Clinical Trials

Inclusion Criteria:

• Participant must be ≥ 18 years of age, inclusive, at the time of signing the informed consent (or of an acceptable age according to local regulations, whichever is older).
• Must have histologically confirmed Stage IB, II, or IIIA NSCLC. Staging will be according to the Tumor, Node, Metastasis staging system for lung cancer (8th edition).
• Must have an activating RET gene fusion in tumor based on polymerase chain reaction (PCR) or next generation sequencing (NGS). Results in blood based on NGS are also acceptable. The RET gene fusion result should be generated by a Lilly designated laboratory using the Oncomine™ Dx Target Test or locally from a laboratory with Clinical Laboratory Improvement Amendments of 1988 (CLIA), International Organization for Standardization (ISO)/International Electrotechnical Commission, College of American Pathologists (CAP), or other similar certification that meets local regulations. In all cases, the presence of the activating RET fusion must be confirmed by review of the molecular pathology report or other report(s) by Lilly or designee.
• Must have received definitive locoregional therapy with curative intent (surgery or radiotherapy) for Stage IB, II, or IIIA NSCLC:
  • Receipt of systemic anti-cancer therapy is allowed but not required.
• Patients must have completely recovered from definitive therapy (surgery or radiotherapy) as well as adjuvant therapy at the time of randomization.
  • Minimum time between date of definitive therapy completion and randomization must be at least:
    • 4 weeks following surgery;
    • 6 weeks following radiotherapy;
      • Completion date of radiotherapy is defined as the date of last fraction of radiation;
      • Minimum time between date of last dose of any anti-cancer therapy to randomization must be 2 weeks;
      • Maximum time allowed between definitive therapy completion and randomization must be 10 weeks if no chemotherapy was administered or 26 weeks if adjuvant chemotherapy was administered.
• Must have Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.
• Male and/or female Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies:
  • Male participants: Male participants are eligible to participate if they agree to the following during the intervention period and for at least the duration of the study or for 2 weeks following completion of study drug administration, whichever is longer:
    • Refrain from donating sperm.
  • Must agree to use contraception/barrier as detailed below:
    • Agree to use a male condom female partner use of an additional highly effective contraceptive method with a failure rate of < 1% per year when having sexual intercourse with a woman of childbearing potential who is not currently pregnant;
    • Agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person.
  • Female participants: Women of child-bearing potential (WOCBP) who are abstinent (if this is complete abstinence, as their preferred and usual lifestyle) or in a same sex relationship (as part of their preferred and usual lifestyle) must agree to either remain abstinent or stay in a same sex relationship without sexual relationships with males. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence just for the duration of a trial, and withdrawal are not acceptable methods of contraception.
• Otherwise, WOCBP participating must agree to use one highly effective method (less than 1% failure rate) of contraception, or a combination of 2 effective methods of contraception for the entirety of the study.
  • Women of child-bearing potential participating must test negative for pregnancy prior to initiation of treatment as indicated by a negative serum pregnancy test at the screening visit followed by a negative urine pregnancy test within 24 hours prior to exposure. [Any pregnancy testing subsequent to this initial test should be based on compound specific concerns and is not mandated by this guidance];
  • Either one highly effective method of contraception (such as combination oral contraceptives, implanted contraceptives or intrauterine device) or a combination of 2 effective methods of contraception (such as male or female condoms with spermicide, diaphragms with spermicide or cervical sponges) will be used. The subject may choose to use a double barrier method of contraception. Barrier protection methods without concomitant use of a spermicide are not a reliable or acceptable method. Thus, each barrier method must include use of a spermicide. It should be noted that the use of male and female condoms as a double barrier method is not considered acceptable due to the high failure rate when these methods are combined.
  • Women not of childbearing potential may participate and include those who are:
    • infertile due to surgical sterilization (hysterectomy, bilateral oophorectomy, or tubal ligation), congenital anomaly such as mullerian agenesis; or
    • post-menopausal – defined as either:
      • A woman at least 40 years of age with an intact uterus, not on hormone therapy, who has cessation of menses for at least 1 year without an alternative medical cause, AND a follicle-stimulating hormone > 40 mIU/mL; or
      • A woman 55 or older not on hormone therapy, who has had at least 12 months of spontaneous amenorrhea; or
      • A woman at least 55 years of age with a diagnosis of menopause prior to starting hormone replacement therapy.
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

Exclusion Criteria:

