The HER3-directed antibody-drug conjugate (ADC) patritumab deruxtecan (U3-1402) is under exploration in the treatment of patients with 

-mutated, metastatic or locally advanced non–small cell lung cancer (NSCLC) who had previously received a TKI and platinum-based chemotherapy.

In the global, multicenter, open-label phase 2 HERTHENA-Lung 01 trial (NCT04619004), investigators are examining the safety and efficacy of the agent in this patient population.

To be eligible for enrollment, patients needed to be aged 18 years or older, have histologically or cytologically confirmed locally advanced or metastatic NSCLC not amenable to curative surgery or radiation, have documented radiological disease progression while on/or after receiving their most recent therapy, and an 

 Moreover, they needed to have at least 1 measurable lesion, an ECOG performance status of 0 or 1, and acceptable bone marrow and organ function.

Participants will be randomized in a 1:1 fashion to receive the ADC at a fixed dose of 5.6 mg/kg every 3 weeks or an up-titration dose of patritumab deruxtecan in 3-week cycles. In the second arm, the ADC will be given at a dose of 3.2 mg/kg in the first treatment cycle, 4.8 mg/kg in the second cycle, and 6.4 mg/kg in the third and subsequent cycles.

The primary end point of the research is objective response rate (ORR), which will be examined per blinded independent central review (BICR). Key secondary end points will include duration of response (DOR), progression-free survival, disease control rate (DCR), and time to response (TTR); all of these end points will be evaluated per BICR and investigator assessment.

Additionally, ORR, overall survival, safety, and tolerability will also be evaluated per investigator assessment. Investigators also plan to examine HER3 protein expression levels in tumor tissue to determine who it might relate to efficacy of patritumab deruxtecan. Other areas of focus for exploration include pharmacokinetics and immunogenicity.

"Our focus is to rapidly and strategically advance the clinical development program of patritumab deruxtecan in cancers where HER3 is frequently overexpressed and is associated with poor prognosis,” Gilles Gallant, BPharm, PhD, FOPQ, senior vice president and global head of Oncology Development, Oncology R&D, at Daiichi Sankyo, stated in a press release. “This study will further inform whether targeting HER3 with an ADC may become a potential treatment strategy to overcome diverse mechanisms of EGFR TKI and chemotherapy resistance seen in patients with metastatic 

phase 1 trial (NCT03260491) examining the HER3-directed ADC

 showed that the agent had clinically meaningful antitumor activity with an acceptable toxicity profile when given at the recommended expansion dose of 5.6 mg/kg in pretreated patients with metastatic or unresectable 

As of April 30, 2020, a total of 57 patients with NSCLC harboring 

 mutations from the dose-escalation and -expansion portions of the trial had received the ADC; 56 of these patients were determined to be evaluable for response.

Results indicated that the confirmed ORR per BICR was 25.0% (95% CI, 14.4%-38.4%); this comprised a 2% complete response rate (n = 1) and a 23% partial response rate (n = 13). Additionally, the stable disease rate with patritumab deruxtecan was 45.0% (n = 25).

In the dose-escalation portion of the phase 1 trial, patients with metastatic or unresectable 

-mutant NSCLC who had progressed on osimertinib (Tagrisso) or who were T790M negative following progression on erlotinib (Tarceva), gefitinib (Iressa), or afatinib (Gilotrif) were given patritumab deruxtecan at a dose of 5.6 mg/kg every 3 weeks.

In the dose-expansion cohort, patients with metastatic or unresectable 

-mutant NSCLC who had previously received at least 1 EGFR TKI and at least 1 platinum-based chemotherapy regimen were given the ADC at a dose of 5.6 mg/kg every 3 weeks.

For this trial, the primary end point was antitumor activity with patritumab deruxtecan, while secondary end points were safety and tolerability.

Study participants had previously received a median of 4 lines of treatment for either advanced or metastatic disease (range, 1-9); 86% of patients had prior osimertinib (n = 49), 5% had another EGFR-targeted therapy (n = 3), 90% had platinum-based chemotherapy (n = 51), and 40% had anti–PD-1/PD-L1 (n = 23). Forty-seven percent of patients had a history of central nervous system metastases (n = 27).

