SAR408701 Versus Docetaxel in Previously Treated, Carcinoembryonic Antigen-related Cell Adhesion Molecule 5 (CEACAM5) Positive Metastatic Non-squamous Non-small-cell Lung Cancer Patients

NCT04154956 | Active Not Recruiting Phase 3 Results DMC FDA Drug

• 4 other identifiers: EFC15858U1111-1233-07812024-515101-26-002019-001273-81
• Study Type: interventional
• Target: 389
• Locations: 26 countries
• Sites: 169

Brief Summary

Primary Objectives:

• Study was designed with multiple primary endpoints analyzed on randomized participants at the time of the cut-off date for each given analysis (progression free survival \[PFS\] and overall survival \[OS\])
• Study success was defined either on PFS or OS
• The primary objective was to determine whether tusamitamab ravtansine improves the progression free survival (PFS) when compared to docetaxel in participants with metastatic non-squamous non-small-cell lung cancer (NSCLC) expressing CEACAM5 greater than or equal to 2+ in intensity in at least 50% of the tumor cell population and previously treated with standard-of-care platinum-based chemotherapy and an immune checkpoint inhibitor (ICI)
• The primary objective was to determine whether tusamitamab ravtansine improves the overall survival (OS) when compared with docetaxel in participants with metastatic non-squamous NSCLC expressing CEACAM5 greater than or equal to 2+ in intensity in at least 50% of the tumor cell population and previously treated with standard-of-care platinum-based chemotherapy and an immune checkpoint inhibitor. Secondary Objectives:
• Compared the objective response rate (ORR) of tusamitamab ravtansine with docetaxel
• Compared the health-related quality of life (HRQOL) of tusamitamab ravtansine with docetaxel
• Evaluated the safety of tusamitamab ravtansine compared to docetaxel
• Assessed the duration of response (DOR) of tusamitamab ravtansine as compared with docetaxel

Conditions

Non-small Cell Lung Cancer Metastatic

Outcome Measures

Primary Outcomes (2)

• Progression-free Survival (PFS)

  PFS was defined as the time from the date of randomization to the date of the first documentation of objective PD as assessed by radiological review committee (IRC) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) definitions or death due to any cause before the study cut-off date, whichever occurred first. PD was defined as unequivocal progression of existing non-target lesions; appearance of 1 or more new lesions; at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeters (mm).

  Tumor assessments performed at screening, and every 8 weeks +/-5 days thereafter, up to 189 weeks

• Overall Survival (OS)

  Overall survival was defined as the time from date of randomization to date of death due to any cause.

  From date of first study treatment administration (Day 1) until the date of death due to any cause, up to 189 weeks

Secondary Outcomes (8)

• Objective Response Rate (ORR)

  Tumor assessments performed at screening, and every 8 weeks +/-5 days thereafter, up to 189 weeks

• Time to Deterioration (TTD) in Disease-related Symptoms as Determined by European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire and Lung Cancer-specific Module With 13 Items (EORTC QLQ LC-13)

  Predose on Day 1 of Cycle 1, then on Day 1 of every 2 docetaxel Cycles, or every 3 tusamitamab ravtansine Cycles (i.e., every 6 weeks) up to 30 days after the last dose of study drug administration, up to 151 weeks

• TTD in Physical Function as Determined by European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Cancer-specific Module With 30 Items (EORTC QLQ C30)

  Predose on Day 1 of Cycle 1, then on Day 1 of every 2 docetaxel Cycles, or every 3 tusamitamab ravtansine Cycles (i.e., every 6 weeks) up to 30 days after the last dose of study drug administration, up to 151 weeks

• TTD in Role Function Measured by EORTC QLQ C30

  Predose on Day 1 of Cycle 1, then on Day 1 of every 2 docetaxel Cycles, or every 3 tusamitamab ravtansine Cycles (i.e., every 6 weeks) up to 30 days after the last dose of study drug administration, up to 151 weeks

• Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

  From date of first study treatment administration (Day 1) up to 30 days after the last dose of study treatment administration, up to 151 weeks

Study Arms (2)

SAR408701 (tusamitamab ravtansine)

EXPERIMENTAL

Participants received tusamitamab ravtansine 100 milligrams per square meter (mg/m\^2) by intravenous (IV) infusion, once every 2 weeks (Q2W) until objective progressive disease (PD), unacceptable adverse event/toxicity, upon participant's request to stop treatment, or Investigator decision, whichever occurred first (maximum exposure: 147 weeks).

