Camidanlumab Tesirine Plus Pembrolizumab Produces Responses But Increases Immune Toxicities in Select Solid Tumors

Treatment with the anti-CD25 antibody-drug conjugate (ADC) camidanlumab tesirine (ADCT-301) was deemed well tolerated as a monotherapy and produced encouraging responses when administered with pembrolizumab (Keytruda) in select pretreated patients with advanced solid tumors. However, the combination was associated with an increase in immune-related adverse effects (AEs), according to findings from a phase 1 trial (NCT03621982) presented at the 2023 SITC Annual Meeting.¹

In the monotherapy cohort (n = 44), 25.0% of patients achieved stable disease (SD). No patients achieved an objective response, and the disease control rate (DCR) was 25.0%. Conversely, 30.3% of patients in the combination cohort (n = 34) achieved SD, 3.0% of patients achieved a complete response (CR), and 12.1% of patients achieved a partial response (PR). The DCR in this cohort was 45.5%. Notably, all 5 responders had ovarian or fallopian cancer.

Among efficacy-evaluable patients with ovarian cancer in the combination arm, who had received a median of 4 prior lines of therapy and were immunotherapy naive (n = 17), the overall response rate (ORR) was 29.4%, and the DCR was 47.0%.

“In terms of safety and tolerability, the drug was very well tolerated as a monotherapy. There were no dose-limiting toxicities observed, and the maximum tolerated dose (MTD) was not reached... [Conversely], there was considerably higher toxicity, particularly immune-related and skin toxicity, noted in the combination cohort,” lead study author Christopher T. Chen, MD, the director of Early Drug Development at Stanford Cancer Institute and an assistant professor of medicine in the Division of Oncology at Stanford University School of Medicine, stated in an oral presentation of the data.

CD25-positive, FOXP3-positive regulatory T cells (Tregs) are known to be key drivers of an immunosuppressive tumor microenvironment, and studies with preclinical animal models have shown that effectively depleting CD25-positive Tregs can inhibit tumor growth and improve survival across solid tumor histologies and lymphomas.

Camidanlumab tesirine consists of a CD25-directed antibody linked via a cleavable linker to a PBD toxin payload. Prior phase 2 research has shown activity and manageable toxicity with camidanlumab tesirine when used as a single agent in patients with relapsed/refractory Hodgkin lymphoma. The agent may also have synergy when used with the anti–PD-(L)1 inhibitor pembrolizumab.

“Unlike most ADCs designed to deplete tumor cells, camidanlumab tesirine is designed to deplete Tregs highly potently,” Chen explained during the presentation. “By doing so, the hope is that we see improvement in the cytotoxic T lymphocyte [CTL]:Treg intratumoral ratio, leading to greater to antitumor activity.”

Based on these data, investigators assessed the clinical, pharmacokinetic, and biomarker data from a phase 1a/b trial of camidanlumab tesirine both as a monotherapy and in combination with pembrolizumab. The multicenter, open-label trial enrolled patients 18 years of age or older with locally advanced or metastatic solid tumors, measurable disease, and an ECOG performance status of 0 or 1. Patients were also required to be refractory or intolerant to existing therapies, including prior immunotherapy or anti–PD-(L)1 therapy. Exclusion criteria included prior anti-CD25 therapy, prior solid organ transplant, autoimmune disease, or recent infection.

The trial utilized a 3+3 design in the dose escalation phase (part 1). Patients in part 1 who were enrolled onto the monotherapy arm received 20 µg/kg to 300 µg/kg of camidanlumab tesirine intravenously (IV) on day 1 of each 3-week cycle. Patients enrolled onto the combination arm received an IV infusion of camidanlumab tesirine at 30 µg/kg to 300 µg/kg on day 1 of each 3-week cycle for 2 cycles on and 2 cycles off. Every 3 weeks, these patients also received 200 mg of pembrolizumab 1 hour after camidanlumab tesirine infusion.

The study’s primary end points were safety and tolerability, with key secondary end points of antitumor activity and pharmacokinetics. The study also evaluated exploratory end points of biomarker data and paired biopsy immune cell profile.

Across both cohorts, most patients were heavily pretreated, having received a mean of at least 4 prior lines of therapy. In the monotherapy cohort, 40.9% of patients were female, and 90.9% of patients were White. The mean age of patients was 60.8 years (standard deviation [SD], 11.35), and the most common tumor types were pancreatic cancer (38.1%) and colorectal cancer (34.1%). Patients received a mean of 2.1 cycles of therapy (SD, 1.06), with a median treatment duration of 27.1 days (SD, 30.80).

In the monotherapy cohort, 67.6% of patients were female, and 82.4% of patients were White. The mean age of patients was 64.1 years (SD, 8.46), and the most common tumor type was ovarian/fallopian cancer (52.9%). Patients received a mean of 3.0 cycles of therapy (SD, 2.88), with a median treatment duration of 49.4 days (SD, 69.29).

