Condition médicale (spécialité visée)
Choix aire thérapeutique
CPNPC
Stades de cancer
Métastatique
Avancé
Biomarqueur
ROS1
PD-L1
EGFR
ALK
Autre
TROP2
Profil des participants
Sexe(s) des participants
TOUS
Aptitude des participants
Majeurs aptes
Critères de sélection
Critères d'inclusion
Critères d'inclusion :
* Participants ≥ 18 ans lors du dépistage
* NSCLC documenté histologiquement ou cytologiquement qui, au moment de la randomisation, est une maladie de stade IIIB ou IIIC non résécable chirurgicalement ou par chimioradiation définitive ou une maladie métastatique de stade IV
* Absence de mutation du tissu tumoral EGFR sensibilisant et de réarrangements ALK et ROS1 et absence d'altérations génomiques tumorales documentées dans NTRK, BRAF, RET, MET ou autres oncogènes moteurs actionnables avec des thérapies approuvées et disponibles (altérations génomiques actionnables).
Les tests ne sont pas requis pour les tumeurs à histologie squameuse, sauf exceptions.
* ECOG PS de 0 ou 1
* Tissu tumoral d'archive
* Réserve de moelle osseuse adéquate et fonction organique dans les 7 jours avant la randomisation
Critères d'exclusion :
* Histologie de cancer du poumon à petites cellules mixtes et NSCLC; variante sarcomatoïde de NSCLC
* Antécédents d'une autre malignité primaire avec exceptions
* Toxicités persistantes causées par une thérapie anticancéreuse précédente non encore améliorées à la Grade ≤ 1 ou à la base, avec exceptions.
* Compression de la moelle épinière ou métastases cérébrales actives cliniquement ou radiologiquement
* Antécédents de carcinomatose méningée.
* Infection active ou non contrôlée par le virus de l'hépatite B ou C.
* Infection non contrôlée ou suspectée nécessitant des antibiotiques, antiviraux ou antifongiques IV.
* Maladie cornéenne cliniquement significative
* Antécédents de ILD/pneumonite non infectieuse nécessitant des stéroïdes, ILD/pneumonite actuelle, ou ILD/pneumonite suspectée ne pouvant être exclue par imagerie lors du dépistage.
Inclusion:
* Participants ≥ 18 years at screening
* Histologically or cytologically documented NSCLC that at the time of randomisation is Stage IIIB or IIIC disease not amenable to surgical resection or definitive chemoradiation or Stage IV metastatic disease
* Lacks sensitising EGFR tumour tissue mutation and ALK and ROS1 rearrangements and has no documented tumour genomic alterations in NTRK, BRAF, RET, MET or other actionable driver oncogenes with approved and available therapies (actionable genomic alterations).
Testing is not required for tumors with squamous histology, with exceptions.
* ECOG PS of 0 or 1
* Archival tumour tissue
* Has adequate bone marrow reserve and organ function within 7 days before randomization
Exclusion:
* Mixed small-cell lung cancer and NSCLC histology; sarcomatoid variant of NSCLC
* History of another primary malignancy with exceptions
* Persistent toxicities caused by previous anti-cancer therapy not yet improved to Grade ≤ 1 or baseline, with exceptions.
* Spinal cord compression or clinically or radiologically active brain metastases
* History of leptomeningeal carcinomatosis.
* Known active or uncontrolled hepatitis B or C virus infection.
* Uncontrolled or suspected infection requiring IV antibiotics, antivirals, or antifungals.
* Clinically significant corneal disease
* History of non-infectious ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
Critères d'exclusion
5.2 Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1 As judged by the investigator, any evidence of diseases (such as severe or uncontrolled
systemic diseases, including active bleeding diseases, active infection, active
ILD/pneumonitis, serious chronic gastrointestinal conditions associated with diarrhoea,
psychiatric illness/social situations or significant cardiac conditions), or history of
allogenic organ transplant, which, in the investigator’s opinion, makes it undesirable for
the participant to participate in the study or that would jeopardise compliance with the
protocol.
