This is an open-label, non-randomised, phase II, multi-centre clinical trial
26 patients will be enrolled in this trial to evaluate the major pathologic response in
patients with neoadjuvant treatment with Carboplatin Pemetrexed Bevacizumab plus Atezolizumab
in patients with non-small cell lung carcinoma locally advanced mutated in EGFR
This is an open-label, non-randomised, phase II, multi-centre clinical trial. Patients
enrolled will receive Atezolizumab 1200mg + Bevacizumab 15mg/Kg + Carboplatin AUC6 +
Pemetrexed 500mg/m2 for 3 cycles every 21 days (+/- 3 days) as neoadjuvant treatment followed
by surgery and 6 months of adjuvant treatment with Atezolizumab 1200 mg Q4W (+/- 3 days).
The primary objective is to evaluate the major pathologic response defined as 10 percent or
fewer viable cancer cells detectable in the resected tumor and in lymph nodes in stage IIIA
EGFR mutated patients treated in neoadjuvant setting with atezolizumab- bevacizumab-
carboplatin and pemetrexed.
Patient accrual is expected to be completed within 2 years excluding a run-in-period of 3-6
months. Treatment and follow-up are expected to extend the study duration to a total of 6
years. Patients will be followed 3 years after adjuvant treatment. The study will end once
survival follow-up has concluded. This will be followed by a close out period of 4 months.
- 1. Previously untreated patients with histologically- or cytologically- documented
NSCLC who present stage IIIA disease (according to 8th version of the International
Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology). PET/CT
including IV contrast (CT of diagnostic quality) will be performed at baseline (28
days +10 before randomization).
- 2. Tumor should be considered resectable before study entry by a multidisciplinary
- 3. Sensitizing EGFR mutation (Del Exon 19 and ins Exon 21).
- 4. ECOG (Performance status) 0-1
- 5. Screening laboratory values must meet the following criteria and should be obtained
within 14 days prior to randomization i. Neutrophils ≥ 1500×109/L ii. Platelets ≥ 100
×109/L iii. Hemoglobin > 9.0 g/dL iv. Serum creatinine ≤ 1.5 x ULN or creatinine
clearance (CrCl) ≥ 40 mL/min (if using the Cockcroft-Gault formula below): a. Female
CrCl = (140 - age in years) x weight in kg x 0.85/ 72 x serum creatinine in mg/dL b.
Male CrCl = (140 - age in years) x weight in kg x 1.00/ 72 x serum creatinine in mg/dL
v. AST/ALT ≤ 3 x ULN vi. Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert
Syndrome, who can have total bilirubin < 3.0 mg/dL) vii. PT/APTT/INR within normal
- 6. Measurable or evaluable disease according to RECIST v1.1.
- 7. The patients need to have a forced expiratory volume (FEV1)≥ 1.2 liters or >40% p-
- 8. All patients are notified of the investigational nature of this study and signed a
written informed consent in accordance with institutional and national guidelines,
including the Declaration of Helsinki prior to any trial-related intervention.
- 9. Patients aged > 18 years.
- 10. Patient capable of proper therapeutic compliance and accessible for correct
- 11. For female patients of childbearing potential, agreement (by patient and/or
partner) to use a highly effective form(s) of contraception that results in a low
failure rate (< 1% per year) when used consistently and correctly, and to continue its
use for 5 months after the last dose of Atezolizumab and/or 6 months after the last
dose of Bevacizumab, whichever is later. Such methods include: combined (estrogen and
progestogen containing) hormonal contraception, progestogen-only hormonal
contraception associated with inhibition of ovulation together with another additional
barrier method always containing a spermicide, intrauterine device (IUD): intrauterine
hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner (on
the understanding that this is the only one partner during the whole study duration),
and sexual abstinence.
- 12. For male patients with female partners of childbearing potential, agreement (by
patient and/or partner) to use a highly effective form(s) of contraception that
results in a low failure rate [< 1% per year] when used consistently and correctly,
and to continue its use for 6 months after the last dose of Bevacizumab. Male patients
should not donate sperm during this study and for at least 6 months after the last
dose of Bevacizumab.
- 13. Oral contraception should always be combined with an additional contraceptive
method because of a potential interaction with the study drugs. The same rules are
valid for male patients involved in this clinical study if they have a partner of
childbirth potential. Male patients must always use a condom.
- 14. Women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea)
or surgically sterile must have a negative serum pregnancy test result within 14 days
prior to initiation of study drug
- 1. All patients carrying other EGFR mutations.
- 2. Patients with known anaplastic lymphoma kinase (ALK) fusion oncogene, STK11 ligand
alteration or ROS1 translocations.
- 3. Clinically significant comorbidities that impaired administration of platinum-based
- 4. Patients with a condition requiring systemic treatment with either corticosteroids
(>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14
days of randomization. Inhaled or topical steroids, and adrenal replacement steroid
doses > 10 mg daily prednisone equivalent, are permitted in the absence of active
- 5. Patients with a history of interstitial lung disease cannot be included if they
have symptomatic ILD (Grade 3-4) and/or poor lung function. In case of doubt please
contact trial team.
- 6. Patients with other active malignancy requiring concurrent intervention and/or
concurrent treatment with other investigational drugs or anti-cancer therapy.
- 7. Patients with previous malignancies (except non-melanoma skin cancers, and the
following in situ cancers: bladder, gastric, colon, endometrial, cervical/dysplasia,
melanoma, or breast) are excluded unless a complete remission was achieved at least 2
years prior to study entry AND no additional therapy is required during the study
- 8. Any medical, mental or psychological condition which in the opinion of the
investigator would not permit the patient to complete the study or understand the
- 9. Patients with positive test for hepatitis B virus surface antigen (HBV sAg) or
hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic
- 10. Patients with known history of testing positive for human immunodeficiency virus
(HIV) or known acquired immunodeficiency syndrome (AIDS).
- 11. Active tuberculosis.
- 12. Severe infections within 4 weeks prior to be included in the study, including but
not limited to hospitalization for complications of infection, bacteremia, or severe
- 13. Patients with history of allergy to study drug components excipients.
- 14. History of severe allergic, anaphylactic, or other hypersensitivity reactions to
chimeric or humanized antibodies or fusion proteins.
- 15. Women who are pregnant or in the period of breastfeeding.
- 16. Sexually active men and women of childbearing potential who are not willing to use
an effective contraceptive method during the study.
- Patients with active, known or suspected 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
- 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).
- Disease is well controlled at baseline and only requiring low-potency
- 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
- 18. Patients with any contraindication for bevacizumab administration.