Drug: SAR408701

Docetaxel

ACTIVE COMPARATOR

Participants received docetaxel 75 mg/m\^2 by IV infusion, once every 3 weeks (Q3W) until objective PD, unacceptable adverse event/toxicity, upon participant's request to stop treatment, or Investigator decision, whichever occurred first (maximum exposure: 115 weeks).

Drug: Docetaxel

Interventions

SAR408701 DRUG

Pharmaceutical form: Concentrate for solution for intravenous infusion Route of administration: intravenous (IV) infusion

SAR408701 (tusamitamab ravtansine)

Docetaxel DRUG

Pharmaceutical form: Concentrate for solution for intravenous infusion Route of administration: IV infusion

Also known as: TAXOTERE

Docetaxel

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• At least 18 years of age or above (or country's legal age of maturity if above 18 years) and signed the informed consent.
• Histologically or cytologically proven diagnosis of non-squamous NSCLC with metastatic disease at study entry; progression after platinum-based chemotherapy and immune checkpoint inhibitor.
• Participants with carcinoembryonic antigen-related cell adhesion molecule (CEACAM) 5 expression of greater than or equal to 2+ in archival tumor sample (or if not available, fresh biopsy sample) involving at least 50% of the tumor cell population as demonstrated prospectively by central laboratory via immune histochemistry (IHC).
• At least one measurable lesion by RECIST v1.1 as determined by local site investigator /radiologist assessment.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
• A female participant who agreed to use highly effective contraceptive methods during and for at least 7 months after the last dose of study intervention.
• A male participant who agreed to use highly effective contraception methods during and for at least 6 months after the last dose of study intervention.

You may not qualify if:

• Participants with untreated brain metastases and history of leptomeningeal disease. if previously treated brain metastases no documentation of non-progressive disease in brain by imaging performed at least 4 weeks after CNS directed treatment and at least 2 weeks prior to the first dose of study intervention.
• Significant concomitant illnesses, including all severe medical conditions that would impair the participation in the study or interpretation of the results.
• History within the last 3 years of an invasive malignancy other than the one treated in this study, with the exception of resected/ablated basal or squamous-cell carcinoma of the skin or carcinoma in situ of the cervix, or other local tumors considered cured by local treatment.
• Non-resolution of any prior treatment related toxicity to less than grade 2 according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version (V) 5.0, except for alopecia, vitiligo and active thyroiditis controlled with hormonal replacement therapy
• History of known acquired immunodeficiency syndrome (AIDS) related illnesses or known HIV disease requiring antiretroviral treatment, or unresolved viral hepatitis
• Previous history of and/or unresolved corneal disorders. The use of contact lenses was not permitted.
• Concurrent treatment with any other anticancer therapy.
• Prior treatment with docetaxel or maytansinoid derivatives (DM1 or DM4 antibody drug conjugate) or any drug targeting CEACAM5.
• Contraindicated the use of corticosteroid premedication.
• Previous enrollment in this study and current participation in any other clinical study involving an investigational study treatment or any other type of medical research.
• Poor bone marrow, liver or kidney functions
• Hypersensitivity to any of the study interventions, or components thereof (EDTA), or drug (paclitaxel, polysorbate 80) or other allergy that, in the opinion of the Investigator, contraindicated participation in the study.
• The above information was not intended to contain all considerations relevant to a potential participation in a clinical trial.