History of another primary malignancy except for malignancy treated with curative intent
with no known active disease within 3 years before the first dose of study intervention
and of low potential risk for recurrence, adequately resected basal cell carcinoma of the
skin or squamous cell carcinoma of the skin, lentigo maligna that has undergone
potentially curative therapy or adequately treated in situ disease without evidence of
disease.
3 Mixed small-cell lung cancer and NSCLC histology; sarcomatoid variant of NSCLC.
4 Persistent toxicities caused by previous anti-cancer therapy, excluding alopecia or
vitiligo, not yet improved to Grade ≤ 1 or baseline. Note: participants may be enrolled
with some chronic, stable Grade 2 toxicities (defined as no worsening to > Grade 2 for at
least 3 months prior to randomisation and managed with SoC treatment) which the
investigator deems related to previous anti-cancer therapy, including (but not limited to):
Chemotherapy-induced neuropathy.
Fatigue.
Participants with irreversible toxicity that is not reasonably expected to be exacerbated by
study intervention may be included (eg, hearing loss) after consultation with the
AstraZeneca study clinical lead.
5 Active or prior documented autoimmune, connective tissue or inflammatory disorders
(including inflammatory bowel disease [eg, colitis or Crohn’s disease], diverticulitis,
systemic lupus erythematosus, Sjögren’s syndrome, sarcoidosis (granulomatosis with
polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, etc.),
autoimmune pneumonitis and autoimmune myocarditis. The following are exceptions to
this criterion:
Participants with vitiligo or alopecia.
Participants with hypothyroidism (eg, following Hashimoto syndrome) stable on
hormone replacement.
Any chronic skin condition that does not require systemic therapy.
Participants without active disease in the last 5 years may be included but only after
consultation with the study clinical lead.
Participants with coeliac disease controlled by diet alone.
6 Spinal cord compression or brain metastases unless asymptomatic, stable, and not
requiring steroids for at least 7 days prior to randomisation. Participants with treated brain
metastases that are no longer symptomatic and who require no treatment with
corticosteroids or anticonvulsants must have recovered from the acute toxic effect of
radiotherapy. A minimum of 2 weeks must have elapsed between the end of radiotherapy
and study enrolment.
7 History of leptomeningeal carcinomatosis.
Clinically significant corneal disease.
9 Known active or uncontrolled hepatitis B or C virus infection. Participants are eligible if
they:
(a) Have been curatively treated for hepatitis C virus infection as demonstrated clinically
and by viral serologies.
(b) Have received hepatitis B virus vaccination with only anti-hepatitis B virus surface
antibody positivity and no clinical signs of hepatitis.
(c) Are hepatitis B surface antigen-negative and anti-hepatitis B core antibody-positive
(ie, those who cleared hepatitis B virus after infection) and meet conditions i to iii
below:
(d) Are hepatitis B surface antigen-positive with chronic hepatitis B virus infection
(lasting 6 months or longer) and meet conditions i to iii below:
(i) Hepatitis B virus DNA viral load < 2000 IU/mL.
(ii) Have normal transaminase values, or if liver metastases are present, abnormal
transaminases, with a result of AST/ALT < 3 × ULN, which are not attributable
to hepatitis B virus infection.
(iii) Start or maintain antiviral treatment if clinically indicated as per the investigator.
10 Uncontrolled infection requiring i.v. antibiotics, antivirals or antifungals; suspected
infections (eg, prodromal symptoms); or inability to rule out infections (participants with
localised fungal infections of skin or nails are eligible).
11 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, CD4+ count
≥ 350, no history of acquired immune deficiency syndrome-defining opportunistic
infection within the past 12 months, and stable for at least 4 weeks on the same anti-HIV
medications (meaning there are no expected further changes in that time to the number or
type of antiretroviral drugs in the regimen). If an HIV infection meets the above criteria,
monitoring of viral RNA load and CD4+ count is recommended and should be performed
per local SoC (eg, every 3 months) in order to determine whether the infection is
controlled and whether the participant is eligible for inclusion into the study. Participants
must be tested for HIV if acceptable by local regulations or an IRB/EC.
12 Known to have active tuberculosis infection (clinical evaluation that may include clinical
history, physical examination and radiographic findings, or tuberculosis testing in line
with local practice).
