Amivantamab plus single‑agent chemotherapy for advanced non‑small cell lung cancer with EGFR exon 20 insertion in people unable to receive platinum

Phase II Trial of Amivantamab Plus Monochemotherapy in Platinum Unfit NSCLC Patients With EGFR exon20 Insertion Mutations.

This trial will test whether adding amivantamab to a single chemotherapy drug helps people with metastatic non‑small cell lung cancer that has an EGFR exon 20 insertion who cannot get platinum chemotherapy.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 33 (estimated)
• Ages: 18 Years to 99 Years
• Sex: All
• Sponsor: Fondazione Ricerca Traslazionale (other)
• Drugs / interventions: chemotherapy, amivantamab
• Locations: 1 site (Roma, Roma (RM))
• Trial ID: NCT07392658 on ClinicalTrials.gov

What this trial studies

This is a multicenter Phase II trial giving subcutaneous amivantamab together with investigator‑selected single‑agent chemotherapy (pemetrexed or gemcitabine) to patients with EGFR exon 20 insertion metastatic non‑squamous NSCLC who are unfit for platinum therapy. Amivantamab is dosed with a split loading schedule in cycle 1 (lower dose day 1, higher doses on days 8 and 15) and then every three weeks thereafter, and treatment continues until progression, unacceptable toxicity, or withdrawal. Tumor response will be measured every eight weeks using RECIST v1.1 and safety monitored by NCI CTCAE v5.0, with primary endpoints including objective response rate and secondary endpoints including progression‑free and overall survival. The trial enrolls patients with ECOG 0–2, measurable disease, and adequate organ function who have not received prior systemic treatment for metastatic disease.

Who should consider this trial

Good fit: Ideal candidates are adults with histologically confirmed metastatic non‑squamous NSCLC harboring an EGFR exon 20 insertion who are treatment‑naïve for metastatic disease, unfit for platinum chemotherapy (for example low GFR, advanced age, neurologic contraindication, or platinum hypersensitivity), have ECOG performance status 0–2 and at least one measurable lesion.

Not a fit: Patients unlikely to benefit include those with prior systemic therapy for metastatic disease, squamous‑cell histology, active symptomatic or progressing brain metastases, or those with severely impaired marrow or organ function that precludes the protocol treatments.

Why it matters

Potential benefit: If successful, this approach could give patients who cannot tolerate platinum chemotherapy a targeted antibody plus single‑agent chemo option that may increase response rates and extend survival.

How similar studies have performed: Amivantamab has shown antitumor activity in earlier clinical programs for EGFR exon 20 insertion mutations, but combining it with single‑agent chemotherapy in platinum‑unfit patients is a less‑tested, newer approach.

Eligibility criteria

Inclusion Criteria:

* Written informed consent;
* Male or female patient aged ≥18 years;
* Histologically or cytologically confirmed stage IV or recurrent non-squamous NSCLC harboring EGFR exon20 insertion mutation;
* No prior systemic treatment;
* Unfit for platinum-based chemotherapy; Unfit for platinum is defined by a glomerular filtration rate (GFR) value less than 50 ml/min/BSA (body surface area) 1.73 m2 (or a CCR value of \<50 ml/min) or age 80 years, presence of neurological disorders or hypersensitivity to platinum.
* At least one radiological measurable disease according to RECIST criteria version 1.1;
* Patients with brain metastases are eligible if they are asymptomatic and stable (i.e. without evidence of progression by imaging for at least two weeks prior to the first dose of trial treatment and without deterioration of any neurologic symptoms);
* Performance status 0-2 (ECOG PS);
* Patient compliance to trial procedures;
* Adequate bone marrow function (ANC ≥ 1.5x109/L, platelets ≥75x109/L, haemoglobin \>9 g/dl);
* Adequate liver function (Total bilirubin ≤1.5 x ULN; subjects with Gilbert's syndrome can enroll if conjugated bilirubin is within normal limits, transaminases no more than 3xULN/\<5xULN in presence of liver metastases);
* Normal level of alkaline phosphatase and Serum creatinine \<1.5 x ULN and creatinine clearance \>45 mL/min as measured or calculated; refer to Appendix --Cockcroft-Gault Formula for Estimated creatinine clearance 12 Patients should be using adequate contraceptive measures, should not be breastfeeding, until 7 months after the last dose, and must have a negative pregnancy test (serum or urine) prior to first dose of study drug (within 72 hours) and must agree to further serum or urine pregnancy tests during the study; or female patients must have an evidence of non-childbearing potential by fulfilling one of the following criteria at screening: Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments; Women under 50 years old would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the post-menopausal range for the institution.

A participant must be either of the following:

* Not of childbearing potential
* Of child-bearing potential and practicing true abstinence during the entire period of the study, including up to 6 months after the last dose of study treatment is given
* Of childbearing potential and practicing 2 methods of contraception, including 1 highly effective user independent method and a second method (examples of highly effective methods of contraception are in section 9.6: Contraceptive Guidance and Collection of Pregnancy Information).

A participant must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for 6 months after receiving the last dose of study treatment.

A participant must wear a condom when engaging in any activity that allows for passage of ejaculate to another person during the study and for 6 months after receiving the last dose of study treatment. A participant who is sexually active with a partner of childbearing potential must agree to use a condom with spermicidal foam/gel/film/cream/suppository and their partner must also be practicing a highly effective method of contraception (ie, established use of oral, injected, or implanted hormonal methods of contraception; placement of an intrauterine device \[IUD\] or intrauterine hormone-releasing system \[IUS\]).

If the participant is vasectomized, they must still use a condom (with or without spermicide) for prevention of passage of exposure through ejaculation, but their partner is not required to use contraception.

A participant must agree not to donate sperm for the purpose of reproduction during the study and for a minimum of 6 months after receiving the last dose of study treatment.

Note: If the childbearing potential changes after start of the study (eg, participant of childbearing potential who is not heterosexually active becomes active, premenarchal participant experiences menarche) the participant must begin birth control, as described above.

Exclusion Criteria:

* Uncontrolled infectious liver disease;
* Positive hepatitis B (hepatitis B virus \[HBV\]) surface antigen (HBsAg) Note: participants with a prior history of HBV demonstrated by positive hepatitis B core antibody are eligible if they have at Screening 1) a negative HBsAg and 2) a HBV DNA (viral load) below the lower limit of quantification, per local testing. Subjects with a positive HBsAg due to recent vaccination are eligible if HBV DNA (viral load) is below the lower limit of quantification, per local testing.
* Positive hepatitis C antibody (anti-HCV). Note: participants with a prior history of HCV, who have completed antiviral treatment and have subsequently documented HCV RNA below the lower limit of quantification per local testing are eligible.
* Participant is positive for human immunodeficiency virus (HIV), with 1 or more of the following:

Receiving ART that may interfere with study treatment (consult sponsor for review of medication prior to enrollment) CD4 count \<350 at screening AIDS-defining opportunistic infection within 6 months of start of screening Not agreeing to start ART and be on ART\>4 weeks plus having HIV viral load \<400 copies/mL at end of 4-week period (to ensure ART is tolerated and HIV controlled).

-Participant has active cardiovascular disease including, but not limited to: A medical history of deep vein thrombosis or pulmonary embolism within 1 month prior to randomization or any of the following within 6 months prior to randomization: myocardial infarction, unstable angina, stroke, transient ischemic attack, coronary/peripheral artery bypass graft, or any acute coronary syndrome. Clinically non-significant thrombosis, such as non-obstructive catheter-associated thrombus, incidental or asymptomatic pulmonary embolism, are not exclusionary.

* Uncontrolled (persistent) hypertension: systolic blood pressure \>160 mm Hg; diastolic blood pressure \>100 mm Hg.
* Congestive heart failure (CHF), defined as New York Heart Association (NYHA) class III-IV or hospitalization for CHF (any NYHA class; refer to Appendix 6: New York Heart Association Criteria) within 6 months of randomization.
* Participant has an uncontrolled illness, including but not limited to:

Uncontrolled diabetes Ongoing or active infection (includes infection requiring treatment with antimicrobial therapy \[participants will be required to complete antibiotics 1 week prior to starting study treatment\] or diagnosed or suspected viral infection.

Active bleeding diathesis Impaired oxygenation requiring continuous oxygen supplementation Psychiatric illness, social situation, or any other circumstances that would limit compliance with study requirements Any ophthalmologic condition that is clinically unstable

* Absence of measurable lesions;
* Concomitant radiotherapy;
* Previous treatment with any EGFR Exon20ins-targeted TKIs;
* Symptomatic or immediately requiring therapy for brain metastases or carcinomatous meningitis. Subjects with asymptomatic and stable or treated brain metastases may participate;
* Participant has concurrent or prior malignancy other than the disease under study. The following exceptions require consultation with the Medical Monitor:

  1. Non-muscle invasive bladder cancer (NMIBC) treated within the last 24 months that is considered completely cured.
  2. Skin cancer (non-melanoma or melanoma) treated within the last 24 months that is considered completely cured.
  3. Non-invasive cervical cancer treated within the last 24 months that is considered completely cured.
* Participant had major surgery excluding placement of vascular access or tumor biopsy, or had significant traumatic injury within 4 weeks before randomization, or will not have fully recovered from surgery, or has surgery planned during the time the participant is expected to participate in the study.

Note: Participants with planned surgical procedures to be conducted under local anesthesia may participate.

* History of extensive disseminated/bilateral or known presence of Grade 3 or 4 interstitial fibrosis or interstitial lung disease including a history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis and pulmonary fibrosis;
* Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses; or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV);
* Pregnancy or lactating female;
* Other serious illness or medical condition potentially interfering with the study.

Where this trial is running

Roma, Roma (RM)

• I.F.O. Istituti Fisioterapici Ospitalieri Istituto Nazionale Tumori "Regina Elena", Medical Oncology 2 — Roma, Roma (RM), Italy (RECRUITING)

Study contacts

• Study coordinator: Federico Cappuzzo

Conditions: Metastatic NSCLC - Non-Small Cell Lung Cancer