As of the data cutoff of December 21, 2022, all patients discontinued the study. Reasons for treatment discontinuation included progressive disease (81.8% with monotherapy; 58.8% with combination), unacceptable toxicity, (2.3%; 20.6%), withdrawal by patients (11.4%; 11.8%), death (4.5%; 5.9%), or study termination by sponsor (0.0%; 2.9%).

Assessment of pharmacokinetics revealed that the maximum serum concentration and area under the curve of the camidanlumab tesirine/PBD–conjugated antibody increased linearly with escalating doses of camidanlumab tesirine. Moderately higher exposures were observed with the combination cohort vs the monotherapy cohort. Moderate interpatient variability was also observed. There was no accumulation of camidanlumab tesirine up to cycle 2, and no clinically relevant antidrug antibody induction effects were observed.

Regarding safety, grade 3 or greater adverse effects (AEs) were seen in 70.5% of patients treated with camidanlumab tesirine monotherapy, the most common of which were anemia (9.1%), abdominal pain (6.8%), pulmonary embolism (PE; 6.8%), and rash (6.8%). Serious AEs occurred in 40.9% of patients. AEs led to death, dose delay, dose reduction, and treatment discontinuation in 11.4%, 22.7%, 0.0%, and 4.5% of patients, respectively.

The MTD was also not reached in the combination cohort. In this cohort, grade 3 or greater AEs were seen in 79.4% of patients, the most common of which were macropapular rash (17.6%), anemia (14.7%), hyponatremia (11.8%), and decreased lymphocyte count (11.8%). Serious AEs occurred in 70.6% of patients. AEs led to death, dose delay, dose reduction, and treatment discontinuation in 5.9%, 41.2%, 0.0%, and 23.5% of patients, respectively.

Two DLT events of grade 3 pneumonitis and pancreatitis were reported in 1 patient each at the 45 µg/kg and 100 µg/kg dose levels, respectively. Additionally, 1 patient treated with 60 µg/kg of camidanlumab tesirine experienced grade 3 encephalitis in cycle 1 with concomitant COVID-19 infection. This event was determined to be treatment-related rather than a DLT, and the patient recovered without sequalae after discontinuing treatment.

Notably, there was an increase in the frequency of skin and soft tissue AEs with the combination (61.8%) vs monotherapy (36.4%). The incidence of autoimmune-related AEs also increased with the combination (55.9%) vs monotherapy (11.4%). One patient experienced Stevens-Johnson syndrome and toxic epidermal necrolysis that was considered related to study treatment more than 30 days after their last dose.

“There was no Guillain-Barre syndrome reported during the study. That is of particular note because in the lymphoma study [of camidanlumab tesirine], there were Guillain-Barre syndrome events [that were] thought to be drug related,” Chen notes.

Responses with the combination regimen according to baseline biopsy biomarker status were assessed in 16 patients with ovarian cancer with available baseline biopsy biomarker data. In this population, patients with baseline CTL infiltration levels in the tumor epithelium that were higher than the median experienced numerically higher response rates. Investigators noted that interpretation of these data should be treated with caution due to the small sample size and different camidanlumab tesirine doses administered. Additionally, the CTL:Treg ratio increased from baseline in approximately half of patients in the monotherapy cohort, and 10 out of 15 patients in this cohort experienced a decrease in Treg infiltration.

Similarly, most patients in the combination cohort experienced an increase in CTL:Treg ratios from baseline. Ten out of 16 patients experienced a decrease in Treg infiltration, although none experienced a concomitant decrease in CTL infiltration. Paired biopsies were available for 10 patients with ovarian cancer treated with the combination. Of these patients, 3 experienced a PR, 1 experienced SD, and 6 had disease progression. All 3 responders had Treg and CTL infiltration levels in the tumor epithelium in the post-treatment biopsy that were higher than the median.

“To point out a notable clinical phenomenon about the kinetics of responses on this study, delayed and prolonged responses were [also] observed in a number of patients… The durability [of response] and fact that several patients showed sustained responses without drug dosing is a striking factor…” Chen added.

Editor’s Note: Dr Chen discloses the following relationships: consulting/advisory roles for Boxer Capital and Guidepoint Global; and research funding from ADC Therapeutics, Gilead, Kinnate Biopharma, Mersana Therapeutics, ORIC Pharmaceuticals, Palleon, Rain Oncology, Riboscience, and Takeda.

Reference

Chen C, Hamilton E. LoRusso P, et al. Results of a phase 1 study investigating camidanlumab tesirine as monotherapy and in combination with pembrolizumab in patients with select advanced solid tumors. Presented at: 2023 SITC Annual Meeting; November 1-5, 2023; San Diego, CA. Abstract 608.