13 Mean resting QTcF > 470 ms, regardless of gender obtained from triplicate 12-lead ECGs
performed at screening.
14 Uncontrolled or significant cardiac disease including myocardial infarction or
uncontrolled/unstable angina within 6 months prior to randomisation, congestive heart
failure (New York Heart Association Class II to IV), cardiac arrhythmia requiring
treatment, or uncontrolled hypertension (resting systolic blood pressure > 180 mmHg or
diastolic blood pressure > 110 mmHg). Participants with atrial fibrillation controlled by
medication or arrhythmias controlled by pacemakers may be permitted upon discussion
with the study clinical lead.
15 History of non-infectious ILD/pneumonitis that required steroids, has current
ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging
at screening.
16 Clinically severe pulmonary function compromise resulting from intercurrent pulmonary
illnesses including, but not limited to, any underlying pulmonary disorder (eg, pulmonary
emboli within 3 months of the study enrolment, severe asthma, severe COPD, restrictive
lung disease, pleural effusion, etc.).
Prior/Concomitant Therapy
17 Prior exposure to:
(a) Durvalumab.
(b) Any agent including ADC containing a chemotherapeutic agent targeting
topoisomerase I.
(c) Chemotherapy or any other systemic therapy for first-line Stage IIIB, IIIC or IV
NSCLC.
(d) TROP2-targeted therapy.
(e) Chloroquine/hydroxychloroquine without an adequate treatment washout period of
> 14 days prior to randomisation.
18 Participants who have received prior anti-PD-1, anti-PD-L1, or anti-cytotoxic
T-lymphocyte-associated antigen-4 (CTLA-4) in the adjuvant or neoadjuvant setting:
(a) Must not have experienced a toxicity that led to permanent discontinuation of prior
immunotherapy.
(b) All AEs while receiving prior immunotherapy must have completely resolved or
resolved to baseline prior to screening for this study.
(c) Must not have experienced a Grade ≥ 3 immune-related AE or an immune-related
neurologic or ocular AE of any grade while receiving prior immunotherapy. Note:
Participants with an endocrine AE of Grade ≤ 2 are permitted to enrol if they are
stably maintained on appropriate replacement therapy and are asymptomatic.
(d) Must not have required the use of additional immunosuppression other than
corticosteroids for the management of an AE, not have experienced recurrence of an
AE if re-challenged, and not currently require doses of > 10 mg prednisone or
equivalent per day.
19 Current or prior use of immunosuppressive medication within 14 days before the first
dose of study intervention. The following are exceptions to this criterion:
Intranasal, inhaled, topical steroids or local steroid injections (eg, intra-articular
injection).
Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone
or its equivalent.
Steroids as premedication for hypersensitivity reactions or as an anti-emetic (eg, CT
scan premedication).
Use of steroids for known central nervous system metastases and/or carcinomatous
meningitis (see exclusion criterion 6).
20 Receipt of live attenuated vaccine within 30 days prior to the first dose of study
intervention (see Appendix I 2).
21 Any concurrent anti-cancer treatment. Concurrent use of hormonal therapy for
non-cancer-related conditions (eg, HRT) is acceptable.
22 Palliative radiotherapy with a limited field of radiation within ≤ 2 weeks or with wide
field of radiation to chest or to more than 30% of the bone marrow within ≤ 4 weeks
before the first dose of study intervention.
23 Major surgical procedure or significant traumatic injury within ≤ 3 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.
Prior/Concurrent Clinical Study Experience
24 Previous randomisation/treatment in the present study or a previous clinical study of
Dato-DXd and/or durvalumab regardless of treatment group assignment.
25 Participation in another clinical study with a study intervention or investigational
medicinal device administered in the last 4 weeks prior to randomisation or concurrent
enrolment in another clinical study unless it is an observational (non-interventional)
clinical study or during the follow-up period of an interventional study.
26 Participants with a known hypersensitivity to study intervention or any of the excipients
of these products including but not limited to polysorbate 80 or other mAbs.
Other Exclusions
27 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
staff and/or staff at the study site).
28 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.
29 Currently pregnant (confirmed with positive pregnancy test), breastfeeding or planning to
become pregnant.