Bemcentinib (BGB324) in Combination With Pembrolizumab in Patients With Advanced Non-small Cell Lung Cancer (NSCLC)

• Pembrolizumab (Drug), also known as Keytruda: Pembrolizumab is a PD-1 inhibitor
• Bemcentinib (Drug), also known as BGB324: Bemcentinib is a selective Axl kinase inhibitor;

Primary outcomes

• Objective Response Rate (ORR) [The disease response is the best improvement or change in a participants cancer burden, as measured from baseline (screening) and then measured again at regular intervals over the whole period of the study, an average of 24 months.]: Objective Response Rate (ORR) includes all participants who have a partial (PR) or complete response (CR) per Response Evaluation Criteria In Solid Tumors Criteria (RECISTv1.0) for target lesions and assessed by CT scan or MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions,. ORR was defined as the percentage of evaluable patients who had at least 1 confirmed overall response CR or PR according to modified RECIST 1.1 evaluation and definitions of disease response.

Secondary outcomes

• Disease Control Rate [Disease response is assessed every 9 weeks for the first 45 weeks and then every 12 weeks until disease progression (worsens) or study completion, an average of 24 months.]: Disease Control Rate includes all participants who have a partial or complete response, or who maintain stable disease.
• Duration of Response [Disease response is assessed every 9 weeks for the first 45 weeks and then every 12 weeks until disease progression or study completion, an average of 24 months.]: Duration of response includes participants with a partial or complete response and is measured from the date of response until the cancer progresses (worsens).
• Progression-free Survival (PFS) [Disease assessments are conducted at screening and then every 9 weeks for the first 45 weeks and then every 12 weeks until disease progression or death, whichever comes first, up to study completion (an average of 24 months)]: PFS is measured from the date of the 1st dose of the 1st cycle until the date of progression (the date on which the progression is initially observed) or the date of death (whichever is earlier).
• Overall Survival [Survival visits are conducted every 12 weeks after disease progression until death or until study completion (an average of 24 months).]: Time to death is measured from the date of first dose until the date of death or the date the participants is last known to be alive. It includes all participants.
• Number of Participants With Adverse Events (AEs) [Adverse events are collected from the date of consent until up to 120 days after cessation of both treatments, up to 24 months of treatment, followed by an additional 120 days following cessation, up to 27 months total.]: The number of participants with each adverse event (AE) will be summarized.
• Pharmacokinetic (PK) Parameters: Maximum Observed Concentration (Cmax) [Up to 106 weeks]: Cmax defined as the maximum observed concentration. These Cmax results are after the maintenance dose.
• PK Parameters: Area Under the Curve (AUC) [Cycle 1 Day 1 and Day 3 pre-dose, and 2, 4, 6, 8 hours post-dose; Cycle 1 Day 2 , Day 4 ,Day 8 and Day 15 pre-dose; Cycle 2 Day 1, and Cycle 3 Day 1., pre-dose. Each cycle is 21 days in duration.]: AUC defined as the area under the concentration versus time curve. Measured as AUC 0-24h, area under the concentration versus time curve from time 0 to 24 hours post-dose at steady state following the maintenance dose per cohort.
• PK Parameters: Elimination Half-life (T½) [Up to 106 weeks]: T½ defined as the elimination half-life. Measured at steady state following the maintenance dose per cohort.
• Frequency of Clinical Laboratory, Vital Signs, and Electrocardiogram (ECG) Abnormalities. [Up to 106 weeks]: Number of events (Frequency) of clinically significant laboratory (hematology, including coagulation, urinalysis), vital signs (temperature, systolic blood pressure, diastolic blood pressure, heart rate, and respiratory rate), and ECG abnormalities.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Provision of signed informed consent.
2. Male and non-pregnant females who were aged 18 years or older at the time of provision of informed consent.
3. Histopathologically or cytologically documented Stage IV adenocarcinoma NSCLC; Note: Patients with a mixed cell histology including a significant area of adenocarcinoma histology were eligible.
4. Cohort A: Had disease progression on or after a prior platinum-containing chemotherapy; Note: Patients with EGFR mutations or ALK genomic rearrangements had to have documented disease progression on at least 1 licensed therapy for these indications and may not have received platinum-containing chemotherapy.

