cancer, J. Thorac. Oncol. 10(12) (2015) 1726–1735. http://doi.org/10.1097/JTO.0000000000000687.

ro

[3] L. Gandhi, D. Rodriguez-Abreu, S. Gadgeel, et al., Pembrolizumab plus chemotherapy in

-p

metastatic non-small-cell lung cancer. N Engl J Med. 378(22) (2018) 2078-2092. http://doi: 10.1056/NEJMoa1801005

re

[4] Merck Sharpe & Dohme Corp., Keytruda: Summary of Product Characteristics, 2017.

December 2017).

(accessed

4

lP

https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125514s012lbl.pdf

[5] X. Meng, Y. Liu, J. Zhang, F. Teng, L. Xing, J. Yu, PD-1/PD-L1 checkpoint blockades in non-

ur na

small cell lung cancer: New development and challenges, Cancer Lett. 405 (2017) 29–37. http://doi.org/10.1016/j.canlet.2017.06.033. [6] Y. Wang, W. Bao, H. Shi, C. Jiang, Y. Zhang, Epidermal growth factor receptor exon 20

Jo

mutation increased in post-chemotherapy patients with non-small cell lung cancer detected with patients' blood samples, Transl. Oncol. 6(4) (2013) 504–510. [7] M.K. Thakur, A.J. Wozniak, Spotlight on necitumumab in the treatment of non-small-cell lung carcinoma, Lung Cancer (Auckl) 8 (2017) 13–19. http://doi.org/10.2147/LCTT.S104207. [8] N. Thatcher, F.R. Hirsch, A.V. Luft, et al., Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-

cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial, Lancet Oncol. 16(7) (2015) 763–774. http://doi.org/10.1016/S1470-2045(15)00021-2. [9] E.A. Akbay, S. Koyama, J. Carretero, et al., Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors, Cancer Discov. 3(12) (2013) 1355–1363. http://doi.org/10.1158/2159-8290.CD-13-0310.

of

[10] Y.F. Hsu, D. Ajona, L. Corrales, et al., Complement activation mediates cetuximab inhibition of non-small cell lung cancer tumor growth in vivo, Mol. Cancer 9 (2010) 139.

ro

http://doi.org/10.1186/1476-4598-9-139.

[11] H.E. Kohrt, A.D. Colevas, R. Houot, et al., Targeting CD137 enhances the efficacy of

-p

cetuximab, J. Clin. Invest. 124(6) (2014) 2668–2682. http://doi.org/10.1172/JCI73014.

re

[12] R.M. Srivastava, S.C. Lee, P.A. Andrade Filho, et al., Cetuximab-activated natural killer and dendritic cells collaborate to trigger tumor antigen-specific T-cell immunity in head and neck

0432.CCR-12-2426.

lP

cancer patients, Clin. Cancer Res. 19(7) (2013) 1858–1872. http://doi.org/10.1158/1078-

ur na

[13] R.L. Ferris, H.J. Lenz, A.M. Trotta, et al., Rationale for combination of therapeutic antibodies targeting tumor cells and immune checkpoint receptors: Harnessing innate and adaptive immunity through IgG1 isotype immune effector stimulation, Cancer Treat. Rev. 63 (2018) 48–60. http://doi.org/10.1016/j.ctrv.2017.11.008.

Jo

[14] M. Tazdait, L. Mezquita, J. Lahmar, et al., Patterns of responses in metastatic NSCLC during PD-1 or PDL-1 inhibitor therapy: Comparison of RECIST 1.1, irRECIST and iRECIST criteria, Eur. J. Cancer 88 (2018) 38–47. http://doi.org/10.1016/j.ejca.2017.10.017. [15] F.R. Hirsch, R.S. Herbst, C. Olsen, et al., Increased EGFR gene copy number detected by fluorescent in situ hybridization predicts outcome in non-small-cell lung cancer patients treated

with

cetuximab

and

chemotherapy,

J.

Clin.

Oncol.

