JUNIPER Trial Branches Out in KRAS Mutation-Positive Advanced NSCLC

Jonathan W. Goldman, MD

Jonathan W. Goldman, MD

In 2008 Linardou et al published results of a meta-analysis of studies in advanced non—small cell lung cancer (NSCLC) and metastatic colorectal cancer.¹They extracted data on 1008 patients; 165 from 17 manuscripts for the NSCLC portion of the meta-analysis hadKRASmutations. They sought to establish whether or notKRASmutations could be candidate predictive biomarkers for antiepidermal growth factor (EGFR) treatments. The analysis yielded empirical evidence thatKRASmutations are highly specific negative predictors of response to EGFR tyrosine kinase inhibitors (TKIs) when given as single agents to patients with advanced NSCLC.¹Further implicating an association ofKRASmutations with poor outcomes, a retrospective analysis of data from 1036 patients with stage IV lung adenocarcinoma andKRASmutation evaluated between 2002 and 2009, found the presence ofKRASmutations to be associated with shorter survival (HR, 1.21;P= .48).²

A Possible New Treatment for Advanced NSCLC WithKRASMutation

Early clinical data from a phase I trial of the small molecule inhibitor of CDK4 and CDK6, abemaciclib (LY2835219), assessing its safety and evidence of clinical activity in a variety of tumor types were presented at the American Society of Clinical Oncology (ASCO) meeting in 2013.³This was followed in 2014, with another presentation of a cohort of patients with advanced NSCLC from the phase I study.⁴Among these 49 patients the disease control rate was 37% for patients with KRAS wild-type disease (n = 19) and 54% (n = 26) for patients withKRASmutations.⁴This indicated that abemaciclib has the potential to fill an unmet need for patients with advanced NSCLC withKRASmutations, who have progressed on standard treatment.

"KRASmutations are common in patients with NSCLC, but there have been few clinical advances in our treatment for these patients," said study presenter Jonathan W. Goldman, MD, of the Department of Medicine, Hematology/Oncology, member of the Signal Transduction and Therapeutics Program Area at UCLA's Jonsson Comprehensive Cancer Center in a news release.⁵Goldman was investigator of the trial's lung cancer cohort. "The results of the lung cohort of this study, which showed that abemaciclib could decrease tumor size in this patient population suggest further clinical investigation of abemaciclib as a single agent for the treatment of NSCLC is warranted, with a particular focus on those tumors withKRASmutations," he said.⁵

At the ASCO 2015 meeting, the results of a phase Ib study of abemaciclib in combination with multiple single agents (pemetrexed, gemcitabine, ramucirumab, or LY3023414, a dual PIK3—mTOR inhibitor) in patients with stage IV NSCLC were presented. No unexpected toxicities were encountered and pharmacokinetics (PK) data will be reviewed with the results to formulate optimal dosing for each combination.⁶

The clinical activity of abemaciclib has a foundation in rigorous preclinical studies. The drug potently inhibits CDK4 and CDK6 at low nanomolar concentrations, and inhibits retinoblastoma protein (Rb) phosphorylation inducing G1 arrest and inhibiting cell proliferation. When administered to mice with human tumor xenografts, it inhibited tumor growth and was safe and well tolerated. The inhibition of tumor growth was found to be dose dependent over a dose range of 25 to 100 mg/kg.^7,8

The JUNIPER Study

The positive phase I clinical results, reflecting encouraging preclinical data, led to the design of a phase III trial, the Juniper study.^9,10

Juniper (NCT02152631) is an open label phase III study currently recruiting patients with stage IV NSCLC with a detectableKRASmutation who have progressed following treatment with platinum-based chemotherapy.^9,10Patients will be randomized to receive either abemaciclib or erlotinib, both with best supportive care. Erlotinib was selected for the control arm because it is the only agent indicated for use in second- and third-line treatment in advanced NSCLC.^9,11The trial expects to enroll approximately 550 patients, 330 will be randomized to the abemaciclib arm and 220 to the erlotinib arm. They will also be stratified according to the number of previous chemotherapy regimens (1 vs 2).^9,10

It is an international endeavor, engaging a total of 181 centers in United States, Canada, South America, Europe, Russia, China, Japan, Turkey, Taiwan, Israel, Korea and Ukraine.¹⁰

The study began in September 2014, and the estimated study completion date and estimated primary completion dates are April 2017 and October 2016 respectively.¹⁰

Outcome Measures

There are two primary outcome measures; progression free survival (PFS), measured from baseline to objective progression or death from any cause (estimated up to 31 months), and overall survival (OS), measured from baseline to the date of death from any cause (estimated up to 31 months).^9,10

Secondary outcome measures include, overall response rates (complete response + partial response), the change in MD Anderson Symptom Inventory Lung Cancer Score, (patient reported changes in pain and disease-related symptoms), the PK of abemaciclib as shown by the area under the concentration curve, the change from baseline in European Quality of Life-5 Dimensions-5 Level Score, and the percentage of patients who are hospitalized as an indicator or resource utilization. The study also aims to characterize the pharmacodynamic properties of abemaciclib, investigate biomarkers for abemaciclib and the disease, and relate them to clinical outcomes and specifically to abemaciclib.^9,10

