NCT01827267

Neratinib With and Without Temsirolimus for Patients With HER2 Activating Mutations in Non-Small Cell Lung Cancer

Completed Phase 2 Results posted Last updated 3 July 2018

What this trial tests

Phase 2 trial testing neratinib in HER2-mutant Non-Small Cell Lung Cancer in 62 participants. Completed in 6 October 2017.

Timeline

1 July 2013

Primary endpoint
20 September 2016

6 October 2017

Quick facts

Lead sponsor	Puma Biotechnology, Inc.
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	62
Start date	1 July 2013
Primary completion	20 September 2016
Estimated completion	6 October 2017
Sites	21 locations across France, United States

Drugs / interventions tested

• neratinib — full drug profile →
• temsirolimus (temsirolimus) — full drug profile →

Conditions studied

• HER2-mutant Non-Small Cell Lung Cancer — all drugs for HER2-mutant Non-Small Cell Lung Cancer →

Sponsor

Puma Biotechnology, Inc. — full company profile →

Who can join

18 and older, any sex, with HER2-mutant Non-Small Cell Lung Cancer. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Objective Response Rate (ORR) Primary · From randomization to last tumor assessment, assessed up to 116.5 weeks. For the Neratinib arm, only tumor assessments prior to crossover were included.

ORR is defined as proportion of subjects who achieved confirmed complete response (CR) or partial response (PR) per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.1: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. A complete or partial response must be confirmed no less than 4-weeks after the criteria for response are initially met.

Group	Value	95% CI
Neratinib	0
Neratinib+Temsirolimus	6

Clinical Benefit Rate (CBR) Secondary · From randomization to last tumor assessment, assessed up to 116.5 weeks. For the Neratinib arm, only tumor assessments prior to crossover were included.

CBR is defined as the proportion of patients who achieved objective response (CR or PR) or stable disease (SD) for at least 12 weeks.

Group	Value	95% CI
Neratinib	6
Neratinib+Temsirolimus	21

Duration of Response (DOR) Secondary · From randomization to last tumor assessment, assessed up to 116.5 weeks. For the Neratinib arm, only tumor assessments prior to crossover were included.

Measured from the time at which measurement criteria were first met for CR or PR (whichever status was recorded first), until the date of first recurrence, progressive disease (PD), or death was objectively documented, taking as a reference for PD the smallest measurements recorded since enrollment, per RECIST (v1.1) criteria.

Less than 3 months

Group	Value	95% CI
Neratinib	0
Neratinib+Temsirolimus	2

3 to less than 6 months

Group	Value	95% CI
Neratinib	0
Neratinib+Temsirolimus	2

6 to less than 12 months

Group	Value	95% CI
Neratinib	0
Neratinib+Temsirolimus	0

Greater than 12 months

Group	Value	95% CI
Neratinib	0
Neratinib+Temsirolimus	2

Progression Free Survival (PFS) Secondary · From randomization to last tumor assessment, assessed up to 116.5 weeks. For the Neratinib arm, only tumor assessments prior to crossover were included.

Defined as time from date of randomization until the first disease recurrence or progression per RECIST V1.1 or death due to any cause; censored at the last assessable evaluation or at the initiation of new anti-cancer therapy. Disease assessment is based on investigator tumor assessments. If no post-baseline tumor assessment then censored at enrollment date.

Group	Value	95% CI
Neratinib	2.9	1.4 – 9.8
Neratinib+Temsirolimus	4.0	2.9 – 5.4

Overall Survival (OS) Secondary · From randomization to death or end of long term follow-up, assessed up to 31.8 months.

Defined as the time (month) from randomization to death due to any cause; censored at the date last known alive.

Group	Value	95% CI
Neratinib	10.0	4.9 – 18.9
Neratinib+Temsirolimus	15.1	10.8 – 17.7

Adverse events — posted to ClinicalTrials.gov

Time frame: From time of first dose through 28 days after last dose, assessed up to 116.5 weeks.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Neratinib

Serious: 7/17 (41%)

Deaths: —

Neratinib+Temsirolimus

Serious: 16/43 (37%)

Deaths: —

Ner+Tem Post Crossover

Serious: 7/11 (64%)

Deaths: —

Serious adverse events (45 terms)

Reaction	System	Neratinib	Neratinib+Temsirolimus	Ner+Tem Post Crossover
Diarrhoea	Gastrointestinal disorders	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—
Nausea	Gastrointestinal disorders	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—
General physical health deterioration	General disorders	—	—	—
Pyrexia	General disorders	—	—	—
Pneumonia	Infections and infestations	—	—	—
Pleural effusion	Respiratory, thoracic and mediastinal disorders	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—
Cardio-respiratory arrest	Cardiac disorders	—	—	—
Tachycardia	Cardiac disorders	—	—	—
Dysphagia	Gastrointestinal disorders	—	—	—
Asthenia	General disorders	—	—	—
Anaphylactic shock	Immune system disorders	—	—	—
Infection	Infections and infestations	—	—	—
Parainfluenzae virus infection	Infections and infestations	—	—	—
Pneumonia bacterial	Infections and infestations	—	—	—
Upper respiratory tract infection	Infections and infestations	—	—	—
Accidental overdose	Injury, poisoning and procedural complications	—	—	—
Infusion related reaction	Injury, poisoning and procedural complications	—	—	—
Blood uric acid increased	Investigations	—	—	—
General physical condition abnormal	Investigations	—	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—	—
Dehydration	Metabolism and nutrition disorders	—	—	—
Hyponatraemia	Metabolism and nutrition disorders	—	—	—

