Pepinemab Plus Avelumab Provides Disease Control in NSCLC

Sharon Worcester

April 21, 2020

ORLANDO, Florida – Combination pepinemab and avelumab is well tolerated and shows antitumor activity in patients with advanced non–small cell lung cancer (NSCLC) who progressed on prior treatment, according to interim results from a phase 1b/2 trial.

Treatment with pepinemab, an anti–semaphorin 4D antibody, and avelumab, a programmed death-ligand 1 (PD-L1) inhibitor, produced disease control rates of 59% in immunotherapy-resistant patients and 81% in immunotherapy-naive patients.

Michael Rahman Shafique, MD, of Moffitt Cancer Center in Tampa, Fla., reported these results at the ASCO-SITC Clinical Immuno-Oncology Symposium.

The CLASSICAL-Lung trial initially enrolled 12 immunotherapy-naive patients with stage IIIb/IV NSCLC into a dose-escalation phase that examined pepinemab at doses of 5, 10, and 20 mg/kg along with 10 mg/kg of avelumab every 2 weeks.

Then, the trial enrolled 50 stage IIIb/IV patients – including 18 immunotherapy-naive patients and 32 who failed prior immunotherapy – into a phase 2 dose-expansion phase.

The 10 mg/kg pepinemab dose and 10 mg/kg avelumab dose were selected for the expansion phase based on the dose-escalation results, Dr. Shafique said. He explained that all three doses were safe, but "we were saturating the target at the 10-mg dose."

Efficacy and Safety

"In general, the safety data were encouraging," Dr. Shafique said. "This was a very well-tolerated combination with no concerning safety signals. The most common adverse events were grade 1 and grade 2 fatigue, chills, pyrexia, and no grade 5 events attributable to the combination were reported."

In the efficacy analysis, there were 29 evaluable patients who received pepinemab and avelumab after progressing on prior immunotherapy and were followed for at least 6 months. Two of these patients experienced a confirmed partial response (PR), and 15 had stable disease, for a disease control rate of 59%. Five patients had durable clinical benefit lasting at least 23 weeks, and three remained on active treatment at last follow-up, including one who had been on treatment for more than a year.

Of 21 evaluable immunotherapy-naive patients followed for at least 6 months, 5 experienced a confirmed PR, and 12 had stable disease, for a disease control rate of 81%. Three patients had clinical benefit lasting at least a year, and two remained on study and continued to receive treatment at last follow-up.

Pre- and on-treatment biopsies performed on the same lesion about 5 weeks apart demonstrated "a pretty drastic reduction in viable tumor," Dr. Shafique noted.

"Even in patients with stable disease, many of them had absent tumor on these repeat, on-treatment biopsies," he said, also noting that CD8-positive T-cell density increased in most tumors following treatment in patients who had a PR or stable disease, and the levels appeared to correspond with response.

Mechanism of Action

Despite advances in immunotherapy, NSCLC patients often are refractory or acquire resistance to currently available agents, but semaphorin 4D "seems to shift the balance in the microenvironment to one of myeloid-induced immune suppression and generally a protumor, if you will, microenvironment," Dr. Shafique said.

"Blockade of semaphorin 4D with pepinemab, we think, helps relieve this suppressive environment and actually seems to stimulate infiltration of T cells and improve T-cell activity in these tumors," he added. He went on to explain that the mechanism of action is believed to generally be through suppression of myeloid cell trafficking to the tumor and myeloid cell cytokine secretion.

Further, and more importantly for cancer immunotherapy, preclinical models suggest that anti–semaphorin 4D antibodies are synergistic with various checkpoint inhibitors, including the PD-L1 inhibitor avelumab and others, Dr. Shafique said.

Indeed, these early CLASSICAL-Lung trial findings "do support the mechanism of action being reversing this myeloid-induced suppression in the microenvironment and improving T-cell infiltration and activity," and they support a potential benefit of combining anti–semaphorin 4D antibodies and checkpoint inhibition in advanced NSCLC after progression on prior therapy, Dr. Shafique added.

Invited discussant Timothy A. Yap, MBBS, of the University of Texas MD Anderson Cancer Center in Houston, said that "inhibition of [semaphorin 4D] promotes functional immune infiltration into the [tumor microenvironment] and, therefore, is a rational way of inhibiting tumor progression" in NSCLC and other cancers.

The CLASSICAL-Lung trial "didn't escalate all the way to the [maximum tolerated dose] but did demonstrate durable on-treatment increases in CD8-positive T-cell infiltration, including in 79% of patients with low or null PD-L1 expression, as proof of mechanism," Dr. Yap said, noting the responses in both immunotherapy-naive and immunotherapy-resistant patients.

"So I guess the key question will be, ‘Is this an active combination in NSCLC?' " Dr. Yap said. "In my opinion, yes it is, but is it going to be enough to take it past registration?"

Next Steps

As next steps for the investigators, Dr. Yap suggested looking at a more specific population of PD-L1–low or –null immunotherapy-resistant NSCLC patients, considering adding a chemotherapy agent to the pepinemab/avelumab combination, or perhaps going "straight to a randomized phase 2/3 trial [comparing the combination with] pembrolizumab."

"The investigators should also consider other tumor types beyond non–small cell lung cancer with this particular combination," he said.

The preclinical data with respect to the anti–semaphorin 4D antibody suggest that study in combination with other agents, such as anti–CTLA-4 agents or anti-LAG3 agents, is also warranted, Dr. Yap added, noting that triplet combinations might also be worth investigating.

The CLASSICAL-Lung trial is funded by Vaccinex and Merck. Dr. Shafique reported a consulting or advisory role with GlaxoSmithKline. Dr. Yap reported relationships with numerous pharmaceutical companies, including Merck. MD Anderson's Institute of Applied Cancer Science, where Dr. Yap serves as medical director, has a commercial interest in DNA damage response inhibitors and other inhibitors.

SOURCE: Shafique MR et al. ASCO-SITC 2020, Abstract 75.

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