Sponsors & Collaborators

• Sanofi: lead

Study Sites (169)

Florida Cancer Specialists South Division- Site Number : 8400020

Fort Myers, Florida, 33901, United States

Location

Florida Cancer Specialists North Division- Site Number : 8400019

St. Petersburg, Florida, 33705, United States

Location

Ca & Hem Center Of W Michigan- Site Number : 8400016

Grand Rapids, Michigan, 49546, United States

Location

Roswell Park Cancer Institute Site Number : 8400011

Buffalo, New York, 14263-0001, United States

Location

Lankenau Hospital Cancer Center- Site Number : 8400017

Wynnewood, Pennsylvania, 19096-3411, United States

Location

Renovatio Clinical- Site Number : 8400032

El Paso, Texas, 79915, United States

Location

Renovatio Clinical - Site Number : 8400013

The Woodlands, Texas, 77380, United States

Location

Medical College of Wisconsin- Site Number : 8400006

Milwaukee, Wisconsin, 53226, United States

Location

Investigational Site Number : 0320009

CABA, Buenos Aires, C1019ABS, Argentina

Location

Investigational Site Number : 0320012

Capital Federal, Buenos Aires, 1012, Argentina

Location

Investigational Site Number : 0320003

Viedma, Río Negro Province, R8500ACE, Argentina

Location

Investigational Site Number : 0320001

Buenos Aires, 1426ANZ, Argentina

Location

Investigational Site Number : 0320004

Buenos Aires, C1125ABD, Argentina

Location

Investigational Site Number : 0320014

Córdoba, ZCX5000AAI, Argentina

Location

Investigational Site Number : 0320002

Salta, 4400, Argentina

Location

Investigational Site Number : 0360002

Blacktown, New South Wales, 2148, Australia

Location

Investigational Site Number : 0360003

Waratah, New South Wales, 2298, Australia

Location

Investigational Site Number : 0360001

Woolloongabba, Queensland, 4102, Australia

Location

Investigational Site Number : 0560006

Anderlecht, 1070, Belgium

Location

Investigational Site Number : 0560004

Edegem, B-2650, Belgium

Location

Investigational Site Number : 0560005

Ghent, 9000, Belgium

Location

Investigational Site Number : 0560001

Leuven, 3000, Belgium

Location

Investigational Site Number : 0560003

Liège, 4000, Belgium

Location

Investigational Site Number : 0560002

Woluwe-Saint-Lambert, 1200, Belgium

Location

Centro Regional Integrado De Oncologia - CRIO- Site Number : 0760002

Fortaleza, Ceará, 60336-232, Brazil

Location

~Instituto De Oncologia Parana- Site Number : 0760008

Curitiba, Paraná, 80530-010, Brazil

Location

Centro Avancado de Oncologia CECAN - Liga Contra o Cancer- Site Number : 0760026

Natal, Rio Grande do Norte, 59062-000, Brazil

Location

Clínica de Oncologia Reichow Site Number : 0760023

Blumenau, Santa Catarina, 89010-340, Brazil

Location

Hospital de Base Sao Jose do Rio Preto Site Number : 0760001

São José do Rio Preto, São Paulo, 15090-000, Brazil

Location

Hospital Sirio Libanes- Site Number : 0760018

São Paulo, São Paulo, 01308050, Brazil

Location

Investigational Site Number : 1000008

Burgas, 8000, Bulgaria

Location

Investigational Site Number : 1000010

Pleven, 5800, Bulgaria

Location

Investigational Site Number : 1000007

Plovdiv, 4002, Bulgaria

Location

Investigational Site Number : 1000004

Sofia, 1330, Bulgaria

Location

Investigational Site Number : 1000003

Sofia, 1618, Bulgaria

Location

Investigational Site Number : 1000001

Sofia, 1797, Bulgaria

Location

Investigational Site Number : 1240003

Greenfield Park, Quebec, J4V 2H1, Canada

Location

Investigational Site Number : 1240010

Montreal, Quebec, H1T 1P7, Canada

Location

Investigational Site Number : 1520007

Santiago, Reg Metropolitana de Santiago, 7500713, Chile

Location

Investigational Site Number : 1520006

