Non Small Cell Lung Cancer
Conditions
Keywords
Advanced Non-Small-Cell Lung Cancer, Therapeutic Cancer Vaccine, Resistance to Immunotherapy, Quality of Life
Brief summary
The aim of this clinical trial was to determine if the therapeutic cancer vaccine OSE2101 (TEDOPI) was more effective than standard chemotherapy (docetaxel or pemetrexed) in treating HLA-A2 positive patients with metastatic NSCLC who progressed after sequential or concurrent chemotherapy and immune checkpoint inhibitor given in first or second-line treatment. The main questions were to compare the survival, the tolerance to treatment and the quality of life of patients between the two arms of treatment (OSE2101 versus standard chemotherapy)
Detailed description
The study was a two-step randomized (2:1) study. Patients were stratified by histology (non-squamous versus squamous), best response to first-line treatment \[complete response or partial response versus stable disease or progressive disease\] and line of treatment with prior ICI (first-line ICI when combined with platinum-based chemotherapy versus second-line ICI when administered as sequential treatment). Primary endpoint was overall survival (OS). Interim OS futility analysis was planned as per Fleming design. In April 2020 at the time of the interim analysis, a decision was taken to early stop the accrual due to COVID-19 after 219 out of 363 patients were randomized. It led to a decrease of the study power from 80% to 62%. At the time of the interim analysis, a subgroup of patients was identified from stratification factor based on a clinical and biological rationale: those who received ICI second line and having received at least 12 weeks ICI. This subgroup was defined as ICI secondary resistance. The final analysis was carried out in the subgroup of patients with ICI secondary resistance and in all patients (ICI primary and secondary resistance).
Interventions
Sponsors
OSE Immunotherapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Two-step open-label study with a planned interim OS futility in experimental arm per Fleming design (Step1) Central randomisation (2:1) with stratification by histology (non-squamous versus squamous), best response to first-line treatment \[complete response (CR) or partial response (PR) versus stable disease (SD) or PD\] and line of prior anti-PD(L)1 treatment (first-line when combined with platinum-based chemotherapy versus second-line when administered as sequential treatment after first-line platinum-based chemotherapy).
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Signed and dated informed consent 2. Willingness and ability to comply with the clinical study procedures. 3. Female or male, 18 years of age or older 4. Histologically or cytologically proven diagnosis of Non-Small Cell Lung Cancer (NSCLC) that is locally advanced (stage III) unsuitable for radiotherapy or metastatic (stage IV) according to the 8th edition of tumor, node, metastasis (TNM) in Lung Cancer 5. Subjects with disease recurrence or progression after immune checkpoint inhibitor and platinum-based chemotherapy: i) either 1st line chemotherapy followed by 2nd line immune checkpoint inhibitor, or ii) 1st line combination of immune checkpoint inhibitor and chemotherapy Patients with progression during or within 12 months after the end of immune checkpoint inhibitor given as sequential or concomitant platinum-based chemotherapy ± radiation for locally advanced disease (stage III) were eligible 6. Subjects with measurable or non-measurable lesions according to RECIST 1.1 7. Subjects must express HLA-A2 phenotype (central test in blood) 8. Subjects must be considered suitable for chemotherapy with single-agent pemetrexed or single-agent docetaxel 9. Subjects with brain metastases were eligible if treated (whole brain radiotherapy, stereotaxic radiotherapy, surgery) at least 3 weeks prior to initiation of study treatment and have no symptoms related to brain metastases for at least 2 weeks before initiation of study treatment and are not taking any forbidden medications 10. Any prior chemotherapy, immunotherapy, hormonal therapy, radiation therapy or surgeries must have been completed at least 3 weeks prior to initiation of study treatment. 11. Any toxicity from prior therapy must have recovered to ≤ Grade 1 (except alopecia) 12. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 13. Adequate organ function as defined by all the following criteria: * Albuminemia \> 25g/L * Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ≤ 1.5 x upper limit of normal (ULN) with alkaline phosphatase ≤ 2.5 x ULN, or AST and ALT ≤ 5 x ULN if liver function abnormalities are due to liver metastases * Total serum bilirubin ≤ 1.5 x ULN * Absolute neutrophil count (ANC) ≥ 1500/L * Platelets ≥ 100000/L * Hemoglobin ≥ 9.0 g/dL (in the absence of transfusion within 2 weeks before randomization) * Creatinine clearance (based on modified Cockcroft-Gault formula) ≥ 45 ml/min.
