A multicentre phase II, open-label, non-randomized study evaluating Platinum-Pemetrexed-Atezolizumab ( Bevacizumab) for patients with stage IIIB/IV non-squamous non-small cell lung cancer with EGFR mutations, ALK rearrangement or ROS1 fusion progressing after Targeted therapies

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Francois Baclesse

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

26 Aug 2019 → 9 Apr 2025

Decision date (initial)

2024-11-05

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Roche

External identifiers

EU CT number

2024-516201-23-00

EudraCT number

2019-000727-41

ClinicalTrials.gov

NCT04042558

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

To assess the efficacy of the combination of Platinum (carboplatin or cisplatin), Pemetrexed, Atezolizumab  Bevacizumab if eligible, in stage IIIB/IV non-squamous non-small cell lung cancer patients with progression-enhancing mutations following targeted therapies. Efficacy will be defined as the objective response rate (ORR) after 4 cycles of treatment.
Two distinct cohorts will be considered as follows since they will allow bringing separate information:
● Cohort with Bevacizumab
It will provide additional data to the Impower 150 study but with reference chemotherapy in patients with "adenocarcinoma" as a tumor type. The obtained findings could also be used to analyse the data of the erlotinib / bevacizumab combination (Seto T., Lancet Oncol, 2014) and thus better define the place of bevacizumab in patients with EGFR mutation.
● Cohort without Bevacizumab
It will provide data on the combination Pemetrexed / Atezolizumab in patients with mutation. There are numerous studies (Keynote 021, 189, Impower 132) that evaluate on the efficacy of this combination in NSCLC patients but not in patients with EGFR / ALK mutations. NCCN and that of the regional network “Rhônes-Alpes-Auvergne” recommendations place this association in first place in case of chemotherapy in front of other associations (such as carboplatin / paclitaxel, rather to reserve it to patients with PS> 2 or over 70 years).

Secondary objectives 9

1. ● The progression-free survival (PFS)
2. ● The duration of response (DOR)
3. ● The time to deterioration (TTD)
4. ● The change from baseline in patient-reported lung cancer symptoms (chest pain, dyspnoea, and cough) scores
5. ● The ORR according to immune RECIST (iRECIST) criteria
6. ● The overall survival (OS)
7. ● The OS rate at 1 and 2 years
8. ● The tolerance profile of the combination in the induction phase and the maintenance phase of treatment
9. ❖ Creation of a biological collection for ancillary analysis (To look at the correlation between PD-L1 expression levels, Tumor Mutation Burden (TMB) expression and antitumor activity).

Conditions and MedDRA coding

Lung Cancer, NSCLC

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. ● Patient older than 18 years
2. ● Subject affiliated to an appropriate social security system
3. ● Signed informed consent before any trial related activities and according to local guidelines
4. ● ECOG performance status of 0 or 1
5. ● Histologically or cytologically confirmed, stage IIIB/IV non-squamous NSCLC (per the Union Internationale contre le Cancer/American Joint Committee on Cancer staging system, 7th edition)
6. ● Patient with a sensitizing mutation in the EGFR gene must have experienced disease progression (during or after treatment) or intolerance to treatment with one or more EGFR TKIs, such as erlotinib, gefitinib, osimertinib or another EGFR TKI appropriate for the treatment of EGFR-mutant NSCLC. Patients with stage IIIB had to be not operable (that means not eligible for radiochemotherapy followed by a maintenance treatment by Durvalumab)
7. ● Patient with an ALK fusion oncogene (confirmed in local laboratory) must have experienced disease progression (during or after treatment) or intolerance to treatment with one or more ALK inhibitors (i.e., crizotinib, alectinib, ceritinib) appropriate for the treatment of NSCLC in patients having an ALK fusion oncogene
8. ● Patient with a ROS1 fusion oncogene (confirmed in local laboratory) must have experienced disease progression (during or after treatment) or intolerance to treatment with one or more ROS inhibitors (i.e., crizotinib,) appropriate for the treatment of NSCLC in patients having an ROS1 fusion oncogene
9. ● No prior chemotherapy treatment for Stage IV non-squamous NSCLC except if less than 3 cycles, with treatment free-interval of at least 1 year from C1 since last chemotherapy
10. ● Patient who has received prior neo-adjuvant, adjuvant chemotherapy, radiotherapy, or chemoradiotherapy with curative intent for non-metastatic disease must have experienced a treatment-free interval of at least 6 months from C1since the last chemotherapy, radiotherapy, or chemoradiotherapy
11. ● Patient with an history of asymptomatic CNS metastases is eligible, provided he meets all of the following criteria: ▪ Only supratentorial and cerebellar metastases allowed (i.e., no metastases to midbrain, pons, medulla, or spinal cord) ▪ No ongoing requirement for corticosteroids as therapy for CNS disease ▪ No stereotactic radiation within 7 days or whole-brain radiation within 14 days prior to C1
12. ● Measurable disease, as defined by RECIST v1.1
13. ● Adequate hematologic and end-organ function, defined by the following laboratory ▪ ANC > 1500 /mm3 without granulocyte colony-stimulating factor support ▪ Platelet count > 100,000/mm3 without transfusion ▪ Hemoglobin ≥ 9.0 g/dL. Patients may be transfused to meet this criterion. ▪ INR or aPTT ≤ 1.5 , upper limit of normal (ULN) This applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be receiving a stable dose. ▪ ASAT, ALAT, and alkaline phosphatase ≤ 2.5xULN, with the following exceptions: Patients with documented liver metastases: ASAT and/or ALAT ≤ 5 x ULN Patients with documented liver or bone metastases: alkaline phosphatase < 5xULN ▪ Serum bilirubin ≤1.5xULN Patients with known Gilbert disease who have serum bilirubin level ≤ 3xULN may be enrolled. Patients with documented liver metastases: Serum bilirubin < 3xULN ▪ Calculated creatinine clearance (CRCL) ≥ 45 mL/min or, if using cisplatin, calculated CRCL must be ≥ 60 mL/min using the Cockcroft-Gault Method
14. ● Adequate method of contraception during the treatment period and at least 5 months after the last dose of atezolizumab or 6 months after the last dose of chemotherapy ▪ For women of childbearing potential, agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% per year. ▪ A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). ▪ Examples of non-hormonal contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, and established, proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. ▪ The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. ▪ For men, agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating sperm, as defined below: ▪ With partners of childbearing potential, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the chemotherapy treatment period and for at least 6 months after the last dose of chemotherapy. ▪ With pregnant partners, men must remain abstinent or use a condom during the chemotherapy treatment period and for at least 6 months after the last dose of chemotherapy. ▪ The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception

Exclusion criteria 49

1. ● Active CNS metastases as determined by CT or magnetic resonance imaging (MRI) evaluation during screening and prior radiographic assessments
2. ● Spinal cord compression not definitively treated with surgery and/or radiation or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for ≥ 2 weeks prior to C1
3. ● Leptomeningeal disease (Presence of cancer cells in cerebral CSF or MRI with leptomeningeal lesion strongly suspected of leptomeningeal disease)
4. ● Uncontrolled tumour-related pain ▪ Patients requiring pain medication must be receiving a stable regimen at study entry. ▪ Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or metastases causing nerve impingement) should be treated prior to C1. Patients should be recovered from the effects of radiation. There is no required minimum recovery period. ▪ Asymptomatic metastatic lesions whose further growth would likely cause functional deficits or intractable pain (e.g., epidural metastasis that is not currently associated with spinal cord compression) should be considered for loco-regional therapy, if appropriate, prior to C1.
5. ● Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently); Patients with indwelling catheters (e.g., PleurX®) are allowed.
6. ● Uncontrolled or symptomatic hypercalcemia (>1.5 mmol/L ionized calcium or calcium >12 mg/dL or corrected serum calcium > ULN)
7. ● Malignancies other than NSCLC within 5 years prior to C1, with the exception of those with a negligible risk of metastasis or death (e.g., expected 5-year OS > 90%) treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous-cell skin cancer, localized prostate cancer treated surgically with curative intent, ductal carcinoma in situ treated surgically with curative intent)
8. ● Women who are pregnant, lactating, or intending to become pregnant during the study
9. ● History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
10. ● Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation
11. ● History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis ▪ Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone are eligible for this study. ▪ Patients with controlled Type 1 diabetes mellitus on a stable dose of insulin regimen are eligible for this study ▪ Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions: - Rash must cover less than 10% of body surface area (BSA). - Well controlled disease at baseline only requiring low potency topical steroids. - No acute exacerbations of underlying condition within the previous 12 months (not requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, high-potency or oral steroids)
12. ● History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan; History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
13. ● Positive test for HIV. All patients will be tested for HIV prior to C1 into the study; patients who test positive for HIV will be excluded from the study.
14. ● Patients with active hepatitis B (chronic or acute; defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as the presence of hepatitis B core antibody [HBcAb] and absence of HBsAg) are eligible only if they are negative for HBV DNA. Patients positive for hepatitis C virus (HCV) antibody are eligible only if PCR is negative for HCV RNA.
15. ● Active tuberculosis
16. ● Severe infections within 4 weeks prior to C1, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
17. ● Received therapeutic oral or IV antibiotics within 1 week prior to C1; Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or to prevent chronic obstructive pulmonary disease exacerbation) are eligible.
18. ● Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction, or cerebrovascular accident within 3 months prior to inclusion, unstable arrhythmias, or unstable angina
19. ● Major surgical procedure other than for diagnosis within 28 days prior to C1 or anticipation of need for a major surgical procedure during the course of the study
20. ● Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or renders the patient at high risk from treatment complications
21. ● Symptomatic brain metastases;
22. ● Patients with illnesses or conditions that interfere with their capacity to understand, follow and/or comply with study procedures
23. ● Concurrent participation in any therapeutic clinical trial
24. ● Patient deprived of liberty or placed under the authority of a tutor
25. ● Assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol
26. ● Any approved anti-cancer therapy, including hormonal therapy within 7 days prior to C1 of study treatment.
27. ● Treatment with any other investigational agent with therapeutic intent within 28 days prior to C1
28. ● Prior treatment with CD137 agonists or immune checkpoint blockade therapies, anti-PD-1, and anti-PD-L1 therapeutic antibodies ▪ Patients who have had prior anti-cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) treatment may be enrolled, provided the following requirements are met: ▪ Last dose of anti-CTLA-4 at least 6 weeks prior to C1 ▪ No history of severe immune-related adverse effects from anti-CTLA-4 (NCI CTCAE Grade 3/4)
29. ● Treatment with systemic immunostimulatory agents (including, but not limited to, interferons, interleukin 2) within 4 weeks or 5 half-lives of the drug, whichever is longer, prior to C1; Prior treatment with cancer vaccines is allowed.
30. ● Treatment with systemic immunosuppressive medications (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to C1Patients who have received acute, low-dose (≤ 10 mg oral prednisone or equivalent), systemic immunosuppressant medications may be enrolled in the study. The use of corticosteroids (≤10 mg oral prednisone or equivalent) for chronic obstructive pulmonary disease, mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension, and low-dose supplemental corticosteroids for adrenocortical insufficiency are allowed.
31. ● History of allergic reactions to cisplatin, carboplatin, or other platinum-containing compounds
32. ● Patients with hearing impairment (cisplatin)
33. ● Grade ≥ 2 peripheral neuropathy as defined by NCI CTCAE v5.0 (cisplatin)
34. ● CRCL < 60 mL/min for cisplatin or < 45 mL/min for carboplatin using the Cockcroft-Gault Method
35. ● Medically uncontrolled hypertension (defined as PAS>150 and/or PAD >100 mmHg)
36. ● Prior history of hypertensive crisis or hypertensive encephalopathy
37. ● Clinically significant cardiovascular disease (within 6 months prior to C1) that is uncontrolled by medication or may interfere with administration of trial treatment: − Aortic aneurysm requiring surgical repair − Recent arterial thrombosis − Haemoptysis (>one-half teaspoon of bright red blood per episode (within one months prior to C1) (grade 2 haemoptysis)
38. ● History of documented haemorrhagic diathesis or coagulopathy
39. ● History of abdominal or tracheosphageal fistula or perforation within 6 months prior to C1
40. ● Core biopsy or other minor surgical procedure within 7 days before bevacizumab
41. ● Clinical signs or gastrointestinal obstruction or requirement for routine parenteral hydration, nutrition or tube feeding
42. ● Evidence of abdominal free air not explained by paracentesis or recent surgical procedure
43. ● Major surgery within 28 days before C1
44. ● Serious, non-healing wound, active ulcer or untreated bone fracture
45. ● Proteinuria >1g/24h urine collection
46. ● All patient with >2+ protein on dipstick urinalysis at baseline must undergo a 24-hour urine collection and must demonstrate ≤1g of protein in 24 hours.
47. ● Known sensitivity to any component of bevacizumab
48. ● Radiation therapy within 21 days before C1 (except Symptomatic lesions amenable to palliative radiotherapy)
49. ● Adequate hematologic, liver, and renal function required (including creatinine clearance 45 mL/min at baseline and 45 mL/min before the start of any subsequent cycle using the Cockcroft-Gault Method.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Objective response rate (ORR), defined as the proportion of patients who achieved an objective response after 4 cycles of induction (or before progression). Objective response will be considered in case of radiologically confirmed complete (CR) or partial response (PR) according to RECIST v1.1 criteria (Response Evaluation Criteria in Solid Tumors version 1.1) assessed by masked, independent central review.