Santiago, Reg Metropolitana de Santiago, 7500921, Chile

Location

Investigational Site Number : 1520009

Santiago, Reg Metropolitana de Santiago, 7650568, Chile

Location

Investigational Site Number : 1520002

Santiago, Reg Metropolitana de Santiago, 8420383, Chile

Location

Investigational Site Number : 1520001

Viña del Mar, Región de Valparaíso, 2520598, Chile

Location

Investigational Site Number : 1560026

Beijing, 100142, China

Location

Investigational Site Number : 1560009

Changchun, 130012, China

Location

Investigational Site Number : 1560010

Changchun, 130021, China

Location

Investigational Site Number : 1560015

Changsha, 410006, China

Location

Investigational Site Number : 1560039

Changsha, 410011, China

Location

Investigational Site Number : 1560032

Chengdu, 610041, China

Location

Investigational Site Number : 1560038

Chengdu, 610041, China

Location

Investigational Site Number : 1560044

Chongqing, 400038, China

Location

Investigational Site Number : 1560043

Chongqing, 400042, China

Location

Investigational Site Number : 1560024

Fuzhou, 350008, China

Location

Investigational Site Number : 1560001

Guangzhou, 510080, China

Location

Investigational Site Number : 1560036

Guangzhou, 510095, China

Location

Investigational Site Number : 1560037

Guangzhou, 510163, China

Location

Investigational Site Number : 1560017

Guangzhou, 510515, China

Location

Investigational Site Number : 1560025

Hangzhou, 310003, China

Location

Investigational Site Number : 1560033

Hangzhou, 310009, China

Location

Investigational Site Number : 1560021

Hangzhou, 310014, China

Location

Investigational Site Number : 1560011

Hangzhou, 310022, China

Location

Investigational Site Number : 1560005

Harbin, 150081, China

Location

Investigational Site Number : 1560050

Huizhou, 516001, China

Location

Investigational Site Number : 1560047

Jinan, 250013, China

Location

Investigational Site Number : 1560023

Nanjing, 210006, China

Location

Investigational Site Number : 1560019

Nanjing, 210009, China

Location

Investigational Site Number : 1560012

Nanning, 530021, China

Location

Investigational Site Number : 1560045

Tianjin, 300060, China

Location

Investigational Site Number : 1560006

Wuhan, 430079, China

Location

Investigational Site Number : 1560016

Zhanjiang, 524001, China

Location

Investigational Site Number : 1560041

Zhengzhou, 450003, China

Location

Investigational Site Number : 1560040

Zhengzhou, 450008, China

Location

Investigational Site Number : 2500010

Bordeaux, 33076, France

Location

Investigational Site Number : 2500008

Caen, 14076, France

Location

Investigational Site Number : 2500006

Créteil, 94010, France

Location

Investigational Site Number : 2500007

Grenoble, 38043, France

Location

Investigational Site Number : 2500001

Marseille, 13015, France

Location

Investigational Site Number : 2500013

Montpellier, 34295, France

Location

Investigational Site Number : 2500011

Paris, 75231, France

Location

Investigational Site Number : 2500014

Paris, 75970, France

Location

Investigational Site Number : 2500009

Pierre-Bénite, 69495, France

Location

Investigational Site Number : 2500003

Rennes, 35033, France

Location

Investigational Site Number : 2500012

Saint-Herblain, 44800, France

Location

Investigational Site Number : 2500002

Saint-Mandé, 94160, France

Location

Investigational Site Number : 2500004

Villejuif, 94800, France

Location

Investigational Site Number : 2760002

Essen, 45147, Germany

Location

Investigational Site Number : 2760001

Heidelberg, 69126, Germany

Location

Investigational Site Number : 3000005

Athens, 11526, Greece

Location

Investigational Site Number : 3000001

Athens, 11527, Greece

Location

Investigational Site Number : 3000003

Heraklion, 71500, Greece

Location

Investigational Site Number : 3000004

Ioannina, 455 00, Greece

Location

Investigational Site Number : 3000006

Thessaloniki, 54645, Greece

Location

Investigational Site Number : 3480003

Budapest, 1121, Hungary

Location

Investigational Site Number : 3480007

Budapest, 1125, Hungary

Location

Investigational Site Number : 3480005

Kaposvár, 7400, Hungary

Location

Investigational Site Number : 3760001

Haifa, 3109601, Israel

Location

Investigational Site Number : 3760002

Kfar Saba, 44281, Israel

Location

Investigational Site Number : 3760003

Petah Tikva, 49100, Israel

Location

Investigational Site Number : 3800004

Ravenna, Emilia-Romagna, 48121, Italy

Location

Investigational Site Number : 3800005

Rozzano, Milano, 20089, Italy

Location

Investigational Site Number : 3800003

Orbassano, Torino, 10043, Italy

Location

Investigational Site Number : 3800006

Catania, Italy

Location

Investigational Site Number : 3800001

Milan, 20133, Italy

Location

Investigational Site Number : 3920002

Nagoya, Aichi-ken, 460-0001, Japan

Location

Investigational Site Number : 3920015

Nagoya, Aichi-ken, 464-8681, Japan

Location

Investigational Site Number : 3920012

Fukuoka, Fukuoka, 810-8563, Japan

Location

Investigational Site Number : 3920008

Kurume-shi, Fukuoka, 830-0011, Japan

Location

Investigational Site Number : 3920016

Sapporo, Hokkaido, 003-0804, Japan

Location

Investigational Site Number : 3920017

Himeji-shi, Hyōgo, 670-8520, Japan

Location

Investigational Site Number : 3920006

Kanazawa, Ishikawa-ken, 920-8641, Japan

Location

Investigational Site Number : 3920005

Yokohama, Kanagawa, 241-8515, Japan

Location

Investigational Site Number : 3920009

Natori-shi, Miyagi, 981-1293, Japan

Location

Investigational Site Number : 3920001

Hirakata-shi, Osaka, 573-1191, Japan

Location

Investigational Site Number : 3920003

Osaka, Osaka, 541-8567, Japan

Location

Investigational Site Number : 3920013

Osaka Sayama-shi, Osaka, 589-8511, Japan

Location

Investigational Site Number : 3920004

Sunto-gun, Shizuoka, 411-8777, Japan

Location

Investigational Site Number : 3920011

Bunkyo-ku, Tokyo, 113-8603, Japan

Location

Investigational Site Number : 3920018

Mitaka-shi, Tokyo, 181-8611, Japan

Location

Investigational Site Number : 3920007

Wakayama, Wakayama, 641-8510, Japan

Location

Investigational Site Number : 3920010

Ube-shi, Yamaguchi, 755-0241, Japan

Location

Investigational Site Number : 4840003

Cuauhtémoc, Mexico City, 06700, Mexico

Location

Investigational Site Number : 5280003

's-Hertogenbosch, 5223 GZ, Netherlands

Location

Investigational Site Number : 5280004

Breda, 4818 CK, Netherlands

Location

Investigational Site Number : 5280005

Utrecht, 3543 AZ, Netherlands

Location

Investigational Site Number : 6160004

Olsztyn, Warmian-Masurian Voivodeship, 10-357, Poland

Location

Investigational Site Number : 6160001

Warsaw, 02-781, Poland

Location

Investigational Site Number : 6200002

Almada, 2801-951, Portugal

Location

Investigational Site Number : 6200001

Lisbon, 1769, Portugal

Location

Investigational Site Number : 6200004

Lisbon, 1998-018, Portugal

Location

Investigational Site Number : 6200005

Porto, 4099-001, Portugal

Location

Investigational Site Number : 6200006

Porto, 4100-180, Portugal

Location

Investigational Site Number : 6420008

Alba Iulia, 510077, Romania

Location

Investigational Site Number : 6420009

Brasov, 500152, Romania

Location

Investigational Site Number : 6420003

Bucaresti, 022328, Romania

Location

Investigational Site Number : 6420010

Cluj-Napoca, 400124, Romania

Location