Exclusion criteria
1. Small-cell lung cancer/mixed NSCLC with small cell component or other neuroendocrine lung cancers (typical and atypical carcinoids, large-cell neuroendocrine carcinomas) 2. Patients with squamous cell carcinoma histology, and who had docetaxel as part of his prior chemotherapy 3. Current or previous treatment with investigational therapy in another therapeutic clinical trial (interrupted less than 4 weeks before study treatment initiation) 4. Patients whose tumor harbors EGFR gene mutation that sensitizes tumors to Tyrosine-Kinase Inhibitor (TKI) (EGFR exon 18-21) or Anaplastic Lymphoma Kinase (ALK) rearrangement 5. Ongoing immunotherapy (checkpoint inhibition, antigen immunotherapy that would be scheduled to continue concomitantly to the study) 6. Spinal cord compression (unless treated with the patient attaining good pain control and stable or recovered neurologic function), carcinomatous meningitis, or leptomeningeal disease 7. Patients with squamous cell histology or non-squamous cell histology previously treated by pemetrexed with a contraindication for docetaxel with grade ≥ 2 neuropathy or hypersensitivity reaction to medications formulated with polysorbate 80 (Tween 80) 8. Patients with a condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications 9. Treatment with corticosteroids in the last 3-week period before inclusion, except for topical, ocular, intra-articular, intranasal, and inhaled corticosteroids with minimal systemic absorption (e.g. with a dose ≤ 500 microgram beclomethasone equivalent for inhaled steroids), or steroid doses ≤ 10 mg daily prednisone equivalent which are permitted 10. A recognized immunodeficiency disease including human immunodeficiency virus (HIV) infection (and other cellular immunodeficiencies, hypogammaglobulinemia or dysgammaglobulinemia; subjects who have hereditary, congenital or acquired immunodeficiencies) 11. Patients with auto-immune disease, with the exception of type I diabetes or treated hypothyroidism 12. Patients with interstitial lung disease 13. Patients with active B or C hepatitis 14. Other malignancy: patients will not be eligible if they have evidence of other active invasive cancer(s) (other than NSCLC) within 5 years prior to screening (except appropriately treated non-melanoma skin cancer or localized cervical cancer, or other local tumors considered cured (e.g.localized and presumed cured prostate cancer) 15. Other severe acute or chronic medical or psychiatric conditions, or laboratory abnormalities that would impart, in the judgment of the investigator and/or sponsor, excess risk associated with study participation or study drug administration, and which would, therefore, make the patient inappropriate for entry into this study 16. Female patients must be surgically sterile or be postmenopausal, or must agree to use effective contraception during the period of the trial and for at least 90 days after completion of treatment 17. Male patients sexually active with a woman of childbearing potential must be surgically sterile or must agree to use effective contraception during the period of the trial and for at least 90 days after completion of treatment. The decision of effective contraception will be based on the judgment of the principal investigator 18. Breastfeeding women 19. Women with a positive pregnancy test.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Approx. 24 months | OS defined as the time from randomisation to death from any cause in patients with ICI secondary resistance |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Changes in Functional Subscales of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Approx. 24 months | Mean change from baseline to treatment discontinuation in Quality of Life (QoL) score of the following functional subscales analyzed separately: global health status, physical, role, cognitive, emotional and social functioning. Each score range from 0 to 100 after normalisation. Highest scores correspond to a better quality of life. The mean score change was assessed using a mixed-effects model for repeated measures analysis with the patient as the random effect, treatment, visit and treatment-by-visit interaction as explanatory variables and baseline score as covariates. If the mean score change is negative, it means a deterioration of QoL. If the mean score change is positive or 0, it means an improvement or stability of QoL |
| Mean Changes in Symptoms Subscales of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Lung Cancer (QLQ-LC13) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Approx. 24 months | Mean change from baseline to treatment discontinuation in Quality of Life (QoL) score of the following symptoms subscales analyzed separately: Alopecia, Peripheral Neuropathy, Sore mouth, Dysphagia, Dyspnea, Pain in arm or shoulder, Pain in chest, Pain in other parts, Hemoptysis, Coughing. Each score range from 0 to 100 after normalisation. Lowest scores correspond to a better QoL. The mean score change was assessed using a mixed-effects model for repeated measures analysis with the patient as the random effect, treatment, visit and treatment-by-visit interaction as explanatory variables and baseline score as covariates. If the mean score change is negative, it means a deterioration of QoL. If the mean score change is positive or 0, it means an improvement or stability of QoL. |
| Disease Control Rate (DCR) at 6 Months | Approx. 6 months | DCR at 6 months defined as the number of patients with Complete Response (CR), Partial Response (PR) or Stable Disease (SD) assessed by investigator per Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions based on CT scan in patients with ICI secondary resistance. Complete Response (CR) defined as disappearance of all target lesions; Partial Response (PR) as \>=30% decrease in the sum of the longest diameter of target lesions; Stable disease (SD) defined as neither sufficient shrinkage (compared to baseline) to qualify for CR or PR nor sufficient increase (taking as reference the smallest sum of diameters at baseline or while on study, whichever is smallest) to qualify for progressive disease (PD) (e.g. decrease of the sum of the longest diameters of target lesions \<30% or increase up to 20%) |
| Progression Free Survival (PFS) in Patients With ICI Secondary Resistance | Approx. 24 months | PFS was defined as the time from randomization to the earliest date of progression assessed by investigator per Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions based on CT scan in patients with ICI secondary resistance. Progressive disease (PD) defined as increase of target lesions \>=20% taking as reference the smallest sum of diameters at baseline or while on study, whichever is smallest) |
| Post-Progression Survival | approximately 24 months | Post-progression survival was defined as the time from the earliest date of progression according to RECIST 1.1 until death in patients with ICI secondary resistance |
| Time to Worsening ECOG PS | Approx. 24 months | Time to Worsening ECOG PS was defined as the time from randomization to the earliest date when ECOG PS was \>1 in patients with ICI secondary resistance. Time to worsening ECPG PS was summarized by treatment arm using the Kaplan-Meier method. The median event time for each treatment arm and the corresponding 2-sided 95% confidence interval were provided. By protocol, ECOG PS was not collected when a patient permanenetly discontinued the study treatment. Patients without ECOG PS worsening were censored at the last time when an ECOG value was recorded. |
| Mean Changes in Symptoms Subscales of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Approx. 24 months | Mean change from baseline to treatment discontinuation in Quality of Life (QoL) score of the following symptoms subscales analyzed separately: Fatigue, Constipation, Dyspnea, Nausea and Vomiting, Pain, Insomnia, Appetite loss, Diarrhea, Financial Difficulties. Each score range from 0 to 100 after normalisation. Lowest scores correspond to a better QoL. The mean score change was assessed using a mixed-effects model for repeated measures analysis with the patient as the random effect, treatment, visit and treatment-by-visit interaction as explanatory variables and baseline score as covariates. If the mean score change is negative, it means a deterioration of QoL. If the mean score change is positive or 0, it means an improvement or stability of QoL. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With Objective Response at 6 Months in ICI Secondary Resistance | Approx. 6 months | Duration of Objective Response (OOR) was defined as number of patients with Complete Response (CR) or Partial Response (PR) at 6 months assessed by investigator per Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions based on CT scan in patients with ICI secondary resistance. Complete Response (CR) defined as disappearance of all target lesions; Partial Response (PR) as \>=30% decrease in the sum of the longest diameter of target lesions |
| Time to Next Lung Cancer Therapy in ICI Secondary Resistance | Approx. 24 months | Time to next lung cancer therapy was defined as the time from randomisation to the date of initiation of the first lung cancer therapy during the survival follow-up form |
| Objective Response Rate (ORR) in ICI Secondary Resistance | Approx. 24 months | Objective Response rate (OOR) was defined as number of patients with Complete Response (CR) + Partial Response (PR) assessed by investigator per Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions based on CT scan in patients with ICI secondary resistance. Complete Response (CR) defined as disappearance of all target lesions; Partial Response (PR) as \>=30% decrease in the sum of the longest diameter of target lesions. Investigator-assessed ORR was an exploratory endpoint as not relevant as primary, nor secondary endpoints to evaluate a cancer vaccine. |
Countries
Czechia, France, Germany, Hungary, Israel, Italy, Poland, Spain, United Kingdom, United States
Participant flow
Recruitment details
