ALK Gene Rearrangement Positive, EGFR Gene Mutation, NSCLC Stage IIIB, NSCLC Stage IV, ROS1 Gene Mutation
Conditions
Brief summary
The objective of this study is 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.
Detailed description
In patients with an EGFR mutation, several phase III studies comparing EGFR tyrosine kinase inhibitors (TKIs) with chemotherapy have shown a benefit of TKI over chemotherapy, with no demonstrated benefit on overall survival. After a first line of treatment with a TKI, most patients progress and are eligible according to the mechanism of progression to a TKI of 3rd generation in case of T790M resistance or chemotherapy. In patients with ALK translocation, crizotinib has been shown to be beneficial in first line compared to a platinum doublet.Despite these major advances, most patients are progressing after targeted treatments and chemotherapy and are facing the problem of anti-PD1 / PDL1 treatment.
Interventions
DRUGCarboplatin + Pemetrexed + Atezolizumab + Bevacizumab
4 cycles of induction every 3 weeks of cisplatine,pemetrexed, atezolizumab + bevacizumab and patients without disease progression, treatment will be followed by maintenance therapy by Atezolizumab + Pemetrexed +/- Bevacizumab administered at the same dosage on 3-week cycles
DRUGCarboplatin + Pemetrexed + Atezolizumab
Carboplatin + Pemetrexed + Atezolizumab
Sponsors
Centre Francois Baclesse
GFPC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open-label, multicentre, non-randomized two parallel cohorts phase II study
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Patient older than 18 years * Subject affiliated to an appropriate social security system * Signed informed consent before any trial related activities and according to local guidelines * ECOG performance status of 0 or 1 * 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). * 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) * 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 * 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 * 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 * 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 * 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 inclusion * Measurable disease, as defined by RECIST v1.1 * Adequate hematologic and end-organ function, defined by the following laboratory * 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
Exclusion criteria
Cancer-specific exclusions * Active CNS metastases as determined by CT or magnetic resonance imaging (MRI) evaluation during screening and prior radiographic assessments * 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 \> or = 2 weeks prior to C1 * Leptomeningeal disease (Presence of cancer cells in cerebral CSF or MRI with leptomeningeal lesion strongly suspected of leptomeningeal disease ) * Uncontrolled tumour-related pain * 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. * Uncontrolled or symptomatic hypercalcemia (\>1.5 mmol/L ionized calcium or calcium \>12 mg/dL or corrected serum calcium \> ULN) * Malignancies other than NSCLC within 5 years prior to C1, with the exception of those with a negligible risk of metastasis or death 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) General medical exclusions * Women who are pregnant, lactating, or intending to become pregnant during the study * History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins * Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation * 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, Sjogren'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 are permitted provided that they meet the following conditions: * Rash must cover less than 10 percent of body surface area (BSA). * 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) * 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. * 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. * 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. * Active tuberculosis * Severe infections within 4 weeks prior to C1, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia * 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. * 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 * 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 * 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 * Symptomatic brain metastases; * Patients with illnesses or conditions that interfere with their capacity to understand, follow and/or comply with study procedures * Concurrent participation in any therapeutic clinical trial * Patient deprived of liberty or placed under the authority of a tutor * Assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) According to RECIST 1.1 | After the end of 4 cycles (15 weeks) | The objective response rate (ORR) is defined as the percentage of patients who achieved an objective response after 4 cycles of induction treatment (or before progression). Objective response will be considered in case of radiologically confirmed complete (CR) or partial response (PR) according to RECIST v 1.1 criteria (Response Evaluation Criteria in Solid Tumors version 1.1) by the masked, independent central board. Per RECIST v1.0, for target lesions and assessed by MRI: 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. Patients not meeting these criteria, including patients without any post-baseline tumour assessment, will be considered non-responders. The confirmation of response in accordance with RECIST v.1.1 is not required, but ORR with confirmation may be evaluated as an exploratory endpoint. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Progression-free Survival (PFS) | 1 year | PFS is 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. Patients who have not progressed and who have not died at the time of analysis will be censored at the time of last tumour assessment date. If no tumour assessments were performed after the date of the first occurrence of a CR or PR, PFS will be censored at the date of the first occurrence of a CR or PR plus 1 day. Progression is defined according to Response Evaluation Criteria In Solid Tumors (RECIST v1.1) as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum recorded on study, with an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or the appearance of new lesions. |
| The Overall Survival | 2 years | OS is defined as the time between the date of inclusion and death from any cause. Patients who are not reported as having died at the date of analysis will be censored at the date when they were last known to be alive. Patients who do not have post-baseline information will be censored at the date of inclusion plus 1 day. |
| The Duration of Response | 1 year | Duration of response will be assessed in patients who had an objective response (CR or PR) as determined by the investigator using RECIST v1.1. DOR is 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. Patients who have not progressed and who have not died at the time of analysis will be censored at the time of last tumour assessment date. If no tumour assessments were performed after the date of the first occurrence of a CR or PR, DOR will be censored at the date of the first occurrence of a CR or PR plus 1 day. |
Countries
France
Participant flow
Recruitment details
A total of 168 patients were screened from September 2019 to October 2021 in 27 centres and 149 were included : 71 in the cohort with bevacizumab (PPAB cohort) and 78 in the cohort without bevacizumab (PPA cohort).
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 63.4 years STANDARD_DEVIATION 10.2 |
| Race and Ethnicity Not Collected | 0 Participants |
| Sex: Female, Male Female | 49 Participants |
| Sex: Female, Male Male | 60 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 6 / 68 | 4 / 72 |
| other Total, other adverse events | 68 / 68 | 65 / 72 |
| serious Total, serious adverse events | 33 / 68 | 29 / 72 |
Outcome results
None listed