Secondary endpoints 6

1. ● Progression-free survival, defined as the time relapsed between inclusion and disease progression (according to RECIST v1.1 criteria as assessed by the investigator) or death from any cause, whichever occurs first
2. ● Duration of response assessed in patients who had an objective response as determined by the investigator using RECIST v1.1 and defined as the time interval from the date of the first occurrence of a CR or PR (whichever status is recorded first) until the first date that progressive disease or death is documented, whichever occurs first
3. ● Time to deterioration in lung-related symptoms, defined as the time from inclusion to the time the patient’s score on the EORTC QLQ C30 or QLQ-LC13 shows a ≥10-point increase above baseline in each of the following EORTC-transformed scores for cough, dyspnea (single item), dyspnea (multi-item subscale) and chest pain.
4. ● Objective response rate according to immune (i)RECIST criteria defined similarly as ORR, with the exception that immune RECIST criteria 2017 are used instead of RECIST v 1.1
5. ● Overall survival, defined as the time between the date of inclusion and death from any cause
6. ● Toxicities occurring during either the induction or maintenance treatment in terms of kind, grade, time of onset, reversibility, according to NCI-CTCAE v5.0 criteria

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Auxiliary 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Francois Baclesse

Sponsor organisation

Centre Francois Baclesse

Address

3 Avenue Du General Harris, Cs 45026 Cs 45026

City

Caen Cedex 5

Postcode

14076

Country

France

Scientific contact point

Organisation

Centre Francois Baclesse

Contact name

Radj GERVAIS

Public contact point

Organisation

Centre Francois Baclesse

Contact name

Jean-Michel GRELLARD

Locations

1 EU/EEA country · 31 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 8 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications