Cisplatin-Pemetrexed Compared With Carboplatin-Paclitaxel-Bevacizumab in KRAS Mutated Non-small Cell Lung Cancer

Chemotherapy in KRAS Mutated Chemotherapy Naive Non-small Cell Lung Cancer Patients: a Phase III Study Comparing Cisplatin-pemetrexed With Carboplatin-paclitaxel-bevacizumab: NVALT 22

The purpose of this study is to determine whether carboplatin-paclitaxel-bevacizumab results in a prolonged progression free survival compared to cisplatin-pemetrexed as first line treatment in patients with KRAS mutated non-small cell lung cancer.

Study Overview

• Status: Active, not recruiting
• Conditions: Carcinoma, Non-Small Cell Lung
• Intervention / Treatment: Drug: carboplatin; Drug: paclitaxel; Drug: Bevacizumab; Drug: Pemetrexed; Drug: cisplatin

Detailed Description

KRAS mutations occur in 30% of patients with non-small cell lung cancer, especially adenocarcinoma. For long time KRAS mutation has been related with poor prognosis and poor response to chemotherapy. Recent data however show that this is both not true. It seems that response, progression free survival and overall survival is similar in KRAS mutated. Until now no specific targeted therapy is available for KRAS mutated NSCLC patients. Optimization of treatment in advanced NSCLC patients with a KRAS mutation could also be achieved by selecting the best available chemotherapy treatment.

Two standard chemotherapy schemes are frequently used and FDA and EMA approved as first line treatment for patients with adenocarcinoma: cisplatin-pemetrexed and carboplatin-paclitaxel-bevacizumab.

The aim of this randomized phase III study is to compare two standard treatment regimens in patients with KRAS mutated, advanced stage NSCLC and the hypothesis is that bevacizumab with chemotherapy improves outcomes compared to chemotherapy alone as first line treatment. Furthermore the outcome for the different KRAS mutations will be studied.

Treatment with one of the two following chemotherapy combinations according to the label: carboplatin-paclitaxel-bevacizumab or cisplatin-pemetrexed q3wks for up to six cycles. Continuation maintenance with bevacizumab and pemetrexed is allowed until progression. Blood and archival tissue will be optionally collected for translational research. This may help to identify subgroups of patients who are likely better treated with a specific treatment regimen.

• Study Type: Interventional
• Enrollment (Actual): 203
• Phase: Phase 3

Contacts and Locations

Study Locations

• Netherlands
  • Almelo, Netherlands, 7609 PP
    • ZGT
  • Amsterdam, Netherlands, 1066CX
    • Antoni van Leeuwenhoek
  • Amsterdam, Netherlands, 1090 HM
    • OLVG
  • Apeldoorn, Netherlands
    • Gelre Ziekenhuis
  • Breda, Netherlands
    • Amphia Hospital
  • Den Bosch, Netherlands
    • Jeroen Bosch Hospital
  • Den Haag, Netherlands, 2545 CH
    • Haga
  • Deventer, Netherlands
    • Deventer Ziekenhuis
  • Dordrecht, Netherlands
    • Albert Schweitzer Ziekenhuis
  • Ede, Netherlands
    • Ziekenhuis Gelderse Vallei
  • Eindhoven, Netherlands, 5631 BM
    • Maxima Medisch Centrum
  • Gouda, Netherlands
    • Groene Hart
  • Groningen, Netherlands
    • Martini Ziekenhuis
  • Groningen, Netherlands, 9713 GZ
    • UMCG
  • Hilversum, Netherlands
    • Tergooi ziekenhuizen
  • Hoofddorp, Netherlands, 2130 AT
    • Spaarne Gasthuis
  • Leeuwarden, Netherlands
    • Medisch Centrum Leeuwarden
  • Maastricht, Netherlands
    • Maastricht University Medical Center
  • Rotterdam, Netherlands, 3045 PM
    • St. Fransicus Gasthuis
  • Rotterdam, Netherlands, 3007 AC
    • Maasstad Ziekenhuis
  • Utrecht, Netherlands, 3582 KE
    • Diakonessenhuis Utrecht
  • Utrecht, Netherlands
    • St. Antonius Ziekenhuis
  • Venlo, Netherlands
    • VieCuri Medisch Centrum voor Noord-Limburg
  • Zwolle, Netherlands, 8000 GK
    • Isala Klinieken
  • the Hague, Netherlands
    • Medical Center Haaglanden
  • Noord-Holland
    • Amsterdam, Noord-Holland, Netherlands, 1081HV
      • VUmc Medical Center
  • Overijssel
    • Enschede, Overijssel, Netherlands, 7500 KA
      • Medical spectrum Twente
  • Utrecht
    • Amersfoort, Utrecht, Netherlands, 3818 ES
      • Meander Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Histologically or cytologically confirmed (non-squamous) NSCLC incurable locally advanced or metastatic (stage IIIB and stage IV) disease.
2. Documented KRAS mutation
3. Chemotherapy-naive NSCLC patients. Adjuvant chemotherapy or chemoradiotherapy is allowed when given > 1 year for study entry. Previous anti-PD(L1) therapy for advanced disease is allowed.
4. At least one unidimensionally measurable lesion meeting RECIST1.1.
5. ECOG PS 0-2
6. Age ≥ 18 years

7. Adequate organ function, including:

   • Adequate bone marrow reserve: ANC ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L.
   • Hepatic: bilirubin ≤1.5 x ULN, AP, ALT, AST ≤ 3.0 x ULN AP, ALT, and AST ≤5 xULN is acceptable if the liver has tumor involvement
   • Renal: calculated creatinine clearance ≥ 60 ml/min based on the Cockroft-Gault formula.
   • Urine protein (dip-stick) < 2 +; when ≥ 2 +: 24 hours urine protein ≤ 1 gr.
8. Signed informed consent
9. Male and female patients with reproductive potential must use an approved contraceptive method, if appropriate. Female patients with childbearing potential must have a negative serum pregnancy test within 7 days prior to study enrollment.

Exclusion Criteria:

1. Pregnant or lactating women
2. Clinically significant (i.e. active) cardiovascular disease: congestive heart failure >NYHA class 2; CVA or myocardial infarction < 6 months prior to study entry; uncontrolled hypertension (blood pressure systolic > 150 mmHg and/or diastolic > 100 mmHg)
3. History of hemoptysis ≥ grade 2 (bright red blood of at least 2,5 ml in the last 3 months)
4. Evidence of tumor invading major blood vessels on imaging (i.e. superior vena cava or pulmonary artery)
5. Patients with evidence or history of bleeding diathesis
6. Non-healing wound or ulcer

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: carboplatin-paclitaxel- bevacizumab; carboplatin AUC 6, paclitaxel 200 mg/m2, bevacizumab 15 mg/kg all administered intravenously on day 1 every 3 weeks for 4-6 cycles, followed by bevacizumab maintenance every 3 weeks until progression	Drug: carboplatin; AUC 6; Drug: paclitaxel; 200mg/m2; Drug: Bevacizumab; 15 mg/kg
Active Comparator: cisplatin-pemetrexed; pemetrexed 500 mg/m2 administered intravenously on day 1 and cisplatin 75 mg/m2 administered intravenously on day 1 every 3 weeks for 4-6 cycles, followed by maintenance pemetrexed every 3 weeks until progression.	Drug: Pemetrexed; 500 mg/m2; Drug: cisplatin; 75 mg/m2

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
progression free survival	Every 6 weeks, from date of randomization until the date of progression of disease or of death from any cause, assessed up to 60 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
disease control rate		Every 6 weeks, from date of randomization until the date of progression of disease or of death from any cause, assessed up to 60 months.
overall survival	Stratification for KRAS mutation (G12V versus G12C versus other)	date of randomization to the date of death from any cause, assessed up to 60 months.
outcome between G12V versus G12C versus other subtypes of KRAS mutations (mutational analysis on plasma and blood platelets).	The two most common KRAS types are G12C in about 40% of cases, G12V in 18% and G12D in 15% of cases. Subgroup analyses are planned to explore treatment effect in these different KRAS mutations groups. At baseline the metastatic patterns of these subgroups will be described. KRAS mutations in NSCLC occur mainly in codon 12 and 13. Stratification for KRAS mutation (G12V versus G12C versus other) at randomization.	date of randomization to the date of death from any cause, assessed up to 60 months.
response by Crabb criteria (if applicable)		Every 6 weeks, from date of randomization until the date of progression of disease or of death from any cause, assessed up to 60 months

Collaborators and Investigators

• Sponsor: The Netherlands Cancer Institute
• Collaborators: Dutch Society of Physicians for Pulmonology and Tuberculosis
• Investigators: Principal Investigator: Anne-Marie C Dingemans, MD PhD, Dutch Society of Physicians for Pulmonology and Tuberculosis

Publications and helpful links

Helpful Links

• ESMO oral presentation sept 2021

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2016
• Primary Completion (Actual): September 19, 2021
• Study Completion (Anticipated): April 1, 2024

Study Registration Dates

• First Submitted: March 17, 2016
• First Submitted That Met QC Criteria: April 18, 2016
• First Posted (Estimate): April 19, 2016

Study Record Updates

• Last Update Posted (Actual): December 21, 2021
• Last Update Submitted That Met QC Criteria: December 6, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Folic Acid Antagonists; Carboplatin; Paclitaxel; Cisplatin; Bevacizumab; Pemetrexed
• Other Study ID Numbers: NVALT 22