Additional results showed that patritumab deruxtecan resulted in a DCR of 70% (95% CI, 55.9%-81.2%; n = 39). The median TTR with the ADC was 2.0 months (range, 1.2-2.8) and the median DOR was 6.9 months (range, 3.0-7.0).

Regarding safety, the most frequently experienced treatment-emergent toxicities that were grade 3 or higher in severity included thrombocytopenia (n = 16; 28%) and neutropenia (n = 11; 19%). Nine percent of patients experienced treatment-emergent adverse effects (TEAEs) that resulted in discontinuation; 2 discontinued due to fatigue, 1 because of decreased appetite, 1 because of interstitial lung disease (ILD), 1 due to pneumonitis, and 1 because of upper respiratory tract infection. No patients who experienced thrombocytopenia or neutropenia discontinued because of their toxicities. Moreover, 5.3% of ILD effects were determined to be associated with treatment. No TEAEs resulted in death.

Data from an exploratory biomarker analysis indicated that almost all evaluable patients (n = 43) expressed membrane HER3 at baseline; out of 300, the median membrane H score was 180 (range, 2-280).

Investigators also detected heterogenous EGFR TKI resistance mechanisms in pretreatment tumor tissue and circulating tumor DNA (ctDNA). Patients with diverse TKI resistance mechanisms still experienced clinical responses with treatment; this included 53% of those with 

 (HER2) mutations, as well as in those with 

Additionally, all patient samples demonstrated a reduction in 

-activating mutations in the ctDNA after receiving the ADC. Notably, those who achieved a confirmed response to treatment were more likely to experience ctDNA clearance of 

-activating mutations at week 3 or week 6. A best overall response of disease progression was determined to be associated with failure to clear these mutations in the ctDNA.

Patritumab deruxtecan is also under investigation in another phase 2 trial

 (NCT04479436) in patients with advanced or metastatic colorectal cancer who are resistant, refractory, or intolerant to at least 2 prior lines of systemic treatment.

 Previous treatment must include chemotherapy, an EGFR-targeted drug if clinically indicated, and a VEGF-targeted therapy unless contraindicated.

HERTHENA-Lung01 phase 2 study of Daiichi Sankyo’s patritumab deruxtecan initiated in patients with EGFR-mutated NSCLC. News release. Daiichi Sankyo Company, Limited. February 3, 2021. Accessed April 1, 2021. 

HERTHENA-Lung01: patritumab deruxtecan in subjects with metastatic or locally advanced EGFR-mutated non-small cell lung cancer. ClinicalTrials.gov. Updated March 9, 2021. Accessed April 1, 2021. 

https://clinicaltrials.gov/ct2/show/NCT04619004

Helena YA, Baik C, Gold K, et al. Efficacy and safety of the novel HER3 directed antibody drug conjugate patritumab deruxtecan (HER3-DXd; U3-1402) in EGFR-mutated NSCLC. Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; virtual. Abstract OA03.04.

Jänne PA, Baik C, Hayashi H, et al. Dynamics of molecular markers in EGFR-mutated NSCLC patients treated with patritumab deruxtecan (HER3-DXd; U3-1402). Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; virtual. Poster P01.04

Daiichi Sankyo initiates phase 2 study of patritumab deruxtecan in patients with HER3 expressing advanced colorectal cancer. News release. Daiichi Sankyo Company, Limited. September 15, 2020. Accessed April 1, 2021. 

Articles

The HER3-directed antibody-drug conjugate patritumab deruxtecan is under exploration in the treatment of patients with EGFR-mutated, metastatic or locally advanced non–small cell lung cancer who had previously received a TKI and platinum-based chemotherapy.

Patritumab Deruxtecan Under Exploration in Phase 2 HERTHENA-Lung01 Trial for EGFR+ NSCLC

The safety and efficacy of the antibody-drug conjugate (ADC) camidanlumab tesirine (ADCT-301) is under investigation in patients with relapsed/refractory Hodgkin lymphoma as part of a phase 2 clinical trial (NCT04052997), which recently completed accrual, according to an announcement from ADC Therapeutics, the drug developer.

