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ASCO Clinical Findings

Clinical findings as presented at the American Society of Clinical Oncology's Annual Meeting in June 2018.

Nearly Half of Patients With Metastatic CSCC Respond to Fast-Tracked Cemiplimab

Mary Caffrey 

After taking the programmed death-1 inhibitor cemiplimab for an average of close to 8 months, nearly half of patients with metastatic cutaneous squamous cell carcinoma (mCSCC) responded to treatment in a phase 2 study. A median duration of response had not been reached, however, according to results presented June 4, 2018, at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Illinois.

The results were simultaneously published in the New England Journal of Medicine.1 The journal featured both reports of the expansion cohort from phase 1, which saw a response from 13 of 26 patients (50%; 95% CI, 30%-70%) as well as results from phase 2, which reported responses from 28 of 59 patients.

“The study of cemiplimab for the treatment of advanced cutaneous squamous cell carcimona was underpinned by the recognition that a high mutation burden may render these tumors sensitive to effector T cells in the context of immune checkpoint blockade,” the authors write.

The study of 54 men and 5 women, with an average age of 71 years (range, 38-93 years), involved a 3-mg/kg dose given intravenously every 2 weeks. Tumor measurements were performed every 8 weeks. Overall response rate (ORR) was the primary endpoint, and duration of response was the key secondary endpoint.

The FDA has already granted priority review status to cemiplimab, which is being developed by Regeneron and Sanofi. A decision on the biologics license application is expected by October 28, 2018.2

CSCC, or skin cancer, is very common in the United States, and most often it is treatable. But in 5% of the cases, it becomes metastatic, and there is no standard of care for this form of the disease. Thus, cemiplimab would fill a significant unmet need for patients with mCSCC. At ASCO 2017, Regeneron presented promising phase 1 results that resulted in the FDA’s earlier designation of cemiplimab as a breakthrough therapy in this indication.3 Results presented this year include data through October 27, 2017.4

At the time of data cutoff, patients had been followed for an average of 7.9 months (range, 1.1-15.6 months). ORR, as measured by an independent review team examining patient scans, was

47% (95% CI, 34%-61%). The rate of durable disease control was 61% (95% CI, 47%-74%), with 4 complete responses and 24 partial responses. The average time to initial response was 1.9 months.Of the 28 patients who had a response, the duration of response exceeded 6 months for 57%, and 82% still had a response and were taking cemiplimab at the time of the data cutoff.

The most common adverse events (AEs) were diarrhea (27%), fatigue (24%), and nausea (17%). The paper reported 25 AEs of grade 3 or higher, including 17 that were serious and 3 that led to discontinuation of treatment; 3 were associated with an outcome of death. The study’s authors said the side effects observed were typical among patients treated with checkpoint inhibitors.3​​​​​​

“The strong results seen with cemiplimab are noteworthy given that advanced CSCC is a very serious condition that currently has no approved treatments once surgery is no longer an option,” Michael R. Migden, MD, co-lead author and associate professor in the Departments of Dermatology and Head and Neck Surgery at The University of Texas MD Anderson Cancer Center, said in a statement. “Advanced CSCC tumors were shown to be responsive to cemiplimab in both metastatic and locally advanced patients, with the results being clinically meaningful and consistent between the phase 1 and phase 2 trials.”5

  1. Migden MR, Rischin D, Schmults CD, et al. PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma [published online June 4, 2018]. N Engl J Med. doi:10.1056/NEJMoa1805131.
  2. FDA to conduct priority review of cemiplimab as a potential treatment for advanced cutaneous squamous cell carcinoma [press release]. Paris, France, and Tarrytown, NY: Sanofi; April 30, 2018. as-a-Potential-Treatment-for-Advanced-Cutaneous-Squamous-Cell-Carcinoma. Accessed June 4, 2018.
  3. Harris J. FDA grants cemiplimab breakthrough designation for CSCC. OncLive® website. Published September 8, 2017. Accessed June 4, 2018.
  4. Rischin D, Migden MR, Chang A, et al. Primary analysis of phase 2 results for cemiplimab, a human monoclonal anti-PD-1, in patients with metastatic cutaneous squamous cell carcinoma (mCSCC). J Clin Oncol. 2018;36(suppl; abstr 9519). record/159083/abstract.
  5. New England Journal of Medicine publishes pivotal cemiplimab trials showing positive results in advanced cutaneous squamous cell carcinoma [press release]. Paris, France, and Tarrytown, NY: Sanofi; June 4, 2018. Medicine-publishes-pivotal-cemiplimab-trials-showing-positive-results-in-advanced-cutaneous-squamous-cell-carcinoma. Accessed June 4, 2018.

KEYNOTE-042 Confirms First-Line Pembrolizumab Superior to Chemotherapy in PD-L1– Low Advanced NSCLC

Surabhi Dangi-Garimella, PhD

A late-breaking abstract presented on June 3 at the 2018 American Society of Clinical Oncology Annual Meeting confirmed that pembrolizumab significantly improved the primary end point of overall survival (OS) over plati- num-based chemotherapy in treatment-naive advanced/metastatic non–small- cell lung cancer (NSCLC). The effect, the authors from the KEYNOTE-042 study found, was agnostic of PD-L1 expression, meaning the monoclonal antibody was effective for tumors expressing PD-L1 at ≥50%, ≥20%, and ≥1%.1

However, the secondary outcome of progression-free survival (PFS) was not met at data cut-off on February 26, 2018.