   Cohort B:
   1. Had received a maximum of 1 prior line of an anti-PD-(L)1 therapy (monotherapy).
   2. Must have had disease control containing at least 2 doses of anti-PD-(L)1 therapy. Disease control was defined as:

   i. Stable disease for at least 12 weeks (date of first progression on anti-PD-(L)1 therapy) Or ii. Confirmed PR or CR - confirmatory scan must have been performed >4 weeks from initial scan) c) Had disease progression when entering Screening (first date of progression of disease was taken as end date of response to previous anti-PD-(L)1 therapy) and this must have been within 12 weeks of last dose of treatment containing an anti-PD-(L)1 therapy. Progression should have been confirmed in 1 of the following ways: i. Having had 2 scan assessments completed at least 4 weeks apart, both showing progression according to response evaluation criteria in solid tumors (RECIST) 1.113 or ii. Having had 1 scan assessment completed showing disease progression according to standards used for previous therapy combined with rapid disease progression / clinical progression.

   Cohort C:
   1. Had received a maximum of 1 prior line of an anti-PD-(L)1 therapy in combination with a platinum-containing chemotherapy.
   2. Must have had disease control containing at least 2 doses of anti-PD-(L)1 therapy. Disease control was defined as:

   i. Stable disease for at least 12 weeks (date of first progression on anti-PD-(L)1 therapy) Or ii. Confirmed PR or CR - confirmatory scan must be performed >4 weeks from initial scan c) Had disease progression when entering Screening (first date of progression of disease was taken as end date of response to previous anti-PD-(L)1 therapy) and this must have been within 12 weeks of last dose of treatment containing an anti-PD-(L)1 therapy. Progression had to be confirmed in 1 of the following ways: i. Having had 2 scan assessments completed at least 4 weeks apart, both showing progression according to RECIST 1.113 or ii. Having had 1 scan assessment completed showing disease progression according to standards used for previous therapy combined with rapid disease progression/clinical progression
5. Measurable disease as defined by RECIST 1.1 on computed tomography (CT) or magnetic resonance imaging (MRI) and as determined by the site study team; tumor lesions situated in a previously irradiated area were considered measurable if progression had been demonstrated in such lesions.
6. Provision of suitable tumor tissue for the analysis of AXL kinase expression and PD-L1 expression; suitable tumor tissue had to consist of a minimum of a newly acquired (fresh) tumor tissue sample (as a formalin-fixed paraffin-embedded \[FFPE\] block), together with either further newly acquired tumor tissue (ie, further FFPE block) or an archival tumor tissue sample (as a further FFPE block or further 10 unstained slides).
7. Eastern Cooperative Oncology Group (ECOG) performance score 0 or 1
8. Life expectancy of at least 3 months
9. Adequate organ function confirmed at Screening within 10 days of treatment initiation as evidenced by:

   1. Platelet count ≥100,000/mm3
   2. Hemoglobin ≥9.0 g/dL (≥5.6 mmol/L)
   3. Absolute neutrophil count >1,500/mm3
   4. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × the upper limit of normal (ULN), or ≤5 × the ULN for patients with liver metastases
   5. Total bilirubin ≤1.5 × the ULN, or direct bilirubin < ULN for patients with total bilirubin levels >1.5 ULN
   6. Creatinine ≤1.5 × the ULN or calculated creatinine clearance 60 mL/min (by Cockcroft Gault formula)
   7. International normalized ratio or prothrombin time ≤1.5 × the ULN and activated partial thromboplastin time ≤1.5 × the ULN; Note: If patient was receiving anticoagulant therapy, then prothrombin time or partial thromboplastin time had to be within the therapeutic range of intended use of anticoagulants.
10. Female patients of childbearing potential had to have a negative urine or serum pregnancy test within 72 hours before the first dose of study treatment. If the urine test was positive or could not be confirmed as negative, a serum pregnancy test was required.
11. Patients (both male and female) of reproductive potential had to be willing to practice highly effective methods of contraception throughout the study and for 120 days after the last dose of study treatment. Abstinence was acceptable if this was the usual lifestyle for the patient. Female patients were considered NOT of childbearing potential if they had a history of surgical sterility or evidence of post-menopausal status defined as any of the following:

    1. ≥45 years of age and not having menses for more than 1 year.
    2. Amenorrheic for <2 years without a hysterectomy and oophorectomy and a follicle stimulating hormone (FSH) value in the post-menopausal range upon Screening evaluation.
    3. Post-hysterectomy, oophorectomy, or tubal ligation; documented hysterectomy or oophorectomy had to be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation had to be confirmed with medical records of the actual procedure.
12. Had resolution of toxic effect(s) of the most recent prior cancer therapy to Grade 1 or less (except alopecia). If patient received major surgery or radiation therapy of >30 Gy, they had to have recovered from the toxicity and/or complications from the intervention.

