Rationale and Design of the Phase 3 KEYLYNK-013 Study of Pembrolizumab With Concurrent Chemoradiotherapy Followed by Pembrolizumab With or Without Olaparib for Limited-Stage Small-Cell Lung Cancer

Abstract

Background:

The current standard of care for patients with newly diagnosed limited-stage small-cell lung cancer (SCLC) is concurrent chemoradiotherapy (CCRT). The prognosis remains poor due to the aggressiveness and high risk of progression or relapse of SCLC even if an initial response is achieved. Therefore, there is an urgent unmet clinical need in this population. The multicenter, phase 3, randomized, placebo-controlled, double-blind KEYLYNK-013 study evaluates the addition of pembrolizumab to CCRT followed by pembrolizumab with or without olaparib in participants with previously untreated limited-stage SCLC. (ClinicalTrials.gov: NCT04624204).

Methods:

Eligible participants aged ≥18 years with newly diagnosed, pathologically confirmed, limited-stage (ie, stage I-III) SCLC will be randomized 1:1:1 to CCRT (ie, etoposide plus carboplatin or cisplatin for 4 cycles and standard thoracic radiotherapy) plus pembrolizumab (Groups A and B) or CCRT plus placebo (Group C). In the absence of disease progression, participants will receive pembrolizumab plus placebo (Group A), pembrolizumab plus olaparib (Group B), or placebo (Group C). Dual primary endpoints are progression-free survival per RECIST version 1.1 by blinded independent central review and overall survival.

Results:

Enrollment began in December 2020 and is ongoing at approximately 150 sites.

Conclusions:

KEYLYNK-013 will provide valuable information on the efficacy and safety of pembrolizumab plus CCRT and pembrolizumab with or without olaparib post CCRT in participants with limited-stage SCLC.

Introduction

At initial diagnosis, 35% to 40% of small-cell lung cancer (SCLC) cases present as limited-stage disease (stage I-III).¹ The standard of care for fit patients with limited-stage SCLC is therefore concurrent chemoradiotherapy (CCRT) with etoposide plus cisplatin or carboplatin and definitive thoracic radiation therapy, but prognosis remains poor due to the high risk of relapse.^2,3

Preclinical and clinical studies have provided a rationale for the combination of the monoclonal anti–PD-1 antibody pembrolizumab concurrently with CCRT and in the consolidation setting for SCLC.^4,5 Notably, in a single-center, open-label, phase 1/2 study of 40 participants with limited-stage SCLC or other neuroendocrine tumors, treatment with pembrolizumab, etoposide, a platinum agent, and thoracic radiotherapy yielded an objective response rate (ORR) of 79%, median progression-free survival (PFS) of 19.7 months, and median overall survival (OS) of 39.5 months.⁴ The most common grade 3 to 4 treatment-related adverse event was neutropenia, occurring in 18% of participants. Three cases of grade 3 treatment-related pneumonitis (8% of participants) and 1 case of grade 4 treatment-related respiratory failure (3% of participants) were observed. No grade 5 treatment-related events occurred. These safety findings were consistent with other studies combining immune checkpoint inhibitor therapies concurrently with CCRT.

Proteomic analyses suggest that poly(ADP-ribose) polymerase (PARP) 1 is highly expressed in SCLC.⁶ Based on evidence from preclinical SCLC models, PARP inhibitors block tumor cell proliferation, significantly increase tumor cell expression of PD-L1 and enhance the antitumor activity of PD-L1 blockade.^7,8 Additionally, PARP inhibitors stimulate the innate immune response via the STING pathway, resulting in increased expression of interferon-β and multiple chemokines associated with cytotoxic T-lymphocyte recruitment and activity.⁸ Finally, PARP inhibition has been shown to potentiate the antitumor effects of cytotoxic chemotherapy or radiation in SCLC cell lines.⁹ Therefore, combined PARP and immune checkpoint inhibition may be a promising approach to delay disease progression following response to CCRT. Olaparib is a PARP inhibitor currently established as maintenance therapy for advanced, platinum-sensitive ovarian and pancreatic cancer.¹⁰ In the KEYLYNK-007 study, olaparib 300 mg twice daily plus pembrolizumab 200 mg every 3 weeks showed antitumor activity and a grade ≥3 treatment-related adverse event rate of 36% in participants with previously treated, advanced solid tumors with homologous recombination repair mutations and/or homologous recombination deficiency.¹¹ The most common treatment-related adverse events observed with this combination were nausea, anemia and fatigue, and pembrolizumab plus olaparib had a safety profile in line with expectations based on the safety profiles of the individual agents.

The addition of pembrolizumab to CCRT in the treatment of participants with newly diagnosed, limited-stage SCLC unselected for homologous recombination repair mutations and/or homologous recombination deficiency, followed by pembrolizumab with or without olaparib in the absence of disease progression, is being investigated in the randomized, placebo-controlled, double-blind, phase 3 KEYLYNK-013 trial.

Participants and Methods

Study Design and Objectives

In the KEYLYNK-013 study (ClinicalTrials.gov identifier NCT04624204), participants with pathologically confirmed, limited-stage SCLC by the American Joint Committee on Cancer version 8 criteria¹² will be randomized 1:1:1 to receive pembrolizumab in combination with CCRT followed by pembrolizumab and olaparib placebo (Group A), pembrolizumab in combination with CCRT followed by pembrolizumab and olaparib (Group B), or pembrolizumab placebo plus CCRT followed by pembrolizumab placebo and olaparib placebo (Group C) (Figure 1). Participants, investigators, and the sponsor will be blinded to treatment assignment in Groups A, B, and C. The dual primary endpoints of the study are PFS per RECIST version 1.1 as assessed by blinded independent central review (BICR) and OS. Secondary endpoints include safety and tolerability, ORR and duration of response (DOR) per RECIST version 1.1 by BICR, the effect of PD-L1 expression levels on PFS, OS, ORR, and DOR, and patient-reported outcomes. Additional biomarkers, event-free survival and time to subsequent therapy are exploratory endpoints.

Figure 1.

KEYLYNK-013 study design. AUC, area under the curve; BID, twice daily; CCRT, concurrent chemoradiotherapy; ECOG, Eastern Cooperative Oncology Group; PCI, prophylactic cranial irradiation; Q3W, every 3 weeks; Q6W, every 6 weeks; UK, United Kingdom. ^aPlatinum doublet chemotherapy comprises etoposide 100 mg/m² on days 1, 2 and 3 of each cycle and investigator’s choice of carboplatin AUC 5 mg/mL/min or cisplatin 75 mg/m² on day 1 of each cycle. Chemotherapy treatments will be administered intravenously Q3W for 4 cycles. ^bRadiotherapy is administered twice daily (45 Gy in 30 twice-daily fractions of 1.5 Gy over 3 weeks, 5 days/week) or daily (66 Gy in 33 daily fractions of 2 Gy over 6.5 weeks, 5 days/week), starting concurrently with chemotherapy on day 1 of cycle 2. ^cPCI occurs after early response assessment (imaging 12 weeks after randomization) and is strongly recommended for participants who achieve complete or partial response following CCRT and is at the investigator’s discretion for participants with stable disease. PCI should be administered no later than 6 weeks after the last dose of cycle 4. The standard dose for PCI to the whole brain is 25 Gy in 10 daily fractions (2.5 Gy/fraction). ^dOlaparib matching placebo. ^ePembrolizumab matching placebo.

Participants

Detailed participant inclusion and exclusion criteria are shown in Table 1. Briefly, participants must be ≥18 years of age, have histologically or cytologically confirmed, newly diagnosed stage I-III SCLC, and received no prior therapy (chemotherapy, radiotherapy, surgery) for SCLC. Eligible participants must have an Eastern Cooperative Oncology Group performance status of 0 or 1, adequate organ function, and should not be expected to require tumor resection during the study.