Trial Statistics

The trial has an 80% statistical power to detect the superiority of the abemaciclib arm over the erlotinib arm for OS and PFS. An independent data monitoring committee will recommend stopping the study after 100 PFS events have occurred if the HR for PFS I > 0.95. The final OS analysis will be carried out when approximately 407 OS events have been documented, and interim safety analyses will be conducted every 6 months until the final OS analysis.⁹

Patients: Inclusion Criteria

The study is recruiting male and female patients 18 years of age and older. They must have stage IV NSCLC, meeting the criteria of the American Joint Committee on Cancer Staging Handbook, and have centrally determined detectable mutations in codons 12 or 13 of theKRASoncogene. Patients can either be ineligible for additional standard second-line chemotherapy, or have progressed following platinum-based chemotherapy and treated with one further chemotherapy for metastases. All patients have to have measurable disease according to the Response Evaluation Criteria in Solid Tumors, and a performance status of 0 to 1 measured on the Eastern Cooperative Oncology Group scale.^9,10

Patients: Exclusion Criteria

Patients will be excluded if they had been treated with a non-approved drug within 14 days (if nonmyelosuppressive) or 21 days (if myelosuppressive) of the first dose of study drug. A personal history of syncope or presyncope, whether unexplained or of cardiovascular origin was also an exclusion criterion as well as ventricular arrhythmia or sudden cardiac arrest. Patients with unstable CNS metastases were excluded but those with a history of CNS metastases or CNS metastases that no longer required therapy, could enter the trial. A brain scan was required within 28 days of randomization for those with a history of CNS metastases.^9,10

Treatment Arms

Participants randomized to abemaciclib receive 200 mg orally twice a day with best supportive care on days 1 to 28. Those randomized to the active comparator erlotinib receive 150 mg once daily with best supportive care on days 1 to 28. Treatment will continue until disease progression or unacceptable toxicity, and there will be short and long-term follow up.^9,10

Looking Forward to Success

Concluding their paper describing JUNIPER, Goldman et al state, “If the co-primary objectives are achieved, the JUNIPER study will provide a new alternative third-line treatment option for patients with advanced metastatic NSCLC whose tumors have detectableKRASmutations.”⁹

References

1. Linardou H, Dahabreh IJ, Kanaloupiti D, et al. Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer.Lancet Oncol. 2008;9:962-972.

2. Johnson ML, Sima CS, Chaft J, et al. Association of KRAS and EGFR mutations with survival in patients with advanced lung adenocarcinomas.Cancer. 2013;119:356-362.

3. Shapiro G, Rosen LS, Tolcher AW et al. A first-in-human phase I study of the CDK4/6 inhibitor, LY2835219, for patients with advanced cancer.J Clin Oncol31, 2013 (suppl; abstr 2500).

4. Goldman JW, Gandhi L, Patnaik A, et al. Clinical activity of LY2835219, a novel cell cycle inhibitor selective for CDK4 and CDK6, in patients with non-small cell lung cancer.J Clin Oncol32:5s, 2014 (suppl; abstr 8026).

5. PR Newswire.http://www.prnewswire.com/news-releases/abemaciclib---lillys-oral-cdk-46-inhibitor---shows-single-agent-activity-in-a-phase-i-study-for-patients-with-a-specific-type-of-lung-cancer-259277611.htmlAccessed October 2, 2015.

6. Kim ES, Kelly K, Goldman JW, et al. A phase Ib study of abemaciclib in combination with multiple single agents in stage IV NSCLC.J Clin Oncol33, 2015 (suppl; abstr 8047).

7. Gelbert LM, Cai S, Lin X, et al. Preclinical characterization of the CDK4/6

inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor

activities alone/in combination with gemcitabine.Invest New Drugs. 2014;32:825-837.

8. Tate SC, Cai S, Ajamie RT, et al. Semi-mechanistic pharmacokinetic/pharmacodynamic modeling of the antitumor activity of LY2835219, a new cyclin-dependent kinase 4/6 inhibitor, in mice bearing human tumor xenografts.Clin Cancer Res. 2014;20:3763-3774.

9. Goldman JW, Shi P, Reck M, et al. Treatment rationale and study design for the JUNIPER study: A randomized phase III study of abemaciclib with best supportive care versus erlotinib with best supportive care in patients with stage IV non-small-cell lung cancer with a detectable KRAS

mutation whose disease has progressed after platinum-based chemotherapy.Clin Lung Cancer. doi:10.1016/j.cllc.2015.08.003.

10. ClinicalTrials.gov.https://clinicaltrials.gov/ct2/show/NCT02152631Accessed October 2, 2015.

11. Tarceva [prescribing information]. Genentech Inc: San Francisco CA; 2015.