Anti-PD-L1 Agent Is Promising for Frontline Lung Cancer Treatment

When given in the frontline for patients with advanced non-small cell lung cancer (NSCLC), avelumab showed promising clinical benefit and durable antitumor activity, according to data presented at the International Association for the Study of Lung Cancer (IASLC) 17th World Conference on Lung Cancer.

After a median follow-up of 13 weeks, the objective response rate with the anti-PD-L1 immunotherapy agent was 22.4 percent and the median progression-free survival (PFS) was 17.6 weeks among 156 patients who participated in one of the NSCLC cohorts of the wide-ranging JAVELIN Solid Tumor trial, Anja von Heydebreck, Ph.D., of Merck KGaA, said in describing early analysis data.

JAVELIN Solid Tumor is an ongoing, multicenter phase 1 study that is exploring avelumab in multiple solid tumor types. The agent is a fully human IgG1 monoclonal antibody that blocks the PD-1/PD-L1 interaction but leaves PD-L2 signaling intact, thereby allowing antibody-dependent cellular cytotoxicity to contribute to antitumor activity.

“This is the largest phase 1 trial ever conducted, with approximately 1,700 patients across 16 cohorts,” von Heydebreck remarked.

In the first-line NSCLC cohort, the primary objective was to evaluate the best overall response of first-line avelumab at 10 mg/kg administered intravenously over one hour every two weeks until progression, unacceptable toxicity or study withdrawal in patients with histologically confirmed stage IV or recurrent NSCLC.

The patients were unselected for expression PD-L1 levels, did not have an activating EGFR mutation or ALK-positive tumors, and had not received previous systemic treatment for metastatic or recurrent disease.

The median patient age was 70 years (range, 41-90 years), ECOG performance score was 0 (29.5 percent), 1 (69.2 percent) or 3 (1.3 percent), and tumor histology was adenocarcinoma (66 percent) or squamous (28.8 percent) in most patients. The median time from diagnosis of metastatic disease was 1.5 months (range, 0.2-92.0 months).

Although patients were not selected by PD-L1 expression levels for admission into this trial, immunohistochemistry analysis revealed that just over half (56.4 percent) of patients were positive for PD-L1 expression using a 1 percent or more staining cutoff.

The best overall response by RECIST v1.1 was complete response in two (1.3 percent) patients, partial responses in 33 (21.1 percent) patients, and stable disease in 67 (42.9 percent) patients. Progressive disease was experience by 40 participants (25.6 percent), and 14 (9 percent) patients could not be evaluated.

Tumor shrinkage was observed in 64.3 percent of patients, and this shrinkage was 30 percent or greater in 28.6 percent of patients.

Overall, the median treatment duration was 20 weeks (range, two to 46 weeks), and 64 (41.0 percent) patients remained on avelumab treatment. The 24-week PFS rate was 37.2 percent (95 percent CI, 28.6-45.7).

Similar to other immunotherapeutic agents, the time to response was rapid; 28 of 35 responding (80 percent) patients demonstrated a response by the first or second assessment and as early as 12 weeks. At data cut-off, 68.6 percent of responding patients maintained response.

Treatment-related adverse events (TRAEs) of any grade occurred in 103 (66 percent) patients with avelumab; the most common adverse events occurring in less than 5 percent of patients were infusion-related reaction (IRR) in 28 (17.9 percent) patients, and fatigue, which was reported in 27 (17.3 percent) patients. Grade 3 or higher TRAEs consisting of IRRs and fatigue occurred in five patients (3.2 percent) patients and 4 (2.6 percent) patients, respectively.

Potential immune-mediated any-grade TRAEs were observed in 16 (10.3 percent) patients; of these, just one (0.6 percent) case of adrenal insufficiency was grade 3. No grade 3 or higher pneumonitis was seen. No treatment-related deaths occurred on study, and 11 (7.1 percent) patients discontinued treatment due to a TRAE.

Serving as discussant for the study, Edward B. Garon M.D., said that avelumab would more than likely not expand the group of patients who could benefit from PD-1/PD-L1 inhibition. “These data support the idea that avelumab could be equivalent to the current standard treatment, but not better,” said Garon, medical director of Thoracic Oncology at David Geffen School of Medicine at UCLA, Santa Monica.

The authors noted that the PD-L1 expression analysis is ongoing, as is a phase 3 trial of avelumab versus platinum-containing doublet chemotherapy as first-line treatment of patients with PD-L1—positive advanced NSCLC.3

Meanwhile, avelumab is advancing in other tumor types; Von Heydebreck noted the recently updated results from a phase 2 trial of avelumab in patients with Merkel cell carcinoma (MCC). The FDA granted avelumab a breakthrough therapy designation as a treatment for patients with metastatic MCC following progression after at least 1 prior chemotherapy regimen.

Merck KGaA, based in Darmstadt, Germany, is sponsoring the NSCLC development of avelumab along with its US biopharmaceutical division, EMD Serono.