Preliminary results from the phase 2 study, which were presented during the 

, showed that the agent elicited an overall response rate (ORR) of 80.9% (n = 38) among 47 evaluable patients.

 Moreover, 38.3% (n = 18) of patients achieved a complete response (CR) with the agent, while 42.6% (n = 20) achieved a partial response and 12.8% (n = 6) experienced disease stability.

"Patients with relapsed/refractory Hodgkin lymphoma who are resistant to brentuximab vedotin [Adcetris] and/or PD-L1 blockade, which are the novel drugs that we have had for some time, really have very few options,” Alex Herrera, MD, an assistant professor in the Department of Hematology and Hematopoietic Cell Transplantation at City of Hope, said during an interview with 

. “This is a population where there really is a tremendous unmet need...There is an important need for new drugs that have new targets and can be effective in patients with very resistant [disease]; that’s where this [camidanlumab tesirine] can potentially play a role.”

Although novel therapies have improved outcomes for patients with relapsed/refractory disease, many do not respond or progress after initial response, which leaves a limited number of options available. The ADC, which is comprised of a human immunoglobulin G1 anti-CD25 monoclonal antibody that is stochastically conjugated to a potent pyrrolobenzodiazepine (PDB) dimer warhead, may address this unmet need. The agent was designed to trigger cell death through the formation of cytotoxic interstrand cross-links.

“Not only can this drug work by delivering chemotherapy directly to the cancer cell, but there can also be a bystander effect by delivering the chemotherapy nearby [through the] targeting [of] lymphocytes in the microenvironment,” Herrera explained.

The multicenter, open-label, single-arm phase 2 trial included a screening period of up to 28 days followed by a treatment period comprised of 3-week cycles and a follow-up period of visits every 12 weeks for up to 3 years following treatment discontinuation.

 Patients may continue treatment up to 1 year or until they experience disease progression, unacceptable toxicity, or they meet other discontinuation criteria.

To be eligible for enrollment, patients must be aged 18 years or older (16 years or older at some sites based in the United States) and have a pathologic diagnosis of classical Hodgkin lymphoma. Patients also needed to have relapsed or refractory disease and have received treatment with at least 3 prior lines of systemic therapy, including brentuximab vedotin, as well as an approved immune checkpoint inhibitor such as nivolumab (Opdivo) or pembrolizumab (Keytruda). Also, patients needed to have measurable disease defined by the 2014 Lugano Classification, an ECOG performance status of 0 or 2 and acceptable organ function defined by screening laboratory values.

Those who have undergone prior treatment with camidanlumab tesirine, who participated in another investigational interventional study, or who had a prior history of hypersensitivity or positive serum human anti-drug antibody to a CD25 antibody were excluded from the trial. Additional exclusion criteria included having undergone allogenic or autologous transplant within 60 days prior to starting treatment with camidanlumab tesirine, having active graft-versus-host disease excluding non-neurologic symptoms (grade 1 or less), and having post-transplant lymphoproliferative disorders, among others.

Study participants received intravenous camidanlumab tesirine on day 1 of every treatment cycle. A 45-μg/kg dose was administered every 3 weeks for 2 cycles followed by a 30-μg/kg dose for all subsequent cycles.

The primary outcome measurement of the study is ORR, with secondary outcome measurements consisting of duration of response, CR rate, relapse-free survival, progression-free survival, and overall survival, among others.

Patients included in the interim phase 2 study had a median age of 36 years (range, 23-74). Notably, participants had received a median of 7 prior lines of therapy (range, 3-20), including transplant. Those who received treatment during the study were given a median of 5 cycles (range, 2-10; mean, 4.9; SD, 1.86) of camidanlumab tesirine.

Investigators determined that the preliminary phase 2 data were consistent with the results reported from the phase 1 dose‐escalation, dose-expansion trial of the ADC. In this trial, 77 patients with classical Hodgkin lymphoma who received camidanlumab tesirine achieved an ORR of 86.5%, including a CR rate of 48.6%.

 The agent was found to have a generally tolerable safety profile, although 6.5% of patients (n = 5/77) developed Guillain-Barré syndrome.