• If known, have additional oncogenic driver mutations of NSCLC; e.g., ALK fusion, or activating mutations of EGFR.
• Evidence of small cell lung cancer.
• Clinical or radiologic evidence of disease recurrence or progression following definitive therapy.
• Known or suspected interstitial fibrosis or interstitial lung disease or history of (noninfectious) pneumonitis that required steroids.
• Have clinically significant active cardiovascular disease or history of myocardial infarction within 6 months prior to planned start of study treatment or prolongation of the QT interval corrected for heart rate using Fridericia’s formula (QTcF) > 470 msec on more than 1 ECG obtained during the baseline period. a. Participants with implanted pacemakers may enter study without meeting corrected QT interval (QTc) criteria due to non-evaluable measurement.
• Have known uncontrolled human immunodeficiency virus (HIV)-1/2 infection:
  • Participants with HIV (known HIV 1/2 antibodies positive) are allowed if all of the following conditions are met: CD4+ T-cell counts ≥ 350 cells/uL;
  • Participants with a history of acquired immunodeficiency syndrome (AIDS)- defining opportunistic infections may be eligible, if they have not had an opportunistic infection within the past 12 months;
  • If participant is on antiretroviral (ARV), evaluation of the specific agents must be performed in order to determine if participant is eligible (e.g., exclusion of participants receiving atazanavir due to P-R interval prolongation and AV block risk, exclusion of participants receiving strong and moderate cytochrome P450 enzymes (CYP) 3A inhibitors, strong or moderate CYP3A inducers, sensitive CYP2C8 substrates). If necessary, evaluate the feasibility of switching to an alternate effective ARV therapy (ART) regimen before study participation;
  • Participants need to be on established ART for at least 4 weeks and have an HIV viral load less than 400 copies/mL prior to enrollment;
  • Screening for HIV infection is not required.
• Have known active Hepatitis B or C:
  • Participants with serological evidence of chronic hepatitis B virus (HBV) infection who have no known underlying liver cirrhosis (screening not required) and an HBV viral load below the limit of quantification with or without concurrent viral suppressive therapy (at a stable dose) are allowed. Participants with detectable HBV deoxyribonucleic acid (DNA) and controlled disease may be permitted on therapy with sponsor approval. Concurrent viral suppressive will be required for participants with detectable HBV DNA;
  • Participants with a history of hepatitis C virus (HCV) infection who have completed viral suppressive therapy and have a viral load below the limit of quantification are allowed;
  • Screening for Hepatitis B or C is not required.
• Have active, uncontrolled, systemic bacterial, viral, or fungal infection that requires treatment or have serious ongoing intercurrent illness that is not controlled, despite optimal treatment (e.g., hypertension, diabetes, clinically active diverticulitis, intra-abdominal abscess, gastrointestinal obstruction, or peritoneal carcinomatosis). Screening for chronic conditions is not required.
• Major surgery, excluding placement of vascular access, within 4 weeks of study drug.
• Have clinically significant active malabsorption syndrome or other condition, including refractory nausea and vomiting, likely to affect gastrointestinal absorption of the study drug.
• Other malignancy unless nonmelanoma skin cancer, carcinoma in situ of the cervix or other in situ cancers, or a malignancy diagnosed ≥ 2 years previously and not currently active. Participants receiving adjuvant hormone therapy for breast or prostate cancer with no evidence of disease are eligible.
• Prior treatment with a selective RET inhibitor (e.g., selpercatinib or pralsetinib).
• Are taking a concomitant therapy that is:
  • known to cause QTc prolongation; or
  • systemic anti-cancer therapy (in addition to study treatment).
• Any unresolved toxicities from prior therapy greater than Common Terminology Criteria in Adverse Events (CTCAE) Grade 1 at the time of starting study treatment except for alopecia or Grade 2 neuropathy.
• Previous randomization and treatment in this study.
• Are currently enrolled in any other clinical study involving an investigational product or any other type of medical research judged not to be scientifically or medically compatible with this study.
• have participated, within the last 30 days; (3 months for studies conducted in the UK), in a clinical study involving an investigational product. If the previous investigational product has a long half-life, 5 half-lives or 30 days 3 months for studies conducted in the UK (whichever is longer) should have passed. Exceptions will be considered on a case by case basis by the sponsor CRP/CRS.

Enrollment Criteria for Crossover Treatment:

• Participants who are randomly assigned to Arm B who discontinue treatment due to disease recurrence or progression, based on cytological/histological confirmation or RECIST 1.1 may be eligible for crossover to selpercatinib if they meet the following criteria:
  • Have stopped their initial treatment with placebo;
  • Are willing and able to provide written informed consent to crossover treatment;
  • Have adequate hematologic, hepatic, and renal function as defined within the inclusion and exclusion criteria for initial eligibility;
  • Without any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of starting study treatment except for alopecia or Grade 2 neuropathy;
  • Have not received any other anticancer systemic therapy since study intervention (placebo);
  • Have an ECOG performance status of 0 to 1.
• Participants are eligible to be considered for crossover if:
  • they meet the criteria above; and
  • they can initiate treatment with selpercatinib within 42 days the time of investigator confirmed progression or recurrence. Exceptions may be made on a case-by-case basis following approval from the sponsor. Participants that may crossover should not complete V801 at the end of their initial treatment, but should enter V300 prior to starting selpercatinib.