Camidanlumab Tesirine Elicits Encouraging Responses in Relapsed/Refractory Classical Hodgkin Lymphoma

Camidanlumab tesirine (ADCT-301) induced an overall response rate of 70.1% (95% CI, 60.9%-78.2%) in heavily pretreated patients with relapsed or refractory classical Hodgkin lymphoma who previously received brentuximab vedotin (Adcetris) and a PD-1 blockade with or without stem cell transplant (SCT), according to updated data from a phase 2 trial (NCT04052997).¹

Findings presented during the 2022 EHA Congress showed that among those who responded to treatment with the antibody-drug conjugate (ADC), the complete response (CR) rate was 33.3%, the partial response (PR) rate was 36.8%, and 17.9% of patients achieved stable disease. Moreover, 5.1% of patients were not found to be evaluable for response, and 6.8% experienced disease progression.

In the 73 patients who previously received brentuximab vedotin and checkpoint inhibition with prior SCT, the ORR achieved with camidanlumab tesirine was 74.0% (95% CI, 62.4%-83.5%); this included a CR rate of 41.1%, a PR rate of 32.9%, and a stable disease rate of 17.8%. In this group, 4.1% of patients were not evaluable for response, and 4.1% experienced progressive disease.

In the 43 patients who previously received brentuximab and checkpoint inhibition without prior SCT, the ORR with the investigative ADC was 62.8% (95% CI, 46.7%-77.0%), which included an 18.6% CR rate, a 44.2% PR rate, and a 18.6% stable disease rate. Seven percent of patients were not response evaluable, and 11.6% had disease progression.

“Very few viable or sustainable treatment options are available for patients with Hodgkin lymphoma who are refractory or relapse following treatment with brentuximab vedotin and PD-1 inhibitor therapy,” Carmelo Carlo-Stella, MD, Department of Biomedical Sciences, Humanitas University, and Department of Oncology and Hematology, IRCCS Humanitas Research Hospital, stated in a recent press release.² “Results from the pivotal phase 2 trial indicate that camidanlumab tesirine, a novel CD25-targeted ADC, has the potential to fill the need for a new treatment option for heavily pretreated patients with Hodgkin lymphoma.”

Limited therapeutic options are available for patients with relapsed or refractory classical Hodgkin lymphoma who are refractory to or relapse after brentuximab vedotin and PD-1 blockade. Camidanlumab tesirine is comprised of a monoclonal antibody that binds to CD25 and conjugated to the pyrrolobenzodiazepine (PBD) dimer payload, tesirine. Once bound to a CD25-expressing cell, the agent is internalized into the cell; the enzymes then release the payload thus eradicating the cell.

Previous data from a phase 1 trial showcased that treatment with the ADC resulted in encouraging antitumor activity with acceptable safety in patients with lymphoma, including those with classical Hodgkin lymphoma.³

The single-arm, multicenter, open-label, phase 2 trial enrolled patients with a pathologic diagnosis of classical Hodgkin lymphoma who were at least 18 years of age and had relapsed disease.^1,4 Patients were required to have received at least 3 previous lines of systemic therapy, which included brentuximab vedotin and a checkpoint inhibitor. Moreover, patients needed to have measurable disease, an ECOG performance status of 0 to 2, and acceptable organ function.

Patients who underwent an allogeneic or autologous hematopoietic SCT (HSCT) 60 days or less prior to the initiation of camidanlumab tesirine, or who had a history of neurotherapy thought to be of autoimmune origin were excluded. Other exclusion criteria included those with a recent infection thought to be caused by prespecified pathogens, clinically significant third-space fluid accumulation or pleural effusion requiring draining or linked with shortness of breath, as well as human immunodeficiency virus, or hepatitis B or C virus requiring antiviral treatment or prophylaxis.

Study participants were administered camidanlumab tesirine at a dose of 45 μg/kg via a 30-minute intravenous infusion on day 1 of each 3-week cycle for cycles 1 and 2. For cycles 3 and on, patients received the agent at a dose of 30 μg/kg for up to 1 year.

The primary end point of the trial was ORR per 2014 Lugano classification and central review assessment. Key secondary end points comprised duration of response (DOR), progression-free survival (PFS), and safety.

Previous findings from the phase 2 trial showed that single-agent camidanlumab tesirine elicited an ORR of 66.3%, with a CR rate of 27.7% in those with relapsed or refractory classical Hodgkin lymphoma. The median follow-up for the data presented during the 2022 EHA Congress was 10.7 months (range, 1.2-25.2+).

As of November 1, 2021, 117 patients had been enrolled to the trial. The median age was 37 years (range, 19-87), with most patients being male (62.4%), having an ECOG performance status of 0 (54.7%), and stage IV disease (58.1%) per Ann Arbor criteria.

The median number of prior systemic therapies received was 6 (range, 3-19). Notably, more than half of patients (61.5%) had received more than 5 prior lines of therapy; 4.3% of patients received at 3 or fewer prior lines of therapy, 15.4% received 4 prior lines, 18.8% received 5 prior lines. Additionally, 50.4% previously underwent autologous HSCT, 2.6% underwent allogeneic HSCT, and 10.3% underwent both procedures.

Moreover, 67.5% of patients had relapsed disease following frontline systemic treatment and 24.8% had refractory disease; this information was missing or not evaluable for 7.7% of patients. Most patients had refractory disease (56.4%) following their last-line systemic therapy, 31.6% had relapsed disease, and this information was missing or not evaluable for 12.0% of patients.

