Biomarkers predict response to pembrolizumab in recurrent, metastatic HNSCC

Issue: July 25, 2016

CHICAGO — Use of PD-L1 expression on tumor cells and inflammatory cells as a biomarker may predict which patients with recurrent or metastatic head and neck squamous cell carcinoma will benefit from treatment with pembrolizumab, according to study results presented at the ASCO Annual Meeting.

Further, biomarkers other than PD-L1 may also better define the tumor microenvironment and predict response to pembrolizumab (Keytruda, Merck).

Laura Q.M. Chow

“The anti–PD-1 antibodies are very active in recurrent and metastatic squamous cell carcinoma of the head and neck and are an incredible breakthrough in this disease,” Laura Q.M. Chow, MD, medical oncologist at Seattle Cancer Care Alliance, associate professor of medical oncology at University of Washington School of Medicine and associate member of clinical research at Fred Hutchinson Cancer Research Center, said in an interview with HemOnc Today. “This is the first full study looking at biomarkers that incorporate inflammatory cells with PD-L1 expression, PD-L2, as well as interferon-gamma gene signatures. By looking at all of these different biomarkers, we were able to use a multivariate approach to finally better define the tumor microenvironment and better predict who is going to respond to pembrolizumab.”

Data from the phase 1 KEYNOTE-012 study showed pembrolizumab had promising clinical activity in recurrent or metastatic HNSCC.

Chow and colleagues conducted the first analysis of potential immune correlative biomarkers — including PD-L1, PD-L2 and interferon-gamma — associated with response to pembrolizumab in the large phase 1B1 and 1B2 cohort of patients from KEYNOTE-012.

The initial cohort included 60 patients with PD-L1–positive (≥ 1%) tumors who received 10 mg/kg pembrolizumab every 2 weeks. An expansion cohort of 132 patients with PD-L1–positive or –negative tumors received 200 mg/kg pembrolizumab every 3 weeks.

All patients continued on treatment for 24 months or until the occurrence of progressive disease status or intolerable toxicities.

Researchers used immunohistochemistry in tumor cells alone (tumor proportions score) or with inflammatory cells (combined proportions score) to determine PD-L1 and PD-L2 negativity and positivity in baseline tissue samples.

They also assessed tissue-extracted RNA for the six-gene interferon-gamma signature — which includes IDO1, CXCL10, CXCL9, HLA-DRA, STAT1 and IFNG — using the NanoString nCounter platform.

Researchers observed an increase in overall response rate with PD-L1–positive vs. PD-L1–negative tumors when both tumor and inflammatory cells were used to measure PD-L1 status (21.1% vs. 5.6%; P = .023). No differences were observed when scoring was based on tumor cells only (17.9% vs. 18.5%).

ORR also was higher among patients with PD-L2–positive vs. –negative tumors when positivity was determined by tumor and inflammatory cells (22.5% vs. 9.8%; P = .022).

Researchers also determined a trend existed toward higher ORR in patients with PD-L1–positive and PD-L2–positive tumors vs. PD-L1–positive and PD-L1–negative tumors.

“It appears that PD-L1 seems correlate with PD-L2, and there is a significant association between PD-L1 and PD-L2 expression,” Chow said.

Results from exploratory analyses indicated ORR, PFS and OS were significantly associated with the interferon-gamma signature score (P < .001 for all).

Moreover, PD-L1–positive status and expression of interferon-gamma signature were not predictive by HPV status.

Area under the receiver operating characteristic curve was 0.74 for the gene expression signature and 0.65 for PD-L1 and PDL2 immunohistochemistry.

“There is a lot of discrepancy as to what the best biomarker should be as well as PD-L1 staining,” Chow said. “There is some difference between our study and the CheckMate 141 study, and these data need to be further explored, especially in terms of whether we should be incorporating inflammatory cells into the PDL-1 assay and what antibodies and cutoffs should be used. A lot of these answers are still not entirely available.” – by Jennifer Southall

Reference:

Chow LQ, et al. Abstract 6010. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.

Disclosure: Chow reports honoraria and consultant/advisory roles with Amgen, Astellas, Bristol-Myers Squibb, Emergent BioSolutions, Pfizer and Sanofi-Genzyme, Novartis; and institutional research funding from, AstraZeneca/MedImmune, Bristol-Myers Squibb, Genentech, Incyte, Lilly/ImClone, Merck Novartis, OSI Pharmaceuticals, Pfizer and VentiRx. Please see the abstract for a list of all other researchers’ relevant financial disclosures.