Investigational Site Number : 6420011

Cluj-Napoca, 407280, Romania

Location

Investigational Site Number : 6420012

Otopeni, 75100, Romania

Location

Investigational Site Number : 6420005

Timișoara, 300166, Romania

Location

Investigational Site Number : 6430001

Moscow, 115478, Russia

Location

Investigational Site Number : 6430003

Saint Petersburg, 197758, Russia

Location

Investigational Site Number : 7020001

Singapore, 308433, Singapore

Location

Investigational Site Number : 7020002

Singapore, 329563, Singapore

Location

Investigational Site Number : 4100008

Busan, Busan, 48108, South Korea

Location

Investigational Site Number : 4100005

Cheongju-si, North Chungcheong, 28644, South Korea

Location

Investigational Site Number : 4100006

Seoul, Seoul-teukbyeolsi, 03722, South Korea

Location

Investigational Site Number : 4100007

Seoul, Seoul-teukbyeolsi, 05505, South Korea

Location

Investigational Site Number : 4100003

Seoul, Seoul-teukbyeolsi, 06351, South Korea

Location

Investigational Site Number : 4100004

Seoul, Seoul-teukbyeolsi, 07061, South Korea

Location

Investigational Site Number : 4100001

Seoul, 06591, South Korea

Location

Investigational Site Number : 7240007

Barcelona, Barcelona [Barcelona], 08028, Spain

Location

Investigational Site Number : 7240005

Barcelona, Barcelona [Barcelona], 08036, Spain

Location

Investigational Site Number : 7240001

L'Hospitalet de Llobregat, Barcelona [Barcelona], 08908, Spain

Location

Investigational Site Number : 7240009

Madrid / Madrid, Madrid, Comunidad de, 28040, Spain

Location

Investigational Site Number : 7240006

Pamplona, Navarre, 31008, Spain

Location

Investigational Site Number : 7240002

Madrid, 28041, Spain

Location

Investigational Site Number : 7240004

Málaga, 29010, Spain

Location

Investigational Site Number : 7240011

Seville, 41013, Spain

Location

Investigational Site Number : 7240008

Valencia, 46026, Spain

Location

Investigational Site Number : 7920008

Adana, 01060, Turkey (Türkiye)

Location

Investigational Site Number : 7920012

Adana, 01140, Turkey (Türkiye)

Location

Investigational Site Number : 7920002

Adana, 01250, Turkey (Türkiye)

Location

Investigational Site Number : 7920011

Ankara, 06800, Turkey (Türkiye)

Location

Investigational Site Number : 7920005

Istanbul, 34214, Turkey (Türkiye)

Location

Investigational Site Number : 7920001

Istanbul, 34303, Turkey (Türkiye)

Location

Investigational Site Number : 7920006

Istanbul, 34722, Turkey (Türkiye)

Location

Investigational Site Number : 7920007

Izmir, Turkey (Türkiye)

Location

Investigational Site Number : 7920010

Izmir, Turkey (Türkiye)

Location

Investigational Site Number : 7920014

Kocaeli, 41100, Turkey (Türkiye)

Location

Investigational Site Number : 7920009

Malatya, Turkey (Türkiye)

Location

MeSH Terms

Interventions

tusamitamab ravtansine; Docetaxel

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes

Results Point of Contact

• Title: Trial Transparency Team
• Organization: Sanofi aventis recherche & développement

Contact-US@sanofi.com

800-633-1610

Study Officials

• Clinical Sciences & Operations

  Sanofi

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 5, 2019
• First Posted: November 7, 2019
• Study Start: February 6, 2020
• Primary Completion: September 22, 2023
• Study Completion: March 31, 2026
• Last Updated: August 5, 2025
• Results First Posted: November 1, 2024

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will share

Locations

SG (2); DE (2); PT (5); ES (9); TU (11); BE (6); CA (2); BR (6); US (8); FR (13); GR (5); IL (3); PL (2); BU (6); CL (5); AU (3); NL (3); AR (7); HU (3); ME (1); JP (17); IT (5); RO (7); CN (29); KR (7); RU (2)