Lessons from KEYNOTE-158 and the role of R-CHOP


In this edition of “How I will treat my next patient,” I take a look at two recent trials – one offers potential in previously-treated cervical cancer patients with poor prognosis and the other confirms the role of R-CHOP as the standard of care in diffuse large B-cell lymphoma.

Dr. Alan P. Lyss, an oncologist who practices in St. Louis

Dr. Alan P. Lyss

Pembrolizumab in KEYNOTE-158

In an international phase 2 “basket trial,” Hyun Cheol Chung, MD, PhD, and colleagues used pembrolizumab 200 mg every 3 weeks in 98 previously treated patients with advanced cervical cancer. Almost 84% of o the patients had PD-L1 positive tumors (greater than 1%). The authors said that viral induction of malignancy leads to antigen production and upregulation of PD-1. Therefore, advanced cervical cancer patients would likely express PD-L1 on tumor cells and respond to immune checkpoint inhibitor therapy.

In this interim report, there were 12 responses (all in PD-L1 positive patients), with three complete responses. Median response duration had not been reached at median follow-up of 10.2 months. Seven of 12 responses were ongoing at 12 months. There were grade 3-4 adverse events in 12.2% of patients and no treatment-related deaths.

The study – “Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer: Results From the Phase II KEYNOTE-158 Study” – was published in the Journal of Clinical Oncology (2019 April 3. doi: 10.1200/JCO.18.01265).

The encouraging results of pembrolizumab in this generally chemotherapy-refractory patient population were consistent with other small, early-phase studies investigating immune checkpoint inhibitors that led to the accelerated approval of pembrolizumab in previously treated PD-L1 advanced cervical cancer patients with progressive disease after chemotherapy.

What this means in practice

Although excitement should be tempered about an interim report of an organ-specific subset of a phase 2 international basket trial that was heavily populated by young PS 0-1 patients and generated an overall response rate of less than 15%, no conventional chemotherapy or biologic agent offers the potential of complete or prolonged response, and disease control rates of 30%.

Clinical trials should always be the first choice, but immune checkpoint inhibitors offer an attractive off-study option.

Among many single agents in National Comprehensive Cancer Network guidelines for recurrent advanced cervical cancer after first-line cisplatin-based chemotherapy, there is a reason why pembrolizumab is listed first. For patients with PD-L1 expressing tumors or MSI-H/dMMR tumors, I would use it.

Frontline therapy in DLBCL

In a large, randomized phase 3 trial, close to 500 stage III-IV patients with diffuse large B-cell lymphoma (DLBCL), including primary mediastinal B-cell lymphoma and intravascular large B-cell lymphoma, were assigned to receive either conventional R-CHOP chemotherapy or the more complex, more toxic DA-EPOCH-R regimen that appeared superior in single-institution studies and was feasible in multi-institutional phase 2 trials.

The study – “Dose-Adjusted EPOCH-R Compared With R-CHOP as Frontline Therapy for Diffuse Large B-Cell Lymphoma: Clinical Outcomes of the Phase III Intergroup Trial Alliance/CALGB 50303” – was published in the Journal of Clinical Oncology (2019 Apr 2. doi: 10.1200/JCO.18.01994).

In the study, progression-free survival and overall survival were no different for R-CHOP and DA-EPOCH-R, but – predictably – DA-EPOCH-R was more toxic and had more treatment discontinuations.

R-CHOP had better outcomes than expected. This suggests that patient-selection bias (more favorable histology, fewer high-risk subsets who required urgent therapy) may have been at work.

Further study of DA-EPOCH-R in higher IPI patients or in patients selected because of more adverse molecular features (DE phenotype, MYC+, double hit) is warranted given the poor outcomes with R-CHOP in high-risk patients, intriguing results in single institution trials of DA-EPOCH-R, and the underrepresentation of high-risk patients in the current study.

What this means in practice

Whether by virtue of the types of patients enrolled or because it is the best regimen in all DLBCL patients, R-CHOP remains the standard of care outside of a clinical trial.

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers, and in expanding access to clinical trials to medically underserved populations.

Next Article: