NEW YORK – Antibody-drug conjugates (ADCs) may play a role in treating patients with PD-L1-expressing cancers, according to interim results from a Phase I study presented during the European Society for Medical Oncology Congress in Barcelona.
Pfizer subsidiary Seagen is developing the PD-L1-directed ADC, dubbed SGN-PDL1V or PF-0804605. The drug comprises a PD-L1 monoclonal antibody attached to the cytotoxic payload monomethyl auristatin E, or MMAE.
Marc Oliva Bernal, a medical oncologist at Llobregat Hospital in Barcelona, presented data from a Seagen-sponsored Phase I study of SGN-PDL1V on Friday. Seagen designed the study to evaluate the ADC both as a monotherapy and in combination with Merck's checkpoint inhibitor Keytruda (pembrolizumab) as a treatment for advanced solid tumors, including head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer, esophageal cancer, ovarian cancer, gastric cancer, triple-negative breast cancer, or melanoma.
"The induction of immunogenic cell death has been known to enhance T-cell responses, which might … provide a strong rationale for [SGN-PDL1V's] combination with immune checkpoint inhibitors," Oliva Bernal said. However, the data presented at the Congress was only from patients who received SGN-PDL1V monotherapy.
Oliva Bernal shared data from the study's dose-escalation and dose-optimization sections, which focused more narrowly on specific cancer histologies. For the dose-escalation portion, investigators considered patients with relapsed or refractory NSCLC, HNSCC, TNBC, and esophageal cancer. For the dose-optimization portion, they narrowed the focus further to NSCLC and HNSCC.
To be eligible for the study, all patients must have been previously treated with standard therapies and have PD-L1-expressing cancers according to local testing on any platform at any time during the course of their disease. Patients in the trial received a median of three prior lines of treatment. Most had previously received PD-1 checkpoint inhibitors and around two-thirds had received taxane-based chemotherapy.
Across 94 patients, Oliva Bernal shared, SGN-PDL1V did not cause any unexpected toxicities. Many of the patients — 71.3 percent — did experience grade 3 or higher toxicities, which correlated with the dose levels they received. Fatigue, neuropathy, and nausea were the most common adverse events, and, overall, Oliva Bernal considered the safety profile to be manageable.
In terms of anti-tumor activity, the ADC led to tumor reductions in more than half the patients, and the response rates increased in accordance with higher dose levels.
Among 33 patients treated with a 1.25 milligram per kilogram dose, the overall response rate was 12.1 percent; among 37 patients who received a 1.5 milligram per kilogram dose, it was 18.9 percent; and among 12 patients who received the 1.75 milligram per kilogram dose, it was 25 percent.
Across all doses and tumor types, the investigator-assessed objective response rate was 27.3 percent, and after a median follow-up of 9.4 months, the median duration of confirmed responses was 7.9 months.
Oliva Bernal zeroed in on patients with NSCLC and HNSCC. Here, the best overall response rate for NSCLC patients was 33.3 percent at the 1.5 milligram per kilogram dose level, and the disease control rate was 67 percent. For HNSCC, the best overall response rate was 42.9 percent at the 1.75 milligram per kilogram dose level, and the disease control rate was 71.4 percent.
During a discussion of the data following Oliva Bernal's presentation, Lillian Siu, a medical oncologist at the University of Toronto's Princess Margaret Cancer Center, pointed out the differences in dosing to achieve a best response across cancer types. "We need a higher dose for head and neck squamous cancer, and a slightly lower dose, which is the recommended dose, for non-small cell lung cancer," she said.
Notably, Oliva Bernal underscored that responses were observed across patients' PD-L1 expression levels in both NSCLC and HNSCC. When achieved, the responses were durable, he noted, pointing to a median duration of response of 5.6 percent for NSCLC.
"The efficacy seen [with SGN-PDL1V monotherapy] was encouraging," Oliva Bernal said. "Because of this favorable activity, the next steps [involve] expanding the evaluation of SGN-PDL1V monotherapy in heavily pretreated non-small cell lung cancer and head and neck squamous cell carcinoma, as well as in the first-line setting in combination with pembrolizumab, for which accrual is actively ongoing."
Looking ahead, Siu said it would be helpful to know whether there is any correlation with prior exposure to immune checkpoint inhibitors in terms of primary resistance versus acquired resistance. "And we're interested, given that this is an MMAE payload, in whether there is any correlation with prior taxane exposures," she said.
Since SGN-PDL1V targets PD-L1, researchers are also interested in exploring how PD-L1 expression in tumors impacts response to the ADC as well as to the ADC-checkpoint inhibitor combination. In the study, patients had to have PD-L1 combined or tumor proportion score of at least 1 or more. None of the enrolled patients were PD-L1-negative. However, there are too few patients in the Phase I study so far to draw definitive conclusions about the ADC's benefit, particularly in terms of their PD-L1 expression levels.
Even if responses to SGN-PDL1V turned out to be different based on PD-L1 expression, Siu noted that the treatment would be easy enough to incorporate into the treatment landscape for head and neck cancer and NSCLC based on the availability of PD-L1 immunohistochemistry. "PD-L1 testing is standard of care for both of these tumor types, so logistically this is fairly straightforward," she said.
Siu also said she will be waiting to see whether combinations with PD-1 checkpoint inhibitors would lead to overlapping activity and toxicity.
Ultimately, Siu called it a "delight" to see data on ADCs targeting immune checkpoints. ADCs have been a central focus of cancer drug development in recent years, but the most success so far has been in targeting proteins like HER2 and TROP2, not immune checkpoints like PD-L1.
On the whole, ADCs have increasingly attracted a great deal of interest — and investment. Pfizer's 2023 Seagen acquisition, which totaled $43 billion, bolstered interest in this drug class, since the deal brought approved and investigational ADCs alike to Pfizer's pipeline.
Around the same time, Merck inked a deal with Daiichi Sankyo — this one worth $22 billion — aiming to bring three ADCs through clinical development.
"We have an increasing portfolio of antibody-drug conjugates approved by regulatory agencies," Siu said. "I hope by the next meeting I can move to the next slide for a new slate of approved antibody-drug conjugates."