26(20)

(2008)

3351–3357.

http://doi.org/10.1200/JCO.2007.14.0111. [16] R.S. Herbst, P. Baas, D.W. Kim, et al., Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled

trial,

Lancet

387(10027)

(2016)

1540–1550.

http://doi.org/10.1016/S0140-

of

6736(15)01281-7. [17] H. Borghaei, L. Paz-Ares, L. Horn, et al., Nivolumab versus Docetaxel in Advanced

ro

Nonsquamous Non-Small-Cell Lung Cancer, N. Engl. J. Med. 373(17) (2015) 1627–1639. http://doi.org/10.1056/NEJMoa1507643.

-p

[18] J. Brahmer, K.L. Reckamp, P. Baas, et al., Nivolumab versus Docetaxel in Advanced

http://doi.org/10.1056/NEJMoa1504627.

re

Squamous-Cell Non-Small-Cell Lung Cancer, N. Engl. J. Med. 373(2) (2015) 123–135.

lP

[19] R.S. Herbst, M.W. Redman, E.S. Kim, et al., Cetuximab plus carboplatin and paclitaxel with or without bevacizumab versus carboplatin and paclitaxel with or without bevacizumab in

ur na

advanced NSCLC (SWOG S0819): a randomised, phase 3 study, Lancet Oncol. 19(1) (2018) 101– 114. http://doi.org/10.1016/S1470-2045(17)30694-0. [20] C. Genova, M.A. Socinski, R.R. Hozak, et al., EGFR Gene Copy Number by FISH May Predict Outcome of Necitumumab in Squamous Lung Carcinomas: Analysis from the SQUIRE

Jo

Study, J. Thorac. Oncol. 13(2) (2018) 228–236. http://doi.org/10.1016/j.jtho.2017.11.109. [21] N. Chen, W. Fang, J. Zhan, et al., Upregulation of PD-L1 by EGFR Activation Mediates the Immune Escape in EGFR-Driven NSCLC: Implication for Optional Immune Targeted Therapy for NSCLC Patients with EGFR Mutation, J. Thorac. Oncol. 10(6) (2015) 910–923. http://doi.org/10.1097/JTO.0000000000000500.

[22] M.J. Ahn, J. Yang, H. Yu, et al., 136O: Osimertinib combined with durvalumab in EGFRmutant non-small cell lung cancer: Results from the TATTON phase Ib trial, J. Thorac. Oncol. 11(4) (2016) S115. http://doi.org/10.1016/s1556-0864(16)30246-5. [23] Oshima Y, Tanimoto T, Yuji K, Tojo A. EGFR-TKI-associated interstitial pneumonitis in nivolumab-treated patients with non-small cell lung cancer. JAMA Oncol. 4(8) (2018) 1112–1115.

of

http:// doi: 10.1001/jamaoncol.2017.4526. [24] D.L. Gibbons, L.Q. Chow, D.W. Kim, et al., 57O Efficacy, safety and tolerability of

ro

MEDI4736 (durvalumab [D]), a human IgG1 anti-programmed cell death-ligand-1 (PD-L1) antibody, combined with gefitinib (G): A phase I expansion in TKI-naïve patients (pts) with EGFR

-p

mutant NSCLC, J. Thorac. Oncol. 11(4) (2016) S79. http://doi.org/10.1016/s1556-

re

0864(16)30171-x.

[25] C. Rudin, A. Cervantes, A. Dowlati, et al., Safety, Clinical Activity and Biomarker Results

lP

from a Phase lb Study of Erlotinib plus Atezolizumab in Advanced CrossMark NSCLC, J. Thorac. Oncol. 12(1) (2017) S1302–S1303.

ur na

[26] S. Gettinger, L.Q. Chow, H. Borghaei, et al., Safety and Response With Nivolumab (AntiPD-1; BMS-936558, ONO-4538) Plus Erlotinib in Patients (Pts) With Epidermal Growth Factor Receptor Mutant (EGFR MT) Advanced Non-Small Cell Lung Cancer (NSCLC), Int. J. Radiat.

