Adaptive Chemotherapy for Pd-l1 High REsEctablE NSCLC: A Chemo-PHREE Trial

Current standard of care for patients with EGFR/ALK wild-type, resectable non-small cell lung cancer (NSCLC) is a combination of platinum-doublet chemotherapy plus anti-PD (L)1 therapy given pre-operatively prior to definitive resection. This is based on repeated positive phase III trials showing improvement in pathologic response, event-free survival and overall survival compared to neoadjuvant chemotherapy alone. However, this one-size-fits all approach does not take into account the role of prognostic and predictive biomarkers to help further personalize and refine neoadjuvant systemic therapy approaches. In the metastatic setting biomarkers, including PD L1 expression of tumors, can help select patients who may receive anti-PD-(L)1 monotherapy. Specifically, for patients with PD-L1 ≥ 50%, evidence shows equivalent survival benefit compared to combination chemoimmunotherapy, effectively sparing this portion of patients the toxicity of chemotherapy. Whether a similar approach may be applied to the early-stage setting is an active question.

To further explore this question our group has performed an extensive systematic review and meta-analysis from 29 prospective neoadjuvant trials utilizing either PD-(L)1 monotherapy or chemoimmunotherapy, assessing pathologic response and EFS rates based on available PD-L1 expression data. Our findings showed PD-L1 expression was associated with both pathologic complete response (pCR) and major pathologic response (MPR) rates after neoadjuvant chemoimmunotherapy and PD-(L)1 monotherapy. Through meta-regression analysis, both PD-L1 expression and type of systemic therapy were independently associated with pCR and MPR. Although chemoimmunotherapy had a numerically higher pCR and MPR rates, a notable proportion of patients with PD L1≥ 50% achieved a MPR when treated with PD-(L)1 monotherapy before surgical resection, suggesting a significant cohort of patients may receive meaningful pathologic regression with just PD-(L)1 therapy alone. Preliminary findings from our analysis utilizing individual patient data with reconstruction of available KM-curves has also indicated superior EFS/RFS with PD-(L)1 monotherapy compared to chemoimmunotherapy for patients with PD-L1 ≥1% disease, again highlighting the potential durable impact of ICB for biomarker-selected patients.

Therefore, in order to prospectively validate the utility of neoadjuvant PD-1 monotherapy for the treatment of resectable NSCLC in patients with PD-L1 ≥50%, we propose a phase 2 pilot study of 30 patients using a novel adaptive treatment strategy. This adaptive treatment strategy will incorporate upfront neoadjuvant single-agent cemiplimab for two cycles followed by radiographic and clinical reassessment. Pending this interval assessment patients will proceed with either one final cycle of cemiplimab monotherapy followed by resection or combination chemotherapy plus cemiplimab for two cycles followed by resection. This interval assessment will allow treating physicians to escalate neoadjuvant systemic therapy if there is any concern for clinical or radiographic progression with single-agent cemiplimab, all in an effort to appropriately tailor our neoadjuvant approach in this biomarker selected cohort.

Inclusion criteria

• Age 18 years or older at time of study entry
• Eastern cooperative oncology group (ECOG) performance status of 0 or 1
• Participants with histologically confirmed stage II-IIIB(N2) NSCLC (per the 9th International Association for the Study of Lung Cancer) with disease that is considered resectable prior to initiation of systemic therapy.
• Subject cases must be reviewed in a multidisciplinary thoracic tumor board setting prior to enrollment to allow for adequate discussion regarding the appropriateness for resection.
• Participants must have a tumor tissue sample available for biomarker testing, including PD-L1 IHC testing and sequencing to confirm EGFR/ALK status. Assessment of PD-L1 IHC, EGFR/ALK status may be performed locally through a CLIA approved laboratory testing method.

a. Tissue source may be a formalin fixed paraffin block (FFPE) of a previous tumor biopsy sample. Source of biomarker testing may be obtained from archived tissue if adequate or from a new biopsy, if needed and clinically indicated.

• Participants must have established PD-L1 Tumor Proportion Score (TPS) expression > or equal to 50%, assessed locally through a CLIA approved laboratory testing method.
• All suspicious mediastinal/hilar lymph nodes including those that are pathologically enlarged or FDG avid on PET/CT require further sampling for pathological confirmation if accessible by mediastinoscopy, thoracoscopy, or EBUS.
• Absence of major associated pathologies that increase the surgery risk to an unacceptable level
• Pulmonary function capacity (eg. FVC, FEV1, TLC, and DLCO) capable of tolerating proposed lung resection according to surgeon.
• Adequate normal organ and marrow function defined below:

• Platelet count > or equal to 100,000/mm3
• Hemoglobin > or equal to 8 g/dL
• Absolute neutrophil count (ANC) > or equal to 1000/mm3
• Creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) > or equal to 40 mL/min
• Total bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome who can have total bilirubin < 3.0 mg/dL)

