A Phase 1/2 Trial Of Larotrectinib And Pembrolizumab In Patients With Solid Tumors Previously Treated With Immune Checkpoint Inhibitor Monotherapy

Patients must meet all of the following inclusion criteria to be eligible for enrollment in the study.

1. Ability to understand and willingness to sign informed consent form prior to initiation of the study and any study procedures.
2. Capable of and willing to comply with scheduled visits, treatment plans, laboratory tests, and other study-related tests and procedures.
3. Age ≥18 years.
4. Histologically documented locally advanced or metastatic lung adenocarcinoma or melanoma.

5. Patients who have previously received ICI monotherapy:

   • Must have a minimum drug exposure of at least 1 dose of ICI and documented disease progression on the treatment.

6. Patients must be willing to undergo tumor biopsy as required by the study, if safe and feasible.

   Patients who are unable or unwilling to undergo pretreatment tumor biopsy may still be eligible for the study following discussion with the principal investigator (PI).

7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Appendix 1) with no deterioration in performance status within 2 weeks prior to study treatment initiation.
8. Measurable disease per the RECIST v1.1 (Appendix 2).

9. Adequate organ function as defined below:

   • Hematologic Function: hematopoietic growth factors are not allowed ≤7 days prior to screening assessment for short-acting growth factors and ≤14 days prior to screening assessment for long-acting growth factors (i.e., half-life >48 hours [e.g., peg-filgrastim]):

     • Hemoglobin >9.0 g/dL (red blood cell/plasma transfusion is not allowed ≤14 days prior to screening assessment)
     • Absolute neutrophil count ≥1500/mL
     • Platelets ≥100,000/mL (platelet transfusion is not allowed ≤7 days prior to screening assessment)

   • Hepatic Function:

     • Total bilirubin \<1.5 × ULN (\<2.0 × ULN for patients with documented Gilbert's syndrome or \<3.0 × ULN for patients for whom the indirect bilirubin level suggests an extrahepatic source of elevation)
     • AST/ALT ≤2.5 × institutional ULN. Transaminases up to 5 × ULN in the presence of liver metastases.
     • Serum albumin ≥2.5 g/dL.

   • Renal Function:

     o Estimated glomerular filtration rate ≥60 mL/min by Modification of Diet in Renal Disease Formula or by 24-hour urine collection.

   • Coagulation:

     • Prothrombin time/international normalized ratio and activated partial thromboplastin time /partial thromboplastin time \<1.5 × ULN, or within target range per institutional guidelines if taking anticoagulant(s), regardless of whether the anticoagulant use is prophylactic or therapeutic.
10. Life expectancy ≥3 months.
11. Able to swallow PO medications.

12. Larotrectinib and pembrolizumab can cause fetal harm when administered to a pregnant woman. For this reason, women of childbearing potential (WOCBP) must agree to use adequate contraception ((hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of the study treatment period, and for 4 months after completion of study treatment.

    (Refer to Pregnancy Assessment Policy MD Anderson Cancer Center [MDACC] Institutional Policy # CLN1114). WOCBP includes all female patients, between the onset of menses (as early as 8 years of age) and 55 years unless the patient presents with an applicable exclusionary factor which may be one of the following:

    • Postmenopausal (no menses in ≥12 consecutive months)
    • History of hysterectomy or bilateral salpingo-oophorectomy
    • Ovarian failure (follicle-stimulating hormone and estradiol in menopausal range and have received whole pelvic radiation therapy)
    • History of bilateral tubal ligation or another surgical sterilization procedure • Approved methods of birth control are as follows: Hormonal contraception (i.e. birth control pills, injection, implant, transdermal patch, vaginal ring), intrauterine device, tubal ligation or hysterectomy, patient/partner post vasectomy, implantable or injectable contraceptives, and condoms plus spermicide. Not engaging in sexual activity for the duration of the study treatment period and the drug washout period is an acceptable practice; however, periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
13. Male patients must agree to use adequate contraception throughout the duration of the study treatment period and for 4 months after the last dose of study treatment.
14. WOCBP must have a negative blood pregnancy test within 14 days of study treatment initiation.

Exclusion Criteria:

1. Documented alterations in NTRK1, NTRK2, or NTRK3 including fusions, rearrangements, deletions, and single nucleotide variants by DNA sequencing or polymerase chain reaction test on circulating tumor DNA, fresh tumor biopsy, or archival tumor tissue (obtained within 3 years of first larotrectinib dose) performed in a Clinical Laboratory Improvement Amendments-certified or equivalent laboratory.
2. Patients who required dose interruption for more than 4 weeks, permanent discontinuation, or required systemic immunosuppression due to severe irAEs associated with previous ICI treatment.

3. Untreated CNS or leptomeningeal metastases. Patients with treated CNS metastases are allowed if ALL of the following conditions are met:

   • Radiation therapy ≥14 days prior to study treatment initiation
   • Surgical resection ≥28 days prior to study treatment initiation; no evidence of clinical or radiographic progression on CNS imaging ≤28 days prior to study treatment initiation
   • Residual neurological symptoms Grade ≤2 and on a stable dose of steroids and/or anticonvulsant therapy (if applicable) ≥14 days prior to study treatment initiation.

4. Has other malignancy(ies) diagnosed or treated within 5 years of study treatment initiation except for:

   • Clinically insignificant tumors for which no systemic anticancer treatment is required (e.g., basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the breast or cervix)
   • Tumors that have been treated with curative intent with low risk for recurrence during trial participation. Note: Approval from the PI is required for exceptions.
5. Patients with known or suspected impairment of GI function including any conditions that might hinder drug absorption, the ability to take PO medication, other malabsorption, or uncontrolled inflammatory GI disease such as Crohn's disease or ulcerative colitis.
6. History of cerebrovascular stroke within 6 months of study treatment initiation.
7. History of interstitial lung disease (ILD) or non-infectious pneumonitis requiring high-dose glucocorticoids or any active ILD or pneumonitis, or prior thoracic radiotherapy within 2 months of enrollment.