Jo

Oncol. 90 (2014) S34–S35.

Figure legends Fig. 1. Study design

Jo

ur na

lP

re

-p

ro

of

D, Day; DLT, dose-limiting toxicity; MTD, maximum tolerated dose; Q3W, every 3 weeks

of

ro

-p

re

lP

ur na

Jo

Jo

ur na

lP

re

-p

ro

of

Fig. 2. Best percent change from baseline in tumor size versus treatment duration

of

ro

-p

re

lP

ur na

Jo

Fig. 3. Progression-free survival by PD-L1 status

Jo

ur na

lP

re

-p

ro

of

PD-L1, programmed death-ligand 1

of

ro

-p

re

lP

ur na

Jo

of

ro

-p

re

lP

ur na

Jo

Table 1. Patient demographics and characteristics Necitumumab 600 mg/800 mg + pembrolizumab 200 mg Characteristic

Overall (N=64)

Jo

ur na

lP

re

-p

ro

of

Age, median (range), y 65 (43, 81) Male, n (%) 46 (71.9) Prior systemic therapy, n (%) 1 line 36 (56.3) 2 lines 15 (23.4) 3 lines 13 (20.3) Cancer type Non-squamous 34 (53.1) Squamous 30 (46.9) Disease stage Stage IV at initial 54 (84.4) Stage IV at entry 5 (7.8) Missing 5 (7.8) Baseline ECOG PS, n (%) 0 17 (26.6) 1 46 (71.9) 2 1 (1.6) PD-L1 status Negative 32 (50.0) Weak positive 12 (18.8) Strong positive 10 (15.6) Unknown 10 (15.6) Tobacco use, n (%) Former 41 (64.1) Current 14 (21.9) Never 9 (14.1) ECOG PS, Eastern Cooperative Oncology Group performance status; PD-L1, programmed death-ligand 1

mPFS, months

Weak positive

<1%

1–49%

(N=64)

(n=32)

(n=12)

23.4 (13.8, 35.7)

12.5 (3.5, 29.0)

25.0 (5.5, 57.2)

4.1 (2.4, 6.9)

2.7 (1.4, 4.1)

74.7 (61.5, 83.9)

68.2 (47.7, 82.0)

(95% CI)

6-month OS, %

ur na

(95% CI)

ro

Negative

Strong positive

5.4 (0.8, NR)

83.3 (48.2, 95.6)

EGFR status

Unknown

FISH-negative

FISH-positive

(n=10)

(n=10)

(n=23)

(n=15)

40.0 (12.2, 73.8)

40.0 (12.2, 73.8)

21.7 (9.7, 41.9)

33.3 (15.2, 58.3)

7.6 (1.0, 12.3)

NR (0.8, NR)

6.8 (2.2, 8.5)

9.4 (1.2, NR)

80.0 (40.9, 94.6)

78.8 (38.1, 94.3)

82.4 (59.6, 93.0)

78.0 (45.5, 92.5)

≥50%

-p

(95% CI)

PD-L1 status

re

ORR, %

Overall

lP

Outcome

of

Table 2. Efficacy results by PD-L1 status

CI, confidence interval; EGFR, epidermal growth factor receptor; FISH, fluorescent in situ hybridization; mPFS, median progression-free survival; NA, not

Jo

applicable; NR, not reached; ORR, overall response rate; OS, overall survival; PD-L1, programmed death-ligand 1

32 Table 3. Safety overview Total (N=64) Number of patients (%) 64 (100)

Grade ≥3 TEAEs

40 (63)

Treatment-related adverse events (TRAEs)

60 (94)

Grade ≥3 TRAEs

20 (31)

Serious TEAEs

27 (42)

Serious TRAEs

11 (17)

of

Any treatment-emergent adverse events (TEAEs)

AEs with outcome of death

a

2 (3)

Two Grade 5 respiratory tract infections

Jo

ur na

lP

re

-p

a

6 (9)

ro

TEAEs leading to discontinuation of study treatment