Exclusion Criteria:

1. Had disease suitable for local therapy administered with curative intent.
2. Had received more than 1 prior line of chemotherapy for advanced or metastatic adenocarcinoma of the lung. For all cohorts: Note: Patients may have received additional prior radiotherapy or chemotherapy in the adjuvant setting, providing it was completed at least 6 months prior to start of study treatment.
3. Cohort A: Had received prior therapy with an immunomodulatory agent; Cohort B: Had received prior chemotherapy alone or in combination with immunotherapy in the metastatic setting.
4. Had a known additional malignancy that was progressing or required active treatment; Note: Exceptions included basal cell carcinoma of the skin, squamous cell carcinoma of the skin that had undergone potentially curative therapy, or in situ cervical cancer.
5. Had known active central nervous system (CNS) metastases and/or carcinomatous meningitis; Note: Patients with previously treated brain metastases could participate provided they were stable (without evidence of progression by scans \[using the identical modality for each assessment, either MRI or CT scan\] for at least 4 weeks prior to the first dose of study treatment and any neurological symptoms had returned to Baseline), having no evidence of new or enlarging brain metastases, and were not using steroids for at least 7 days prior to study treatment.
6. History of the following cardiac conditions:

   1. Congestive cardiac failure of > Grade II severity according to the New York Heart Association (defined as symptomatic at less than ordinary levels of activity).
   2. Ischemic cardiac event including, myocardial infarction, within 3 months before the first dose.
   3. Uncontrolled cardiac disease, including unstable angina, uncontrolled hypertension (ie, sustained systolic blood pressure (BP) >160 mm Hg or diastolic BP >90 mm Hg), or need to change medication because of lack of disease control within 6 weeks before the provision of consent.
   4. History or presence of sustained bradycardia (≤55 beats per minute), left bundle branch block, cardiac pacemaker, or ventricular arrhythmia; Note: Patients with a supraventricular arrhythmia requiring medical treatment but with a normal ventricular rate were eligible.
   5. Family history of long QTc syndrome, personal history of long QTc syndrome, or previous drug-induced QTc prolongation of at least Grade 3 (QTc >500 msec).
7. Abnormal left ventricular ejection fraction on echocardiography or multigated acquisition scan (MUGA) (less than the lower limit of normal for a patient of that age at the treating institution or <45%, whichever was lower).
8. Current treatment with any agent known to cause Torsades de Pointes which could not be discontinued at least 5 half-lives or 2 weeks prior to the first dose of study treatment.
9. Screening 12-lead electrocardiogram (ECG) with a measurable QTc interval according to Fridericia's correction >450 msec.
10. Was currently participating and receiving study therapy or had participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of study treatment.
11. Had participated in a study involving any immune checkpoint inhibitor other than currently approved immune checkpoint inhibitors for their lung cancer.
12. Received chemotherapy or targeted small-molecule therapy or radiation therapy within 2 weeks before starting study treatment or who had not recovered (ie, ≤ Grade 1 at Baseline) from adverse events (AEs) due to a previously administered agent.
13. Received an anti-cancer mAb within 4 weeks prior to the first dose of study treatment or who had not recovered (ie, ≤ Grade 1 or Baseline) from AEs due to agents administered more than 4 weeks earlier.
14. Major surgery within 28 days before start of study treatment and failure to have recovered adequately from the toxicity and/or complications from the intervention prior to the first dose of study treatment.
15. Received transfusion of blood products (including platelets or red blood cells) or administration of colony-stimulating factors (CSFs) (including granulocyte-CSF, granulocyte macrophage-CSF, or recombinant erythropoietin) within 4 weeks prior to the first dose of study treatment.
16. Had a diagnosis of immunodeficiency or was receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment; Note: The use of physiologic doses of corticosteroids could have been approved after consultation with the Sponsor.
17. Active autoimmune disease that had required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs);
18. Known history of human immunodeficiency virus (HIV 1/2 antibodies).
19. Had known active infection with hepatitis B (eg, hepatitis B surface antigen reactive) or hepatitis C (eg, hepatitis C virus RNA \[qualitative\] was detected).
20. Had received a live-virus vaccination within 30 days of planned treatment start.
21. Had a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
22. Had a history of interstitial lung disease.
23. Inability to swallow or tolerate oral medication.
24. Existing gastrointestinal disease affecting drug absorption, such as celiac disease or Crohn's disease, or previous bowel resection, which was considered to be clinically significant or could interfere with absorption.
25. Known lactose intolerance.
26. Required vitamin K antagonists.
27. Treatment with any of the following: proton pump inhibitors or antacids within 7 days of the start of the study.
28. Treatment with any medication that was predominantly metabolized by CYP3A4 and had a narrow therapeutic index.
29. Known severe hypersensitivity (≥ Grade 3) to bemcentinib, pembrolizumab, and/or any of their excipients.
30. Any evidence of severe or uncontrolled systemic conditions (eg, severe hepatic impairment) or current unstable or uncompensated respiratory or cardiac conditions or ongoing.
31. Had active infection requiring systemic therapy (apart from cutaneous infections)
32. Had received radiation to the lung of >30 Gy within 6 months of the first dose.
33. Had a history or current evidence of any condition, therapy, or laboratory abnormality that could confound the results of the study, interfere with the patient's participation for the full duration of the study, or mean it was not in the best interest of the patient to participate, in the opinion of the Investigator.
34. Was pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting from Screening through to 120 days after the last dose of study treatment.
35. Had known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.
36. Cohorts B and C: Had an EGFR mutation or ALK genomic rearrangement.
37. Had received an allogeneic tissue/solid organ transplant.