Table 1.

Key Inclusion and Exclusion Criteria for the KEYLYNK-013 Study

Inclusion Criteria	Exclusion Criteria
• Age ≥18 years	• Extensive-stage SCLC, defined as stage IV or T3–4 that cannot be encompassed in a tolerable radiation plan
• Histologically/cytologically confirmed, newly diagnosed, limited-stage (stage I-III by AJCC eighth edition) SCLC that can be safely treated with radiotherapy	• Known MDS/AML, or features suggestive of MDS/AML
• At least 1 measurable lesion per RECIST version 1.1 as assessed by the local investigator	• Documented >10% weight loss from baseline in the preceding 3 months
• No evidence of metastatic disease	• Prior olaparib or other PARP inhibitor therapy or prior anti-PD-1, PD-L1, PD-L2 or other stimulatory or co-inhibitory T-cell receptor therapy
• No prior chemotherapy, radiotherapy or surgery for limited-stage SCLC	• Major surgery <4 weeks prior to initiation of study treatment
• Not expected to require tumor resection during the course of the study	• Received colony-stimulating factors ≤28 days prior to initiation of study treatment
• Provision of newly obtained (strongly preferred) or archival tumor tissue sample for PD-L1 assessment	• Known additional malignancy that is progressing or required active treatment ≤5 years prior to initiation of study treatment
• ECOG PS of 0 or 1	• Uncontrolled, potentially reversible cardiac conditions
• Adequate pulmonary function testing, defined as a FEV1 >50% of predicted normal volume and a DLCO >40% of predicted normal value	• History of/current pneumonitis or interstitial lung disease
• Adequate organ function	• Active infection requiring systemic therapy
• Life expectancy at least 6 months	• Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy ≤7 days prior to initiation of study treatment
• Written informed consent	• Active autoimmune disease requiring systemic treatment in the past 2 years
	• Known history of HIV or Hepatitis B or active Hepatitis C infection

Abbreviations: AJCC = American Joint Committee on Cancer; AML = acute myeloid leukemia; DLCO = carbon monoxide lung diffusing capacity; ECOG PS = Eastern Cooperative Oncology Group performance status; FEV = forced expiratory volume; HIV = human immunodeficiency virus; MDS = myelodysplastic syndrome; PARP = poly (ADP-ribose) polymerase; SCLC = small-cell lung cancer.

Treatments

Participants in Groups A, B and C will receive etoposide and investigator’s choice of carboplatin or cisplatin for 4 cycles concurrently with standard thoracic radiotherapy (Figure 1). Participants in Groups A and B will receive pembrolizumab 200 mg intravenously every 3 weeks concurrently with CCRT, followed by pembrolizumab 400 mg every 6 weeks plus olaparib matched placebo or olaparib 300 mg administered orally twice daily, respectively. Participants in Group C will receive pembrolizumab placebo with CCRT, followed by pembrolizumab placebo and olaparib placebo. Pembrolizumab, olaparib and the respective placebos will be administered in the post CCRT setting for up to 9 cycles of pembrolizumab 400 mg every 6 weeks (approximately 12 months), or until specific discontinuation criteria are met (including request to discontinue study treatment, unblinding of treatment assignment, disease progression or recurrence, or pregnancy). Permitted dose modifications of pembrolizumab are limited to interruption or discontinuation. The dosage of olaparib may be reduced to 250 mg twice daily, and then to 200 mg twice daily if needed, with no further dose reductions permitted. Overlapping toxicities between olaparib and pembrolizumab such as pneumonitis and renal dysfunction will be monitored and managed according to the protocol.

Prophylactic cranial irradiation will be strongly recommended for participants who achieve a complete or partial response following CCRT and offered at the investigator’s discretion to participants who have stable disease and no clinical evidence of brain metastases.

Assessments

Tumor response and PFS per RECIST version 1.1 will be evaluated radiographically. The first scan following CCRT should be performed approximately 12 weeks after study treatment initiation. Subsequent radiographic imaging will be performed to assess response every 9 weeks until the end of the second year, every 12 weeks until the end of the third year, every 16 weeks until the end of the fourth year, every 6 months until the end of the fifth year, and annually thereafter until confirmed disease progression, the start of a new anticancer therapy, pregnancy, death, withdrawal of consent or the end of the study.

All adverse event data will be reported from the time of randomization to 30 days after discontinuation of study treatment, except for serious adverse events, which will be collected for up to 90 days following discontinuation of study treatment.

Statistical Analysis

Treatment differences in the dual primary endpoints of PFS per RECIST version 1.1 by BICR and OS will be compared between Groups A and B vs. C using a stratified log-rank test. Hazard ratios will be estimated using a stratified Cox regression model, and event rates over time will be estimated using the Kaplan-Meier method. Efficacy will be evaluated in the intention-to-treat population, comprised of all randomized participants. Safety will be assessed in the as-treated population, comprised of all participants who receive ≥1 dose of study treatment.

External Data Monitoring Committee

An independent, external data and safety monitoring committee will oversee the trial and assess outcomes at protocol-specified interim analyses.

Results

Current Status

Enrollment for this study began in December 2020 and is ongoing at approximately 150 sites. The current estimated study completion date is October 2027. Planned sample size is approximately 672 participants.

Discussion

SCLC is an aggressive cancer that is characterized by heterogeneity and sensitivity to chemotherapy regimens, followed by rapid progression or recurrence.^1,13 Prognosis for patients with limited-stage SCLC is poor, with a median OS with standard CCRT of 25 to 30 months.² New treatment options that delay disease progression and prolong survival are urgently needed.

Investigations into the possible role for immune checkpoint inhibitors as consolidation therapy following CCRT for limited-stage SCLC are ongoing. In the STIMULI trial, consolidation therapy with nivolumab plus ipilimumab (4 cycles) followed by nivolumab for up to 12 months was compared vs. observation for participants without progressive disease after CCRT. However, study accrual was closed early and the study failed to meet its primary endpoint of PFS.¹⁴ Similar studies, including the phase 3 ADRIATIC study of durvalumab with or without tremelimumab vs. placebo after CCRT, are further investigating this treatment approach. Introduction of immunotherapy earlier in the treatment paradigm, ie, in conjunction with CCRT, may be another strategy in this disease setting. To that effect, the phase 3 NRG-LU005 study is evaluating CCRT plus atezolizumab followed by atezolizumab monotherapy vs. CCRT alone, and the phase 3 KEYLYNK-013 trial is evaluating CCRT plus pembrolizumab followed by pembrolizumab with or without olaparib vs. CCRT alone.

Early data suggest that the addition of pembrolizumab to CCRT and its continuation post CCRT may be an efficacious treatment strategy in limited-stage SCLC.⁴ Based on the established antitumor activity of pembrolizumab across tumor types, including lung cancer, introducing immune checkpoint inhibition concurrently with CCRT may improve responsiveness to treatment and prolong the duration of benefit for patients with newly diagnosed limited-stage SCLC. In the absence of disease progression, continued pembrolizumab after CCRT may prolong disease control. Early-phase trials have suggested that PARP inhibitors in combination with cytotoxic chemotherapy or an immune checkpoint inhibitor are active in SCLC.^15–18 Therefore, the addition of olaparib to continued pembrolizumab post CCRT may contribute further towards antitumor activity and the maintenance of response or stable disease in participants with limited-stage SCLC.

In conclusion, the KEYLYNK-013 study aims to identify whether the addition of pembrolizumab to CCRT and pembrolizumab with or without olaparib following CCRT improves outcomes for participants with newly diagnosed, limited-stage SCLC, a disease setting with few recent advancements in treatment.