AST, ALT, Alkaline phosphatase ≤ 3 x ULN per local testing 11. Subjects are deemed capable of giving informed consent and must have signed and dated an IRB approved written informed consent form. This written consent must be obtained before the performance of any protocol related procedures that are not part of normal standard of care. 12. Women of childbearing potential (WOCBP) must have negative serum or urine pregnancy testing within 30 days of study start

Exclusion criteria

• Presence of locally advanced unresectable (regardless of stage) or metastatic disease (stage IV).
• Participants with large-cell neuroendocrine carcinoma tumor or small cell carcinoma histology, including those with presence of mixed histology.
• Participants with known sensitizing EGFR mutations (L858R, Exon 19 deletion, Exon 20 insertion, atypical mutations including G719X L861Q, S768I) or ALK translocation via local CLIA approved testing methods.

a. For patients in whom more comprehensive testing is performed, those with identified targetable alterations in ROS1, NTRK, RET, METex14, HER2 genes will also be excluded. Screening for these specific alterations (ROS1/NTRK/RET/METex14/HER2), however, are not required for enrollment.

• Participants with brain metastases are excluded from this study. All patients should have pre-study MRI brain or CT head with contrast to confirm the absence of intracranial disease, per standard of care staging procedures.
• Prior therapy with an anti-PD-(L)1, anti-CTLA-4 antibody or any other antibody targeting t-cell co-regulatory pathways.
• Active prior malignancy within the previous 3 years, except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the prostate, cervix or breast.
• History of allogeneic organ transplantation.
• Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data.
• New York Heart Association heart failure classifications of Class II, III, or IV; or myocardial infarction, or acute coronary syndrome within 12 months of first dose of study medication; or Transient ischemic attack or stroke within 1 year
• Any condition that requires ongoing/continuous corticosteroid therapy (>10 mg prednisone/day or anti-inflammatory equivalent) within 1 week prior to the first dose of study medication. Participants who require a brief course of steroids (up to 2 days in the week before enrollment) or physiologic replacement are not excluded.
• Ongoing or significant autoimmune disease that required treatment with systemic immunosuppressive treatments within the last 5 years. Note: The following are not exclusionary: vitiligo, childhood asthma that has resolved, endocrinopathies (such as hypothyroidism or type 1 diabetes) that require only hormone replacement, or psoriasis that does not require systemic treatment.
• Any infection requiring hospitalization or treatment with IV anti-infectives within 2 weeks of first dose of study medication
• Uncontrolled infection with HIV, hepatitis B or hepatitis C infection, diagnosis of immunodeficiency, and/or tuberculosis (active or latent).

• Participants with known controlled HIV infection (undetectable viral load on HIV RNA PCR) and CD4 count above 350 either spontaneously or on a stable antiviral regimen are eligible. For these participants monitoring will be performed per local standards.
• Participants with HBsAg positive who have controlled infection (serum HBV DNA PCR that is below the limit of detection and receiving anti-viral therapy for hepatitis B) are eligible. Participants with controlled infections must undergo periodic monitoring of HBV DNA. Participants must remain on anti-viral therapy for at least 6 months beyond the last dose of investigational study medication.
• Participants with HBsAg negative but total HBcAb positive are permitted with the following requirements: If serum HBV DNA PCR is above the limit of detection at screening, initiate HBV antiviral therapy before study entry. If serum HBV DNA PCR is below the limit of detection, periodic monitoring of HBsAg must be performed.
• Participants who are HCV Ab+ who have controlled infection (undetectable HCV RNA by PCR either spontaneously or in eligible
• Receipt of a live vaccine within 4 weeks of start of study medication
• Receipt of COVID-19 vaccination within 1 week of planned start of study medication or for which the planned COVID-19 vaccinations would not be completed 1 week prior to start of study medication.
• Known hypersensitivity to the active substances or to any of the excipients.
• WOCBP* and men** who are unwilling to practice highly effective contraception prior to the initial dose/start of the first treatment, during the study, and for at least 4 months after the last dose of cemiplimab. Highly effective contraceptive measures include:

• Stable use of combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to screening;
• Intrauterine device; intrauterine hormone-releasing system;
• Bilateral tubal occlusion/ligation;
• Vasectomized partner (provided that the male vasectomized partner is the sole sexual partner of the WOCBP study participant and that the vasectomized partner has obtained medical assessment of surgical success for the procedure); and/or
• Sexual abstinence†,‡. Pregnancy testing and contraception are required for WOCBP. Pregnancy testing and contraception are not required for women who are postmenopausal or permanently sterile.

• WOCBP are defined as women who are fertile following menarche until becoming postmenopausal, unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high FSH level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to determine the occurrence of a postmenopausal state. The above definitions are according to the CTFG guidance. Pregnancy testing and contraception are not required for women with documents hysterectomy or tubal ligation. **Male participants: A male participant will be excluded from the study if that participant does not agree to use condoms or practice sexual abstinence†‡, unless vasectomized, prior to the initial dose/start of study medication, during the study, and for at least 4 months after the last dose of cemiplimab. Sperm donation is also prohibited during the same period. Vasectomy success must be confirmed by semen analysis. †Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drugs. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the participant. ‡Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method are not acceptable methods of contraception. Female condom and male condom should not be used together.