The median number of cycles dosed was 5 (range, 1-15, and the median duration of treatment with the ADC was 85 days (range, 1-330). The majority of responses occurred following the first 2 cycles of treatment. Moreover, 15 patients who initially had a PR were found to subsequently achieve a CR.

Fourteen patients discontinued the ADC to receive transplant; 12 of these patients were transplanted. Twelve patients underwent allogeneic transplant, 3 of whom progressed 2 to 5 months after the procedure. Four patients underwent autologous transplant, 1 of whom progressed 2 months post procedure. Nine patients are still being followed, 5 withdrew consent, and 2 died due to progressive disease and septic shock.

Additional data showed that the median DOR with camidanlumab tesirine was 13.73 months (95% CI, 7.36-14.65). The median time to the first CR or PR was 41 days (range, 32-148). The median time to first CR was 45 days (range, 32-222).

The median DOR in those with a CR was 14.52 months (95% CI, 7.36–not reached [NR]). In those who achieved a PR with the ADC, the median DOR was 7.85 months (95% CI, 3.84-NR); the median DOR was 13.73 months (95% CI, 7.36-14.65) in those with a CR + PR.

Moreover, the median PFS was 9.10 months (95% CI, 5.13-15.01) per independent review in the all-treated patient population. In those who achieved a CR with camidanlumab tesirine, the median PFS was 15.87 (95% CI, 9.13-NR); in those with a PR, the median PFS was 9.00 months (95% CI, 5.13-NR). In those with a CR + PR, the median PFS was 15.01 months (95% CI, 9.10-15.87).

Any-grade treatment-emergent adverse effects (TEAEs) occurred in 99.1%. The most common TEAEs included fatigue (38.5%), maculopapular rash (32.5%), pyrexia (29.9%), nausea (27.4%), and rash (26.5%). All-grade PBD-associated TEAEs reported with the ADC included skin or nail reactions (74.4%), hepatobiliary test abnormalities (29.1%), and edema/effusion (17.1%).

Grade 3 or higher TEAEs experienced with camidanlumab tesirine included thrombocytopenia (9.4%), anemia (8.5%), hypophosphatemia (7.7%), neutropenia (7.7%), maculopapular rash (6.8%), and lymphopenia (5.1%). The grade 3 or higher PBD-related TEAEs included skin or nail reactions (20.5%) and hepatobiliary test abnormalities (6.8%).

TEAEs resulted in dose delays or reductions in 56.4% of patients and treatment withdrawal in 27.4% of patients. Serious TEAEs were experienced by 39.3% of patients, and fatal TEAEs occurred in 3.4% of patients.

Moreover, 32.5% of patients experienced immune-related TEAEs (ir-TEAEs), with grade 3 or higher irTEAEs reported in 10 patients. The median age of these patients was 45.5 years (range, 22-75), and 80% previously underwent autologous transplant. The median number of cycles of the ADC received was 3.5 cycles (range, 2-12). Fifty percent of the grade 3 or higher irTEAEs occurred following 2 to 3 treatment cycles, and half of patients had onset following 30 days after their last dose of the ADC. The median days since the last checkpoint inhibitor received was 183 days (range, 76-2097).

Among the 8 patients with Guillain–Barré syndrome (GBS)/polyradiculopathy, the median age was 35 years (range, 23-68). Three patients previously received transplant. These patients had a median of 3.5 cycles (range, 2-7) of camidanlumab tesirine, with a median of 187 days (range, 50-377) since receipt of their last checkpoint inhibitor. Half of the cases presented after 2 cycles of treatment with the ADC, and 3 had onset at 30 days or longer following their last dose.

“GBS/polyradiculopathy remains a concern,” Carlo-Stella concluded in a presentation. “With prompt management, such as intravenous immunoglobulin, plasma exchange, and/or high-dose steroids, GBS resolved in 4 of 8 patients and decreased in severity to grade 1 in 3 of 8 patients.”

References

1. Carlo-Stella C, Ansell S, Zinzani PL, et al. Camidanlumab tesirine: updated efficacy and safety in an open-label, multicenter, phase 2 study of patients with relapsed or refractory classical Hodgkin lymphoma (R/R cHL). Presented at: 2022 EHA Congress; June 9-12, 2022. Accessed July 11, 2022. Abstract S201.
2. ADC Therapeutics announces results from pivotal phase 2 clinical trial of camidanlumab tesirine (cami) in relapsed or refractory Hodgkin lymphoma. News release. ADC Therapeutics SA. June 10, 2022. Accessed July 11, 2022. https://bit.ly/3O0Ghfs
3. Hamadani M, Collins GP, Caimi PF, et al. Camidanlumab tesirine in patients with relapsed or refractory lymphoma: a phase 1, open-label, multicentre, dose-escalation, dose-expansion study. Lancet Haematol. 2021;8(6):e433-e445. doi:10.1016/S2352-3026(21)00103-4
4. Study to evaluate the efficacy and safety of camidanlumab tesirine (ADCT-301) in patients with relapsed or refractory Hodgkin lymphoma. ClinicalTrials.gov. Updated March 8, 2022. Accessed July 11, 2022. https://clinicaltrials.gov/ct2/show/NCT04052997