From Feb 2016 to Apr 2020, patients with advanced NSCLC were recruited in clinics or hospitals specialized in oncology in Europe, US and Israel to prescreen potential patients for HLA-A2 typing (by central lab). Only HLA-A2 positive patients who fulfilled all eligibility criteria were randomized. A total of 219 patients with ICI resistance were randomized, including 118 patients with ICI secondary resistance (disease progression after ICI \>= 12 weeks - primary population for efficacy analysis)
Pre-assignment details
Only patient with HLA-A2 positive phenotype were eligible
Participants by arm
| Arm | Count |
|---|---|
| OSE2101 Subcutaneous injection at 5 mg, 1 ml every 3 weeks for 6 cycles, then every 8 weeks until 1 year of treatment and thereafter every 12 weeks | 139 |
| Docetaxel or Pemetrexed Docetaxel by intravenous infusion over 1 hour at 75 mg/m2 every 3 weeks Pemetrexed by intravenous infusion over 10 minutes at 500 mg/m2 every 3 weeks both with premedication according to international guidelines | 80 |
| Total | 219 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | patient alive at end of study | 22 | 8 |
| Overall Study | Withdrawal by Subject | 1 | 7 |
Baseline characteristics
| Characteristic | OSE2101 | Docetaxel or Pemetrexed | Total |
|---|---|---|---|
| Age, Categorical All randomized patients with ICI primary and secondary resistance <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical All randomized patients with ICI primary and secondary resistance >=65 years | 70 Participants | 35 Participants | 105 Participants |
| Age, Categorical All randomized patients with ICI primary and secondary resistance Between 18 and 65 years | 69 Participants | 45 Participants | 114 Participants |
| Age, Continuous All randomized patients with ICI primary and secondary resistance | 65.3 years | 63.6 years | 64.7 years |
| Race/Ethnicity, Customized All patients with ICI primary and secondary resistance Asian | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized All patients with ICI primary and secondary resistance Black or African American | 4 Participants | 2 Participants | 6 Participants |
| Race/Ethnicity, Customized All patients with ICI primary and secondary resistance white | 124 Participants | 76 Participants | 200 Participants |
| Region of Enrollment Czechia | 0 participants | 1 participants | 1 participants |
| Region of Enrollment France | 51 participants | 31 participants | 46 participants |
| Region of Enrollment Germany | 2 participants | 3 participants | 1 participants |
| Region of Enrollment Hungary | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Israel | 8 participants | 3 participants | 4 participants |
| Region of Enrollment Italy | 30 participants | 18 participants | 31 participants |
| Region of Enrollment Poland | 1 participants | 3 participants | 2 participants |
| Region of Enrollment Spain | 33 participants | 15 participants | 26 participants |
| Region of Enrollment United States | 14 participants | 5 participants | 7 participants |
| Sex: Female, Male All patients with ICI primary and secondary resistance Female | 40 Participants | 24 Participants | 64 Participants |
| Sex: Female, Male All patients with ICI primary and secondary resistance Male | 99 Participants | 56 Participants | 155 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 116 / 139 | 65 / 80 |
| other Total, other adverse events | 125 / 139 | 67 / 80 |
| serious Total, serious adverse events | 47 / 139 | 33 / 80 |
Outcome results
Primary
Overall Survival (OS)
OS defined as the time from randomisation to death from any cause in patients with ICI secondary resistance
Time frame: Approx. 24 months
Population: OS analysis in patients with ICI secondary resistance defined as disease progression after ICI second line \> or equal to 12 weeks (n=118) OS analysis in the ITT population with ICI resistance (primary and secondary resistance) is described in statistical analysis 2 (n=219)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| OSE2101 | Overall Survival (OS) | 11.1 Months |
| Docetaxel or Pemetrexed | Overall Survival (OS) | 7.5 Months |
p-value: <0.0595% CI: [0.38, 0.91]t-test, 2 sided
Comparison: OS in the ITT population with ICI resistance (primary and secondary resistance)p-value: 0.3695% CI: [0.62, 1.19]t-test, 2 sided
Secondary
Disease Control Rate (DCR) at 6 Months
DCR at 6 months defined as the number of patients with Complete Response (CR), Partial Response (PR) or Stable Disease (SD) assessed by investigator per Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions based on CT scan in patients with ICI secondary resistance. Complete Response (CR) defined as disappearance of all target lesions; Partial Response (PR) as \>=30% decrease in the sum of the longest diameter of target lesions; Stable disease (SD) defined as neither sufficient shrinkage (compared to baseline) to qualify for CR or PR nor sufficient increase (taking as reference the smallest sum of diameters at baseline or while on study, whichever is smallest) to qualify for progressive disease (PD) (e.g. decrease of the sum of the longest diameters of target lesions \<30% or increase up to 20%)
Time frame: Approx. 6 months
