Neo-DIANA: Neoadjuvant Treatment for EGFR Mutated Patients

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.

• Atezolizumab (Drug), also known as Tecentriq: Patients will receive 1200 mg of Atezolizumab every 21 days (QW3) (+/- 3 days) during neoadjuvant phase and every 28 days (QW4) (+/- 3 days) at adjuvant phase in a monitored setting where there is immediate access to trained personnel and adequate equipment/medicine to manage potentially serious reactions. First Infusion * No premedication administered for atezolizumab specifically is permitted * Infuse atezolizumab (1200 mg in a 250 mL 0.9% NaCl IV bag) over 60 (+/- 15) minutes. Subsequent Infusions: * If patient experienced infusion-related reaction during any previous infusion, premedication with antihistamines may be administered for Cycles > 2 at the discretion of the treating physician. * If the patient tolerated the first infusion well without infusion-associated adverse events, the successive infusion may be delivered over 30 (+/- 10) minutes.
• Bevacizumab (Drug), also known as Avastin: Patients will receive 15mg/Kg of Avastin® (bevacizumab) administered by IV infusion every 21 days, for 3 cycles during neoadjuvant phase, in a monitored setting where there is immediate access to trained personnel and adequate equipment/medicine to manage potentially serious reactions.
• Carboplatin (Drug), also known as Paraplatin: Structure: The cis-diamino (cyclobutan-1, 1 dicarboxilate) platin. Stability: 24 hours at ambient temperature in 5% glucose, glucosaline or physiologic saline. It is recommended not to dilute with chlorinated solutions since this could affect the carboplatin. Route of administration: Intravenous infusion Patients will receive Carboplatin AUC6 administered by IV infusion every 21 days, for 3 cycles during neoadjuvant phase. Guidelines of Carboplatin administration: According to the standard of each center
• Pemetrexed (Drug), also known as Alimta: Patients will receive Pemetrexed 500mg/m2 administered by IV infusion every 21 days, for 3 cycles during neoadjuvant phase. Pemetrexed disodium (ALIMTA®, pemetrexed) is a novel pyrrolo\[2,3 d\]pyrimidine-based folic acid analogue. Route of administration: Intravenous infusion. Guidelines of Pemetrexed administration: According to the standard of each center

Primary outcomes

• Overall Response [From date of end of neoadjuvant treatment until the date of last follow up, assessed up to 36 months]: To determine the antitumor activity in terms of objective response rate (ORR) of neoadjuvant treatment with carboplatin-pemetrexed-bevacizumab plus atezolizumab for the treatment of locally advanced and potentially resectable NSCLC patients with EGFR mutations. Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) 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. Progressive disease (PD): at least a 20% increase in the sum of diameters of target lesions.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* 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 team
* 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 limits
* 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- predicted value.
* 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 follow-up.
* 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

Exclusion Criteria:

* 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 chemotherapy.
* 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 autoimmune disease.
* 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 period.
* 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 patient information.
* 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 infection.
* 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 pneumonia.
* 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.
* 17\.

  * 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 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 (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 topical steroids.
    * 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).
* 18\. Patients with any contraindication for bevacizumab administration.

Participant flow

Outcome results

• Overall Response (Primary), Count of participants, Participants: Experimental: Neo-Adjuvant Immunotherapy 1

Adverse events

Time frame: 40 months

Serious adverse events by term

Other adverse events by term

Limitations and caveats: The recruitment was closed prematurely to due to slow recruitment, so there are no consistent data to achieve any relevant conclusion at this point.

• Study Protocol and Statistical Analysis Plan (PDF, 2022-02-16)

• Mariano Provencio, MD, Principal investigator, Hospital Puerta del Hierro