Previously, pembrolizumab monotherapy has shown significant improvement in OS over docetaxel as second-line treatment in metastatic NSCLC with PD-L1 tumor proportion score (TPS) ≥1%. Additionally, patients whose NSCLC had a PD-L1 TPS of ≥50% saw significant improvements in both PFS and OS with first-line pembrolizumab, compared with platinum-based chemotherapy (KEYNOTE-024).2

Results from the KEYNOTE-189 study, published earlier this year, emphasized the advantage of combining chemotherapy with pembrolizumab: The researchers showed that the combination approach as first-line treatment in patients with metastatic NSCLC, who had no EGFR or ALK alterations, was significantly better than chemotherapy alone and was agnostic of PD-L1 expression.3

“Our trial, KEYNOTE-042, is evaluating pembrolizumab monotherapy against platinum-based chemotherapy for metastatic NSCLC with low expression of PD-L1,” said lead author Gilberto Lopes, MD, MBA, Sylvester Comprehensive Cancer Center, University of Miami Health System. The trial was designed to develop a more effective and tolerable first-line treatment for metastatic NSCLC, he said.

Eligibility criteria included locally advanced or metastatic tumors with PD-L1 TPS ≥1%, without EGFR or ALK alterations. The ECOG status had to be 0 or 1; patients had to be free of untreated or unstable CNS metastases.

Treatment-eligible patients were randomized 1:1 to ≤35 cycles of pembroli- zumab 200 mg every 3 weeks or investigator’s choice of ≤6 cycles of paclitaxel + carboplatin or pemetrexed + carboplatin with optional pemetrexed maintenance (nonsquamous only). Primary end points were OS in patients with TPS≥50%, ≥20%, and ≥1%. Secondary end points were PFS and objective response rate for all 3 TPS, and safety in patients with TPS ≥1%.

At 12.8 months median follow-up, 13.7% of patients were still on pembrolizumab and 4.9% were receiving pemetrexed maintenance treatment.

In the TPS ≥50% subset, median OS at 24 months was 20 months (range, 15.4-24.9) in the pembrolizumab-treated patients (event rate: 44.7%) and 12.2 months (range, 10.4-14.2) in those treated with chemotherapy (event rate: 30.1%). Similarly, in the TPS ≥20% subset, median OS at 24 months was 17.7 months (range, 15.3-22.1) in the pembrolizumab-treated patients (event rate: 40.5%) and 13.0 months (range, 11.6-15.3) in those treated with chemotherapy (event rate: 29.6%). Among patients whose tumors expressed a low level of PD-L1 (TPS ≥1%), median OS at 24 months was 16.7 months (range, 13.9-19.7) in the pembrolizumab-treated arm (event rate: 39.3%) and 12.1 months (range, 11.3-13.3) in those treated with chemotherapy (event rate: 28.0%).

Lopes shared the PFS data in the TPS ≥20% cohort. Median PFS at 12 months was 6.2 months (range, 5.1-7.8) in the pembrolizumab-treated arm (event rate: 32.4%) and 6.6 months (range, 6.2-7.3) in those treated with chemotherapy (event rate: 28.8%).

Grade 3-5 drug-related adverse events (AEs) were less frequent with pembroli- zumab, Lopes said (17.8% vs 41.0% for chemotherapy). However, the rates of discontinuation (about 9.0%) and treatment-related deaths (about 2.0%) were similar between the 2 groups. Immune-related AEs (irAEs) are significant concerns that accompany the use of immune checkpoint inhibitors such as pembrolizumab.4 Lopes shared that about 27.8% of patients treated with pembrolizumab experienced irAEs, and 1 patient died as a result. Only 7% of patients in the chemotherapy arm had irAEs.

“KEYNOTE-042 is the first study with a primary end point of overall survival to demonstrate superiority of pembrolizumab over platinum-based chemotherapy in patients with previously untreated advanced/metastatic NSCLC without sensitizing EGFR or ALK alterations and a PD-L1 TPS ≥1%,” the authors concluded.

“Our data confirm and potentially extend the role of pembrolizumab monotherapy as a standard first-line treatment for patients with PD-L1–expressing tumors,” said Lopes. He shared that based on the advice of their external drug monitoring committee, the trial continues to evaluate PFS in this trial population.

Leena Gandhi, MD, currently the director of thoracic medical oncology and an associate professor of medicine at the New York University School of Medicine, who will soon be joining Eli Lilly and Company,5 was the discussant for this abstract.

Comparing the performance of nivolumab, the other PD-1 inhibitor, with pembrolizumab, Gandhi questioned whether the crossover allowed in the CheckMate-026 study may have resulted in the failure of nivolumab as first-line treatment in advanced/metastatic NSCLC. “Overall, the studies are more similar than they are different,” she said. However, CheckMate-026 allowed 60.4% of patients in the chemotherapy arm to cross over to the nivolumab arm, whereas only 19.8% in KEYNOTE-042 who received chemotherapy were subsequently treated with pembrolizumab.

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