Participant flow

Outcome results

• Objective Response Rate (ORR) (Primary), Count of participants, Participants: Cohort A 10; Cohort B 0; Cohort C 0; Total Patients 10
• Disease Control Rate (Secondary), Count of participants, Participants: Cohort A 24; Cohort B 12; Cohort C 10; Total Patients 46
• Duration of Response (Secondary), Median, months: Cohort A 8.1 (3.9 to 25.6); Cohort B ; Cohort C ; Total Patients 8.1 (3.9 to 25.6)
• Progression-free Survival (PFS) (Secondary), Median, weeks: Cohort A 35.7 (18.0 to 54.1); Cohort B 26.1 (9.6 to 36.0); Cohort C 26.0 (9.7 to 64.4); Total Patients 27.1 (19.0 to 38.0)
• Overall Survival (Secondary), Median, weeks: Cohort A 61.0 (46.3 to 75.9); Cohort B 43.7 (29.1 to 70.1); Cohort C 64.4 (27.9 to 110.7); Total Patients 56.6 (43.7 to 66.7)
• Number of Participants With Adverse Events (AEs) (Secondary), Count of participants, Participants: Cohort A 49; Cohort B 29; Cohort C 20; Total Patients 98
• Pharmacokinetic (PK) Parameters: Maximum Observed Concentration (Cmax) (Secondary), Mean, ng/mL: Cohort A 270 +/- 165; Cohort B 304 +/- 153; Cohort C 244 +/- 134; Total Patients 275 +/- 156
• PK Parameters: Area Under the Curve (AUC) (Secondary), Mean, ng.h/mL: Cohort A 6250 +/- 3880; Cohort B 7090 +/- 3620; Cohort C 5640 +/- 3200; Total Patients 6370 +/- 3680
• PK Parameters: Elimination Half-life (T½) (Secondary), Mean, hours: Cohort A 181 +/- 263; Cohort B 192 +/- 195; Cohort C 135 +/- 89.9; Total Patients 175 +/- 218
• Frequency of Clinical Laboratory, Vital Signs, and Electrocardiogram (ECG) Abnormalities. (Secondary), Number, events: Bemcentinib + Pembrolizumab 19

Adverse events

Time frame: Up to 106 weeks

Serious adverse events by term

Other adverse events by term

176 more terms not shown.

• Results publication: Li H, Liu Z, Liu L, Zhang H, Han C, Girard L, Park H, Zhang A, Dong C, Ye J, Rayford A, Peyton M, Li X, Avila K, Cao X, Hu S, Alam MM, Akbay EA, Solis LM, Behrens C, Hernandez-Ruiz S, Lu W, Wistuba I, Heymach JV, Chisamore M, Micklem D, Gabra H, Gausdal G, Lorens JB, Li B, Fu YX, Minna JD, Brekken RA. AXL targeting restores PD-1 blockade sensitivity of STK11/LKB1 mutant NSCLC through expansion of TCF1+ CD8 T cells. Cell Rep Med. 2022 Mar 15;3(3):100554. doi: 10.1016/j.xcrm.2022.100554. eCollection 2022 Mar 15. PMID 35492873

• Study Protocol and Statistical Analysis Plan (PDF, 2022-01-26)

NIH grants: 2016