8. Has any of the following cardiovascular abnormalities:

   • Medically uncontrolled hypertension (≥160 mmHg systolic blood pressure or ≥100 mmHg diastolic blood pressure based on an average of 3 readings)
   • Acute coronary syndrome (e.g., unstable angina, coronary artery stenting or angioplasty, bypass grafting) within 6 months prior to enrollment
   • History of uncontrolled clinically significant unstable arrhythmias. Patients who have pacemakers to control atrial arrhythmia are eligible for the study. Patients with medically controlled atrial fibrillation >1 month prior to study treatment initiation are eligible.
   • History of congenital long QT syndrome or prolonged corrected QT interval (QTc) using Fridericia's method >470 ms (unless a pacemaker is in place)
   • Left ventricular ejection fraction \<50%
   • Symptomatic congestive heart failure (New York Heart Association Class II or higher).
9. Has active systemic infection requiring systemic therapy within 72 hours prior to study treatment initiation.
10. History of severe allergic reaction or known sensitivity to any of the study treatment components.
11. Patients who have had a major surgical procedure(s) ≤28 days or minor procedure(s) ≤7 days prior to study treatment initiation; in all cases, the patient must be sufficiently recovered and stable before study treatment initiation.
12. Has active severe acute respiratory syndrome coronavirus 2 infection. If symptomatic, the symptoms must have resolved prior to study treatment initiation.

13. Has active, untreated human immunodeficiency virus (HIV) infection (CD4+ T cell count ≤350 cells/μL and presence of acquired immunodeficiency syndrome [AIDS]-defining opportunistic infections in the past 12 months). For patients with CD4+ T cell counts >350 cells/μL or in the absence of AIDS-defining opportunistic infections, enrollment will be considered, if the following conditions are met:

    • Patient must be on an established antiretroviral therapy for at least 28 days prior to enrollment and treatment must not conflict with other study restrictions
    • Patient must have an HIV viral load less than 400 copies/mL prior to enrollment.
14. Has active/chronic hepatitis B or C virus infection (patients who are positive for hepatitis B surface antigen are excluded; patients who are positive for hepatitis B core antibody or hepatitis C antibody must have a negative hepatitis B DNA or hepatitis C RNA test result, respectively, before enrollment).
15. Has an active autoimmune disease, or ongoing any grade irAE from ICIs/other immunomodulatory treatments requiring systemic treatment (i.e., with use of disease modifying agents, non-physiologic doses of corticosteroids, or immunosuppressive drugs). Patients with autoimmune or ICI inhibitor/other immunomodulatory treatment-induced endocrine disorder on hormonal supplementation may be enrolled.
16. Any other unstable or clinically significant concurrent medical condition (including, but not limited to substance abuse, uncontrolled intercurrent illness including symptomatic arterial thrombosis, pulmonary embolism, etc.) that would, in the opinion of the investigator, jeopardize the safety of a patient, have an impact on their expected survival through the end of study participation, and/or affect their ability to comply with the requirements of the study.

17. Patients receiving specific oncologic therapies:

    1. Prior therapy with any NTRK-targeted therapy
    2. Treatment with targeted therapy, chemotherapy, or biologics/mAbs (nonimmunotherapy) ≤21 days or 5 half-lives (whichever is shorter) prior to study treatment initiation
    3. Treatment with radiation therapy ≤14 days prior to study treatment initiation
    4. Treatment with immunotherapy (e.g., ICIs) ≤28 days prior to study treatment initiation
    5. Treatment with any other anticancer treatment not included in "a" through "d" ≤28 days prior to study treatment initiation
    6. Treatment with any other investigational drug(s) not included in "a" through "e" ≤28 days prior to study treatment initiation (with the exception of provisionally approved mAb prophylaxis).
18. Patients who require treatment with systemic cyclosporin A or derivative.
19. Concomitant use of medications known to prolong QTc.
20. Concomitant use of medications that are sensitive or narrow therapeutic index substrates of cytochrome P450 (CYP) 3A, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), or organic anion transporting polypeptide 1B3 (OATP1B3) during study treatment.
21. Concomitant use of medications known to be moderate or strong CYP3A4 or P-gp inhibitors and/or moderate or strong CYP3A4 inducers is prohibited within 7 days prior to study treatment initiation and during the study treatment period.
22. Pregnant or breastfeeding.
23. Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study treatment administration. Inhaled or topical steroids and adrenal replacement doses \<10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Patients are permitted to use topical, ocular, intraarticular, intranasal, and inhalational corticosteroids (with minimal systemic absorption).

24. Patients who received a live, attenuated vaccine within 30 days prior to Cycle 1 Day 1.

    Enrolled patients should not receive live vaccine during the study. Non-live COVID vaccines will be allowed on study, but it is recommended to avoid their use during the first treatment cycle (from 3 days prior to Cycle 1 Day 1 through Cycle 2 Day 3). Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines and are not allowed.

25. Unresolved toxicities from prior therapy (defined as having not resolved to Grade ≤1 or baseline) or any other toxicity that is deemed irreversible by the investigator. Exceptions include endocrinopathies from prior therapy or disease and successfully treated (such as hypothyroidism, diabetes mellitus), alopecia, vitiligo, and Grade ≤2 peripheral neuropathy.