Other adverse events (147 terms — click to expand)

Reaction	System	Neratinib	Neratinib+Temsirolimus	Ner+Tem Post Crossover
Diarrhoea	Gastrointestinal disorders	—	—	—
Nausea	Gastrointestinal disorders	—	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—	—
Stomatitis	Gastrointestinal disorders	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—
Constipation	Gastrointestinal disorders	—	—	—
Fatigue	General disorders	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—
Hypokalaemia	Metabolism and nutrition disorders	—	—	—
Dysgeusia	Nervous system disorders	—	—	—
Asthenia	General disorders	—	—	—
Epistaxis	Respiratory, thoracic and mediastinal disorders	—	—	—
Rash	Skin and subcutaneous tissue disorders	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—
Aspartate aminotransferase increased	Investigations	—	—	—
Weight decreased	Investigations	—	—	—
Headache	Nervous system disorders	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—
Dry skin	Skin and subcutaneous tissue disorders	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—
Dizziness	Nervous system disorders	—	—	—
Oedema peripheral	General disorders	—	—	—
Hypoalbuminaemia	Metabolism and nutrition disorders	—	—	—
Insomnia	Psychiatric disorders	—	—	—
Hypertriglyceridaemia	Metabolism and nutrition disorders	—	—	—
Haematuria	Renal and urinary disorders	—	—	—
Chills	General disorders	—	—	—
Gamma-glutamyltransferase increased	Investigations	—	—	—
White blood cell count decreased	Investigations	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—	—
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	—	—	—
Erythema	Skin and subcutaneous tissue disorders	—	—	—
Rash maculo-papular	Skin and subcutaneous tissue disorders	—	—	—
Lymphopenia	Blood and lymphatic system disorders	—	—	—
Neutropenia	Blood and lymphatic system disorders	—	—	—
Dysphagia	Gastrointestinal disorders	—	—	—
Pyrexia	General disorders	—	—	—
Rhinitis	Infections and infestations	—	—	—

Most-reported serious reactions: Diarrhoea, Dyspnoea, Nausea, Vomiting, General physical health deterioration, Pyrexia, Pneumonia, Pleural effusion.

Data from ClinicalTrials.gov NCT01827267 adverse events section.

Sponsor's own description

This is a Phase 2, therapeutic-exploratory, adaptive design, open-label, multicenter, multinational study evaluating neratinib monotherapy and neratinib plus temsirolimus combination therapy in patients with non-small cell lung cancer (NSCLC) who have documented somatic HER2 mutations.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Role of lysosomes in physiological activities, diseases, and therapy.
   Zhang Z, Yue P, Lu T, Wang Y, et al · · 2021 · cited 238× · PMID 33990205 · DOI 10.1186/s13045-021-01087-1
2. EGFR-TKI resistance in NSCLC patients: mechanisms and strategies.
   Lin Y, Wang X, Jin H. · · 2014 · cited 170× · PMID 25232485
3. Molecular pathways and therapeutic targets in lung cancer.
   Shtivelman E, Hensing T, Simon GR, Dennis PA, et al · · 2014 · cited 150× · PMID 24722523 · DOI 10.18632/oncotarget.1891
4. The PI3K/Akt/mTOR pathway in lung cancer; oncogenic alterations, therapeutic opportunities, challenges, and a glance at the application of nanoparticles.
   Sanaei MJ, Razi S, Pourbagheri-Sigaroodi A, Bashash D. · · 2022 · cited 148× · PMID 35168143 · DOI 10.1016/j.tranon.2022.101364
5. Targeting the PI3K/AKT/mTOR Signaling Pathway in Lung Cancer: An Update Regarding Potential Drugs and Natural Products.
   Iksen, Pothongsrisit S, Pongrakhananon V. · · 2021 · cited 139× · PMID 34279440 · DOI 10.3390/molecules26134100
6. Targeting HER2 in non-small-cell lung cancer (NSCLC): a glimpse of hope? An updated review on therapeutic strategies in NSCLC harbouring HER2 alterations.
   Riudavets M, Sullivan I, Abdayem P, Planchard D. · · 2021 · cited 134× · PMID 34479034 · DOI 10.1016/j.esmoop.2021.100260
7. Activating HER2 mutations as emerging targets in multiple solid cancers.
   Connell CM, Doherty GJ. · · 2017 · cited 111× · PMID 29209536 · DOI 10.1136/esmoopen-2017-000279
8. HER2-targeted therapies in cancer: a systematic review.
   Zhu K, Yang X, Tai H, Zhong X, et al · · 2024 · cited 83× · PMID 38308374 · DOI 10.1186/s40364-024-00565-1