Population: 116 out of 118 patients had measurable lesions per RECIST 1.1 at baseline (n=78/80 in OSE2101 arm, 38/38 in docetaxel or pemetrexed arm). One patient had no post-baseline RECIST 1.1 assessement (n=1 in OSE2101 arm).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| OSE2101 | Disease Control Rate (DCR) at 6 Months | 24.7 percentage of participants |
| Docetaxel or Pemetrexed | Disease Control Rate (DCR) at 6 Months | 23.7 percentage of participants |
Comparison: DCR at 6 months in patients with ICI secondary resistancep-value: 0.8795% CI: [0.43, 2.75]Mantel Haenszel
Comparison: DCR at 6 months in ITT patients with ICI resistance (primary and secondary)p-value: 0.3795% CI: [0.36, 1.46]Mantel Haenszel
Secondary
Mean Changes in Functional Subscales of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance
Mean change from baseline to treatment discontinuation in Quality of Life (QoL) score of the following functional subscales analyzed separately: global health status, physical, role, cognitive, emotional and social functioning. Each score range from 0 to 100 after normalisation. Highest scores correspond to a better quality of life. The mean score change was assessed using a mixed-effects model for repeated measures analysis with the patient as the random effect, treatment, visit and treatment-by-visit interaction as explanatory variables and baseline score as covariates. If the mean score change is negative, it means a deterioration of QoL. If the mean score change is positive or 0, it means an improvement or stability of QoL
Time frame: Approx. 24 months
Population: Patients with ICI secondary resistance
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| OSE2101 | Mean Changes in Functional Subscales of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Global Health Status | 0.77 score on a scale |
| OSE2101 | Mean Changes in Functional Subscales of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Physical functioning | -2.74 score on a scale |
| OSE2101 | Mean Changes in Functional Subscales of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Role functioning | -5.09 score on a scale |
| OSE2101 | Mean Changes in Functional Subscales of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Emotional functioning | 0.50 score on a scale |
| OSE2101 | Mean Changes in Functional Subscales of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Cognitive functioning | -3.20 score on a scale |
| OSE2101 | Mean Changes in Functional Subscales of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Social funtioning | -3.82 score on a scale |
| Docetaxel or Pemetrexed | Mean Changes in Functional Subscales of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Cognitive functioning | -7.64 score on a scale |
| Docetaxel or Pemetrexed | Mean Changes in Functional Subscales of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Global Health Status | -6.19 score on a scale |
| Docetaxel or Pemetrexed | Mean Changes in Functional Subscales of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Emotional functioning | -2.75 score on a scale |
| Docetaxel or Pemetrexed | Mean Changes in Functional Subscales of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Physical functioning | -8.75 score on a scale |
| Docetaxel or Pemetrexed | Mean Changes in Functional Subscales of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Social funtioning | -10.43 score on a scale |
| Docetaxel or Pemetrexed | Mean Changes in Functional Subscales of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Role functioning | -16.78 score on a scale |
Comparison: QLQ-C30 Role functioning in patients with ICI secondary resistancep-value: <0.05Mixed Models Analysis
Comparison: QLQ C30 Global Health Status in Patients with ICI secondary resistancep-value: <0.05Mixed Models Analysis
Comparison: QLQ-C30 Physical functioning in patients with ICI secondary resistancep-value: 0.07Mixed Models Analysis
Comparison: QLQ-C30 Emotional functioning in patients with ICI secondary resistancep-value: 0.36Mixed Models Analysis
Comparison: QLQ-C30 Cognitive functioning in patients with ICI secondary resistancep-value: 0.24Mixed Models Analysis
p-value: 0.11Mixed Models Analysis
Secondary
Mean Changes in Symptoms Subscales of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Lung Cancer (QLQ-LC13) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance
Mean change from baseline to treatment discontinuation in Quality of Life (QoL) score of the following symptoms subscales analyzed separately: Alopecia, Peripheral Neuropathy, Sore mouth, Dysphagia, Dyspnea, Pain in arm or shoulder, Pain in chest, Pain in other parts, Hemoptysis, Coughing. Each score range from 0 to 100 after normalisation. Lowest scores correspond to a better QoL. The mean score change was assessed using a mixed-effects model for repeated measures analysis with the patient as the random effect, treatment, visit and treatment-by-visit interaction as explanatory variables and baseline score as covariates. If the mean score change is negative, it means a deterioration of QoL. If the mean score change is positive or 0, it means an improvement or stability of QoL.
Time frame: Approx. 24 months
Population: QLQ-LC 13 symptoms score changes from baseline in patients with ICI secondary resistance
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| OSE2101 | Mean Changes in Symptoms Subscales of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Lung Cancer (QLQ-LC13) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Alopecia | 0.44 units on a scale |
| OSE2101 | Mean Changes in Symptoms Subscales of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Lung Cancer (QLQ-LC13) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Peripheral neuropathy | 2.65 units on a scale |
| OSE2101 | Mean Changes in Symptoms Subscales of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Lung Cancer (QLQ-LC13) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Sore mouth | 0.82 units on a scale |
| OSE2101 | Mean Changes in Symptoms Subscales of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Lung Cancer (QLQ-LC13) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Dysphagia | 0.44 units on a scale |
| OSE2101 | Mean Changes in Symptoms Subscales of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Lung Cancer (QLQ-LC13) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Dyspnea | 4.99 units on a scale |
| OSE2101 | Mean Changes in Symptoms Subscales of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Lung Cancer (QLQ-LC13) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Pain in arm or shoulder | 5.00 units on a scale |
| OSE2101 | Mean Changes in Symptoms Subscales of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Lung Cancer (QLQ-LC13) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Pain in chest | 1.61 units on a scale |
| OSE2101 | Mean Changes in Symptoms Subscales of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Lung Cancer (QLQ-LC13) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Pain in other parts | 8.17 units on a scale |
| OSE2101 | Mean Changes in Symptoms Subscales of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Lung Cancer (QLQ-LC13) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Hemoptysis | 0.05 units on a scale |
| OSE2101 | Mean Changes in Symptoms Subscales of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Lung Cancer (QLQ-LC13) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Coughing | -3.62 units on a scale |
| Docetaxel or Pemetrexed | Mean Changes in Symptoms Subscales of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Lung Cancer (QLQ-LC13) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Pain in other parts | 6.56 units on a scale |
| Docetaxel or Pemetrexed | Mean Changes in Symptoms Subscales of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Lung Cancer (QLQ-LC13) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Alopecia | 25.83 units on a scale |
| Docetaxel or Pemetrexed | Mean Changes in Symptoms Subscales of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Lung Cancer (QLQ-LC13) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Pain in arm or shoulder | 1.16 units on a scale |
| Docetaxel or Pemetrexed | Mean Changes in Symptoms Subscales of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Lung Cancer (QLQ-LC13) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Peripheral neuropathy | 13.23 units on a scale |
| Docetaxel or Pemetrexed | Mean Changes in Symptoms Subscales of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Lung Cancer (QLQ-LC13) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Coughing | -6.67 units on a scale |
| Docetaxel or Pemetrexed | Mean Changes in Symptoms Subscales of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Lung Cancer (QLQ-LC13) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Sore mouth | 8.52 units on a scale |
| Docetaxel or Pemetrexed | Mean Changes in Symptoms Subscales of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Lung Cancer (QLQ-LC13) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Pain in chest | -1.37 units on a scale |
| Docetaxel or Pemetrexed | Mean Changes in Symptoms Subscales of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Lung Cancer (QLQ-LC13) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Dysphagia | 7.41 units on a scale |
| Docetaxel or Pemetrexed | Mean Changes in Symptoms Subscales of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Lung Cancer (QLQ-LC13) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Hemoptysis | -1.84 units on a scale |
| Docetaxel or Pemetrexed | Mean Changes in Symptoms Subscales of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Lung Cancer (QLQ-LC13) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Dyspnea | 5.19 units on a scale |
Comparison: QLQ-LC13 Alopecia in ICI secondary resistancep-value: <0.0001Mixed Models Analysis
Comparison: QLQ-LC 13 Peripheral neuropathy in ICI secondary resistancep-value: 0.03Mixed Models Analysis
Comparison: QLQ-LC13 Sore mouth in ICI secondary resistancep-value: 0.01Mixed Models Analysis
Comparison: QLQ-LC13 Dysphagia in ICI secondary resistancep-value: 0.01Mixed Models Analysis
Comparison: QLQ-LC13 Pain in arm and shoulderp-value: 0.35Mixed Models Analysis
Comparison: QLQ-LC13 Pain in chest in ICI secondary resistancep-value: 0.43Mantel Haenszel
Comparison: QLQ-LC13 Pain in other partsp-value: 0.78Mixed Models Analysis
Comparison: QLQ-LC 13 Hemoptysis in ICI secondary resistancep-value: 0.23Mixed Models Analysis
Comparison: QLQ-LC13 Coughing in ICI secondary resistancep-value: 0.54Mixed Models Analysis
Secondary
Mean Changes in Symptoms Subscales of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance
Mean change from baseline to treatment discontinuation in Quality of Life (QoL) score of the following symptoms subscales analyzed separately: Fatigue, Constipation, Dyspnea, Nausea and Vomiting, Pain, Insomnia, Appetite loss, Diarrhea, Financial Difficulties. Each score range from 0 to 100 after normalisation. Lowest scores correspond to a better QoL. The mean score change was assessed using a mixed-effects model for repeated measures analysis with the patient as the random effect, treatment, visit and treatment-by-visit interaction as explanatory variables and baseline score as covariates. If the mean score change is negative, it means a deterioration of QoL. If the mean score change is positive or 0, it means an improvement or stability of QoL.
Time frame: Approx. 24 months
Population: QLQ-C30 Symptoms score changes from baseline in patients with ICI secondary resistance
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| OSE2101 | Mean Changes in Symptoms Subscales of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Constipation | -5.57 score on a scale |
| OSE2101 | Mean Changes in Symptoms Subscales of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Insomnia | 0.42 score on a scale |
| OSE2101 | Mean Changes in Symptoms Subscales of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Nausea and Vomiting | -1.49 score on a scale |
| OSE2101 | Mean Changes in Symptoms Subscales of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Appetite loss | 0.08 score on a scale |
| OSE2101 | Mean Changes in Symptoms Subscales of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Dyspnea | 3.99 score on a scale |
| OSE2101 | Mean Changes in Symptoms Subscales of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Diarrhea | -4.12 score on a scale |
| OSE2101 | Mean Changes in Symptoms Subscales of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Pain | 4.23 score on a scale |
| OSE2101 | Mean Changes in Symptoms Subscales of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Financial difficulties | 2.22 score on a scale |
| OSE2101 | Mean Changes in Symptoms Subscales of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Fatigue | 4.47 score on a scale |
| Docetaxel or Pemetrexed | Mean Changes in Symptoms Subscales of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Financial difficulties | 5.82 score on a scale |
| Docetaxel or Pemetrexed | Mean Changes in Symptoms Subscales of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Fatigue | 11.95 score on a scale |
| Docetaxel or Pemetrexed | Mean Changes in Symptoms Subscales of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Constipation | 7.84 score on a scale |
| Docetaxel or Pemetrexed | Mean Changes in Symptoms Subscales of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Dyspnea | 2.77 score on a scale |
| Docetaxel or Pemetrexed | Mean Changes in Symptoms Subscales of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Nausea and Vomiting | 1.21 score on a scale |
| Docetaxel or Pemetrexed | Mean Changes in Symptoms Subscales of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Pain | 0.71 score on a scale |
| Docetaxel or Pemetrexed | Mean Changes in Symptoms Subscales of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Insomnia | -0.29 score on a scale |
| Docetaxel or Pemetrexed | Mean Changes in Symptoms Subscales of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Appetite loss | -2.33 score on a scale |
| Docetaxel or Pemetrexed | Mean Changes in Symptoms Subscales of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) From Baseline to Treatment Discontinuation in Patients With ICI Secondary Resistance | Diarrhea | -3.85 score on a scale |
Comparison: QLQ-C30 Fatigue in ICI secondary resistancep-value: 0.06Mixed Models Analysis
Comparison: QLQ-C30 Constipation in ICI secondary resistancep-value: 0.0003Mixed Models Analysis
Comparison: QLQ-C30 Dyspnea in ICI secondary resistancep-value: 0.8Mixed Models Analysis
Comparison: QLQ-C30 Nausea and Vomiting in ICI secondary resistancep-value: 0.21Mixed Models Analysis
Comparison: QLQ-C30 Pain in ICI secondary resistancep-value: 0.45Mixed Models Analysis
Comparison: QLQ-C30 Insomnia in ICI secondary resistancep-value: 0.87Mixed Models Analysis
Comparison: QLQ-C30 Appetite loss in ICI secondary resistancep-value: 0.59Mixed Models Analysis
Comparison: QLQ-C30 Diarrhea in ICI secondary resistancep-value: 0.88Mixed Models Analysis
Comparison: QLQ-C30 Financial difficulties in ICI secondary resistancep-value: 0.37Mixed Models Analysis
Secondary
Post-Progression Survival
Post-progression survival was defined as the time from the earliest date of progression according to RECIST 1.1 until death in patients with ICI secondary resistance
Time frame: approximately 24 months
Population: Patients with ICI secondary resistance defined as disease progression after ICI second line \> or equal to 12 weeks (n=118)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| OSE2101 | Post-Progression Survival | 7.7 months |
| Docetaxel or Pemetrexed | Post-Progression Survival | 4.6 months |
Comparison: Post-progression survival in patients with ICI secondary resistancep-value: 0.00495% CI: [0.27, 0.79]t-test, 2 sided
Comparison: Post-progression survival in ITT population with ICI resistance (primary and secondary)p-value: 0.003595% CI: [0.39, 0.83]t-test, 2 sided
Secondary
Progression Free Survival (PFS) in Patients With ICI Secondary Resistance
PFS was defined as the time from randomization to the earliest date of progression assessed by investigator per Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions based on CT scan in patients with ICI secondary resistance. Progressive disease (PD) defined as increase of target lesions \>=20% taking as reference the smallest sum of diameters at baseline or while on study, whichever is smallest)
Time frame: Approx. 24 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| OSE2101 | Progression Free Survival (PFS) in Patients With ICI Secondary Resistance | 2.69 Months |
| Docetaxel or Pemetrexed | Progression Free Survival (PFS) in Patients With ICI Secondary Resistance | 2.99 Months |
Comparison: Median PFS in patients with ICI secondary resistancep-value: 0.2995% CI: [0.82, 2]t-test, 2 sided
Comparison: Median PFS in ITT patients with ICI resistance (primary and secondary)p-value: <0.0595% CI: [1.18, 2.28]t-test, 2 sided
Secondary
Time to Worsening ECOG PS
Time to Worsening ECOG PS was defined as the time from randomization to the earliest date when ECOG PS was \>1 in patients with ICI secondary resistance. Time to worsening ECPG PS was summarized by treatment arm using the Kaplan-Meier method. The median event time for each treatment arm and the corresponding 2-sided 95% confidence interval were provided. By protocol, ECOG PS was not collected when a patient permanenetly discontinued the study treatment. Patients without ECOG PS worsening were censored at the last time when an ECOG value was recorded.
Time frame: Approx. 24 months
Population: Patients with ICI secondary resistance
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| OSE2101 | Time to Worsening ECOG PS | 9.0 months |
| Docetaxel or Pemetrexed | Time to Worsening ECOG PS | 3.3 months |
Comparison: Time to worsening ECOG PS \>1 in patients with ICI secondary resistancep-value: 0.00695% CI: [0.23, 0.8]t-test, 2 sided
Comparison: Time to worsening ECOG PS in the ITT population with ICI resistance (primary and secondary)p-value: 0.0295% CI: [0.35, 0.92]t-test, 2 sided
Other Pre-specified
Objective Response Rate (ORR) in ICI Secondary Resistance
Objective Response rate (OOR) was defined as number of patients with Complete Response (CR) + Partial Response (PR) assessed by investigator per Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions based on CT scan in patients with ICI secondary resistance. Complete Response (CR) defined as disappearance of all target lesions; Partial Response (PR) as \>=30% decrease in the sum of the longest diameter of target lesions. Investigator-assessed ORR was an exploratory endpoint as not relevant as primary, nor secondary endpoints to evaluate a cancer vaccine.
Time frame: Approx. 24 months
Population: 116 out of 118 patients had measurable lesions per RECIST 1.1 at baseline (n=78/80 in OSE2101 arm, 38/38 in docetaxel or pemetrexed arm). One patient had no post-baseline RECIST 1.1 assessement (n=1 in OSE2101 arm)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| OSE2101 | Objective Response Rate (ORR) in ICI Secondary Resistance | 7.7 percentage of participants |
| Docetaxel or Pemetrexed | Objective Response Rate (ORR) in ICI Secondary Resistance | 18.4 percentage of participants |
p-value: 0.0795% CI: [0.1, 1.11]Mantel Haenszel
p-value: 0.00295% CI: [0.08, 0.59]Mantel Haenszel
Post Hoc
Overall Survival Before and During the COVID-19 Period
Survival was assessed from date of randomisation to death in the pre COVID-19 pandemic (patients randomised before february 2019 and followed up to 12 months) and during COVID-19 pandemic (patients randomised after february 2019 and followed up to january 2021)
Time frame: Approx. 24 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| OSE2101 | Overall Survival Before and During the COVID-19 Period | 9.4 months |
| Docetaxel or Pemetrexed | Overall Survival Before and During the COVID-19 Period | 8.1 months |
p-value: <0.0595% CI: [1, 1.86]t-test, 2 sided
Other Pre-specified
Percentage of Patients With Objective Response at 6 Months in ICI Secondary Resistance
Duration of Objective Response (OOR) was defined as number of patients with Complete Response (CR) or Partial Response (PR) at 6 months assessed by investigator per Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions based on CT scan in patients with ICI secondary resistance. Complete Response (CR) defined as disappearance of all target lesions; Partial Response (PR) as \>=30% decrease in the sum of the longest diameter of target lesions
Time frame: Approx. 6 months
Population: 22 out of 118 patients had an ORR and was analyzed for duration of response (n=7/80 in OSE2101 arm, 15/38 in docetaxel or pemetrexed arm).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| OSE2101 | Percentage of Patients With Objective Response at 6 Months in ICI Secondary Resistance | 33.3 percentage of with objective response |
| Docetaxel or Pemetrexed | Percentage of Patients With Objective Response at 6 Months in ICI Secondary Resistance | 26.8 percentage of with objective response |
p-value: 0.8895% CI: [0.25, 5.3]Regression, Cox
p-value: 0.5795% CI: [0.43, 4.6]Regression, Cox
Other Pre-specified
Time to Next Lung Cancer Therapy in ICI Secondary Resistance
Time to next lung cancer therapy was defined as the time from randomisation to the date of initiation of the first lung cancer therapy during the survival follow-up form
Time frame: Approx. 24 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| OSE2101 | Time to Next Lung Cancer Therapy in ICI Secondary Resistance | 5.4 months |
| Docetaxel or Pemetrexed | Time to Next Lung Cancer Therapy in ICI Secondary Resistance | 9.4 months |
p-value: 0.0495% CI: [1.03, 3.31]Regression, Cox
p-value: 0.0295% CI: [1.07, 2.36]Regression, Cox