A Mixed Start for Immunotherapy in Childhood Cancers

Megan Brooks

January 02, 2020

Interim results from the first prospective study of the immune checkpoint inhibitor pembrolizumab (Keytruda, Merck) in children with advanced malignancies suggests "encouraging" antitumor activity in relapsed or refractory Hodgkin lymphoma, which is consistent with the experience in adults. However, there was low activity in many other tumor types, including melanoma.

Early data from the KEYNOTE-051 study also suggest that programmed death ligand 1 (PD-L1) expression alone is not a sufficient biomarker to select pediatric patients who are likely to respond to checkpoint inhibitor therapy.

The interim results were published online December 4 in Lancet Oncology.

Checkpoint inhibitors that block T-cell inhibitory molecules, such as cytotoxic T lymphocyte–associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and PD-L1, have substantially improved outcomes in adults with cancer. T-cell infiltrates have also been found in some tumors of children with cancer, supporting the rationale for use of immune checkpoint inhibitors in some pediatric cancers.

"Impressive" Activity in Hodgkin's

The KEYNOTE-051 study recruited children aged 6 months to 17 years at 30 hospitals in 11 countries. The phase 1-2 study established a recommended pediatric dose of pembrolizumab of 2 mg/kg given intravenously every 3 weeks to be safe and to generate drug exposures similar to adult dosing.

A total of 154 patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumor or lymphoma and whose Lansky Play/Karnofsky Performance status score was 50 or higher received at least one dose of pembrolizumab at this dose.

Overall, pembrolizumab at the pediatric dose was generally safe. Immune function analyses conducted in a subset of patients showed no major untoward effects on the developing immune system, report Birgit Geoerger, MD, Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France, and colleagues.

Of the 154 patients, 13 (8%) had grade 3–5 treatment-related adverse events, most commonly decreased lymphocyte count, seen in three (2%) patients, and anemia, seen in two (1%) patients.

Fourteen (9%) patients had serious treatment-related adverse events, most commonly pyrexia, seen in four (3%) patients, and hypertension and pleural effusion, seen in two each (1%). Four patients (3%) stopped treatment because of treatment-related adverse events, and two (1%) died ― one from pulmonary edema, and one from pleural effusion and pneumonitis.

Among the 15 patients with relapsed or refractory Hodgkin lymphoma, nine patients achieved an objective response (60.0%; 95% confidence interval [CI], 32.3% to 83.7%), including two complete and seven partial responses.

The antitumor activity observed in relapsed refractory Hodgkin lymphoma is "impressive," Hussein Tawbi, MD, University of Texas MD Anderson Cancer Center, Houston, writes in a comment in Lancet Oncology.

However, pembrolizumab had "low antitumor activity" in most other tumor types, the researchers report. Of 136 patients with solid tumors and other lymphomas, only eight had partial responses ― two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumor. Only 5.9% of these patients had an objective response (95% CI, 2.2% to 11.3%).

PD-L1 positivity in tumor tissue was not a predictor of response to pembrolizumab in pediatric patients. The researchers say plausible reasons for this include "low mutation rate, low expression of major histocompatibility complex (which might impair a T-cell response to any neoantigen), the immaturity of the immune system in young children, and the immaturity of or alterations in the gut microbiome."

Final results of KEYNOTE-051 are expected in September 2022 and will include further data on the activity of pembrolizumab in pediatric Hodgkin lymphoma and other tumor types and characteristics.

New Paradigm for Pediatric Drug Development

Tawbi notes that the use of checkpoint inhibitors in children poses several challenges, the most evident being the contrasting biology of childhood malignancies.

Knowledge of the pharmacokinetics of pembrolizumab and determination of a recommended dose in children are "extremely important findings" of KEYNOTE-051 and will be crucial for future development of combination immunotherapies in children, he points out.

The pharmacokinetic analyses corroborate those in adults and provide "an excellent framework" for drug development in the pediatric population, he adds.

However, Tawbi says detailed pharmacodynamic analysis and tissue-based translational studies would have been useful for understanding the mechanism of action of PD-1 blockade in this population.

"The absence of these steps was certainly a missed opportunity," says Tawbi, "and tissue-based analyses should be an integral component of future studies, so that the determinants of immune response and resistance can be identified and used to guide rational combination treatment strategies."

Summing up, Tawbi says, "We are only just beginning to understand the effect of checkpoint inhibition in various settings, and immune modulation to treat cancer might indeed be in its infancy. KEYNOTE-051 lays a solid foundation for further early phase studies of combination immunotherapy in pediatric malignancies, and establishes a new paradigm for drug development in this population."

The study was funded by Merck. Several authors have disclosed financial relationships with Merck and other pharmaceutical companies. A complete list is available with the original article. Tawi has received grants and personal fees from Merck, Bristol-Myers Squibb, Novartis, Roche, Celgene, and GlaxoSmithKline.

Lancet Oncol. Published online December 4, 2019. Abstract, Comment

Follow Medscape on Facebook, Twitter, Instagram, and YouTube.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as: