Condition médicale (spécialité visée)
Choix aire thérapeutique
Maladies pulmonaires et respiratoires
Oncologie – Poumon
Stades de cancer
Métastatique
Biomarqueur
ALK
EGFR
PD-L1
ROS1
Profil des participants
Sexe(s) des participants
Hommes
Femmes
Aptitude des participants
Majeurs aptes
Critères de sélection
Critères d'inclusion
Critères d'inclusion :
* NSCLC non squameux histologiquement ou cytologiquement documenté.
* Stade IV mNSCLC (selon la 8e édition du Comité conjoint américain sur le cancer) non éligible à un traitement curatif.
* Absence de mutations sensibilisantes EGFR (y compris, mais sans s'y limiter, délétion de l'exon 19 et mutations L858R de l'exon 21, L861Q de l'exon 21, G719X de l'exon 18, et S768I de l'exon 20) et réarrangements ALK et ROS1.
* Absence de résultats de mutation génomique tumorale documentés issus de tests réalisés dans le cadre de la pratique locale standard pour tout autre oncogène conducteur d'action pour lequel il existe des thérapies ciblées 1L approuvées localement.
* Fourniture d'un échantillon tumoral acceptable, pour confirmer l'expression de PD-L1 tumorale TC ≥ 1%.
* Au moins une lésion non précédemment irradiée qui qualifie comme une TL RECIST 1.1 à la ligne de base et peut être mesurée avec précision à la ligne de base comme ≥ 10 mm dans le plus long diamètre (à l'exception des ganglions lymphatiques, qui doivent avoir un axe court ≥ 15 mm) avec CT ou IRM et convient pour des mesures répétées précises.
* Fonction adéquate des organes et de la moelle osseuse
Critères d'exclusion :
* Présence de composants histologiques à petites cellules et neuroendocrines.
* Métastases cérébrales sauf si asymptomatiques, stables et ne nécessitant pas de stéroïdes ou d'antiépileptiques pendant au moins 7 jours avant la randomisation. Un minimum de 2 semaines doit s'être écoulé entre la fin du traitement local (radiothérapie cérébrale ou chirurgie) et la randomisation. Les participants doivent s'être remis de l'effet toxique aigu de la radiothérapie (par exemple, vertiges et signes d'augmentation de la pression intracrânienne) ou de la chirurgie avant la randomisation.
* Tout traitement systémique antérieur reçu pour un NSCLC avancé ou mNSCLC. Un traitement systémique antérieur dans un cadre néoadjuvant ou adjuvant et/ou une radio- ou chimioradiothérapie définitive pour une maladie de stade précoce sont autorisés, à condition que la récidive ou la progression se soit produite > 12 mois après la fin du traitement.
* Toute exposition antérieure à une thérapie anti-TIGIT ou à toute autre thérapie anticancéreuse ciblant les récepteurs ou mécanismes régulateurs immunitaires.
* Tout traitement antérieur avec un agent anti-PD-1 ou anti-PD-L1.
* Antécédents d'une autre malignité primaire sauf pour une malignité traitée avec intention curative sans maladie active connue ≥ 2 ans avant la première dose de l'intervention à l'étude et à faible risque potentiel de récidive.
* Troubles auto-immuns ou inflammatoires actifs ou documentés antérieurement nécessitant un traitement chronique avec des stéroïdes ou d'autres traitements immunosuppresseurs.
* Déficience immunitaire primaire active/maladie(s) infectieuse(s) active(s).
* Infection tuberculeuse active.
Inclusion Criteria:
* Histologically or cytologically documented non-squamous NSCLC.
* Stage IV mNSCLC (based on the American Joint Committee on Cancer Edition 8) not amenable to curative treatment.
* Absence of sensitizing EGFR mutations (including, but not limited to, exon 19 deletion and exon 21 L858R, exon 21 L861Q, exon 18 G719X, and exon 20 S768I mutations) and ALK and ROS1 rearrangements.
* Absence of documented tumor genomic mutation results from tests conducted as part of standard local practice in any other actionable driver oncogenes for which there are locally approved targeted 1L therapies.
* Provision of acceptable tumor sample, to confirm tumor PD-L1 expression TC ≥ 1%.
* At least one lesion not previously irradiated that qualifies as a RECIST 1.1 TL at baseline and can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes, which must have short axis ≥ 15 mm) with CT or MRI and is suitable for accurate repeated measurements.
* Adequate organ and bone marrow function
Exclusion Criteria:
* Presence of small cell and neuroendocrine histology components.
* Brain metastases unless asymptomatic, stable, and not requiring steroids or anticonvulsants for at least 7 days prior to randomization. A minimum of 2 weeks must have elapsed between the end of local therapy (brain radiotherapy or surgery) and randomization. Participants must have recovered from the acute toxic effect of radiotherapy (eg, dizziness and signs of increased intracranial pressure) or surgery prior to randomization.
* Any prior systemic therapy received for advanced or mNSCLC. Prior systemic therapy in the neoadjuvant or adjuvant setting and/or definitive radio- or chemoradiotherapy for early-stage disease are allowed, provided that recurrence or progression has occurred \> 12 months after the end of treatment.
* Any prior exposure to an anti-TIGIT therapy or any other anticancer therapy targeting immune-regulatory receptors or mechanisms.
* Any prior treatment with an anti-PD-1 or anti-PD-L1 agent.
* History of another primary malignancy except for malignancy treated with curative intent with no known active disease ≥ 2 years before the first dose of study intervention and of low potential risk for recurrence.
* Active or prior documented autoimmune or inflammatory disorders requiring chronic treatment with steroids or other immunosuppressive treatment.
* Active primary immunodeficiency/active infectious disease(s).
* Active tuberculosis infection.
Critères d'exclusion
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1 As judged by the investigator, any severe or uncontrolled systemic diseases, including, but not limited to, uncontrolled hypertension, and active bleeding diseases, ongoing or active known infection; ILD (of any grade), serious chronic gastrointestinal conditions associated with diarrhea (eg, active inflammatory bowel disease), active non-infectious skin disease (including any grade rash, urticaria, dermatitis, ulceration, or psoriasis) requiring systemic treatment, psychiatric illness/social situations, substance abuse, or significant cardiac conditions which, in the investigator’s opinion, makes it undesirable for the participant to participate in the study or that would jeopardize compliance with the protocol.
2 History of organ transplant.
3 Active or prior documented autoimmune or inflammatory disorders requiring chronic treatment with steroids or other immunosuppressive treatment.
4 History of another primary malignancy except for malignancy treated with curative intent with no known active disease ≥ 2 years before the first dose of study intervention and of low potential risk for recurrence. Exceptions include adequately resected non-melanoma skin cancer and curatively treated in situ disease.
5 Presence of small cell and neuroendocrine histology components.
6 Persistent toxicities (CTCAE Grade ≥ 2) caused by previous anticancer therapy, excluding alopecia. Participants may be enrolled with the following chronic, stable Grade 2 toxicities (defined as no worsening to > Grade 2 for at least 3 months prior to the first dose of study intervention and managed with SoC treatment) which the investigator deems related to previous anticancer therapy:
(a) Chemotherapy-induced neuropathy.
(b) Fatigue.
(c) Vitiligo.
(d) Endocrine disorders, that are controlled with replacement hormone therapy.
(e) Participants with irreversible toxicity that is not reasonably expected to be exacerbated by study intervention in the opinion of the investigator may be included (eg, hearing loss).
7 Spinal cord compression.
8 Brain metastases unless asymptomatic, stable, and not requiring steroids or anticonvulsants for at least 4 weeks prior to start of study intervention. A minimum of 2 weeks must have elapsed between the end of brain radiotherapy and study enrollment. Participants must have recovered from the acute toxic effect of radiotherapy (eg, dizziness and signs of increased intracranial pressure).
9 Active primary immunodeficiency/active infectious disease(s): Known active hepatitis A, chronic or active hepatitis B, or chronic or active hepatitis C infection:
- Participants who have chronic HBV and are receiving suppressive antiviral therapy are allowed to be enrolled if viral load is controlled and ALT is normal. Those with ALT < 3 × ULN (in presence of liver metastases), not attributable to HBV infection and with controlled viral load could be enrolled. Controlled hepatitis B viral load is defined as serum HBV DNA < 100 U/mL by PCR. Participants with controlled hepatitis B viral load must remain on antiviral therapy, per institutional practice, during the study treatment and follow-up period to ensure adequate viral suppression.
- Participants who have chronic HCV are allowed to be enrolled if ALT is normal and HCV RNA undetectable by PCR, either spontaneously or in response to a successful prior course of anti-hepatitis C therapy. Controlled hepatitis C
viral load is defined as undetectable HCV RNA by PCR either spontaneously or in response to a successful prior course of anti-hepatitis C therapy.
• Known HIV infection that is not well controlled. All of the following criteria are required to define an HIV infection that is well controlled: undetectable viral RNA load, CD4+ count of ≥ 350 cells/μL, no history of AIDS-defining opportunistic infection within the past 12 months, and stable for at least 4 weeks on the same anti-HIV medications.
10 Active tuberculosis infection (clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice).
11 History of clinically significant arrhythmia, cardiomyopathy of any etiology; symptomatic congestive heart failure (as defined by New York Heart Association class ≥ 3), history of myocardial infarction within the past 6 months.
12 Medical contraindication to platinum-based doublet chemotherapy.
Prior/Concomitant Therapy
13 Any concomitant medication known to be associated with Torsades de pointes.
14 Any prior systemic therapy received for advanced or mNSCLC.
Note: Prior systemic therapy in the neoadjuvant or adjuvant setting and/or definitive radio- or chemoradiotherapy for early-stage resectable disease are allowed, provided that recurrence or progression has occurred > 12 months after the end of treatment.
15 Any prior exposure to an anti-TIGIT therapy or any other anticancer therapy targeting immune-regulatory receptors or mechanisms.
16 Any prior treatment with an anti-PD-1 or anti-PD-L1 agent.
17 Any concurrent chemotherapy, radiotherapy, immunotherapy, investigational, or biologic or hormonal therapy for cancer treatment other than those under investigation in this study. Concurrent use of hormonal therapy for non-cancer-related conditions (eg, insulin for diabetes, HRT, gonadotropin-releasing hormone analogs, and bisphosphonates) is acceptable.
18 Palliative radiotherapy with a limited field of radiation within 2 weeks or with a wide field of radiation or to more than 30% of the bone marrow within 4 weeks, prior to the first dose of study intervention. Note: Local treatment of isolated lesions for palliative intent is acceptable
19 Major surgical procedure (excluding placement of vascular access) or significant traumatic injury within 4 weeks of the first dose of study intervention or an anticipated
need for major surgery during the study. Note: Local surgery of isolated lesions for palliative intent is acceptable.
20 Current or prior use of immunosuppressive medication within 14 days before the first dose of study intervention is excluded. The following are exceptions to this criterion
(a) Intranasal, inhaled, topical steroids, or local steroid injections (eg, intraarticular injection).
(b) Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication), as premedication for chemotherapy, or a single dose for palliative purpose (eg, pain control).
(c) Systemic corticosteroids at physiological doses not to exceed 10 mg/day of prednisone or 2 mg/day of dexamethasone or equivalent (except for the treatment of adverse events)
21 Herbal or natural products intended as treatment or prophylaxis for any type of cancer that may interfere with the activity of the study intervention are excluded.
22 Receipt of live attenuated vaccine within 30 days prior to the first dose of study intervention. Note: Participants, if enrolled, should not receive live vaccine while receiving study intervention and up to 30 days after the last dose of study intervention. See
Prior/Concurrent Clinical Study Experience
23 Participation in another clinical study with a study intervention or investigational medicinal device administered in the last 12 months or the combination/comparator agent (unless the safety profile is known prior to randomization), or concurrent enrollment in another clinical study (unless the study is observational [non-interventional], or the participant is in the follow-up period of an interventional study).
24 Participants with a known hypersensitivity to study intervention or any excipients of the products.
Other Exclusions
25 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
26 Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.
27 Previous enrollment in the present study.
28 For females only: Currently pregnant (confirmed with positive pregnancy test) or breast-feeding, or who are planning to become pregnant.
29 Female participants should refrain from breastfeeding from screening throughout the study and until 4 months after last dose of blinded study treatment and 6 months after last dose of chemotherapy.