All evaluable patients in the phase 2 trial experienced treatment-related adverse effects (TRAEs) with the ADC. The most commonly reported AEs included fatigue (46.8%; n = 22); nausea, pyrexia, and maculopapular rash (38.3% each; n = 18); anemia and headache (25.5% each; n = 12); pruritus (23.4%; n = 11); and arthralgia, constipation, diarrhea, hypophosphatemia, and rash (21.3% each; n = 10). Similar to what had been observed in the phase 1 study of the agent, 6.4% of patients (n = 3) developed Guillain-Barré syndrome.

"We saw pretty similar findings to what was reported in the phase 1 study of this drug. Some characteristic toxicities occurred due to the chemotherapy payload that is attached to the antibody, PDB,” Herrera explained. “Patients had skin toxicities and rash—often photosensitive rash. Patients could have edema or effusions, although that was a relatively low percentage of [patients, at] less than 20%."

Moreover, 57.4% of patients (n = 27) experienced grade 3 or higher TRAEs, the most common of which were hypophosphatemia (12.8%; n = 6) and increased gamma-glutamyltransferase (6.4%; n = 3). In total, 3 patients had TRAEs that led to dose reductions or treatment delays, while 6 had TRAEs that resulted in treatment discontinuation.

In April 2020, the FDA put a partial hold on the phase 2 study after 2 patients developed Guillain-Barré syndrome.

, allowing for the continuation of the phase 2 trial, which was intended to support a biologics license application for the agent.

“A few patients on the study developed Guillain-Barré syndrome. It was 6% of patients at the time of presentation, which is why we did this preliminary presentation. A safety pause that was protocol specified [was put in place] based on a specific number of Guillain-Barré events, noted Herrara. “We reviewed the Guillain-Barré events in detail. [We noted] 3 [cases] in just under 50 patients; [these patients] were treated with appropriate measures [such as] intravenous immunoglobulin or plasmapheresis. The drug was stopped, of course. A couple of the patients did, ultimately, improve over time. My understanding is that 1 of the patients does still have some symptoms. Based on a review of the safety data thus far, the safety pause was lifted, and enrollment was allowed to continue.”

ADC Therapeutics completes enrollment in pivotal phase 2 clinical trial of camidanlumab tesirine (Cami) in relapsed or refractory Hodgkin lymphoma. News release. ADC Therapeutics. February 2, 2021. Accessed February 23, 2021. 

Herrera AF, Carlo-Stella C, Collins GP, et al. Preliminary results of a phase 2 study of camidanlumab tesirine (Cami), a novel pyrrolobenzodiazepine-based antibody-drug conjugate, in patients with relapsed or refractory Hodgkin lymphoma. 

. 2020;136(suppl 1):21-23. doi:10.1182/blood-2020-137451

Study to evaluate the efficacy and safety of camidanlumab tesirine (ADCT-301) in patients with relapsed or refractory Hodgkin lymphoma. ClinicalTrials.gov. Updated February 5, 2021. Accessed February 23, 2021. 

https://clinicaltrials.gov/ct2/show/NCT04052997

ADC Therapeutics announces presentation of preliminary findings from phase 1b clinical trial of camidanlumab tesirine (Cami) in advanced solid tumors at ESMO Virtual Congress 2020. News release. ADC Therapeutics. September 17, 2020. Accessed February 23, 2021. 

One IPO attempt pulled, a drug on partial hold and a pandemic, but ADC tries again. News release. Fierce Biotech. April 29, 2020. Accessed February 23, 2021. 

ADC Therapeutics announces US Food and Drug Administration has lifted partial clinical hold on pivotal phase 2 clinical trials of camidanlumab tesirine. News release. ADC Therapeutics. July 6, 2020. Accessed February 23, 2021. http://bit.ly/3uoJUn5

The safety and efficacy of the antibody-drug conjugate camidanlumab tesirine is under investigation in patients with relapsed/refractory Hodgkin lymphoma as part of a phase 2 clinical trial, which recently completed accrual. 

Camidanlumab Tesirine Under Investigation in Relapsed/Refractory Hodgkin Lymphoma 

AbbVie and Caribou Biosciences, Inc have announced that the companies have entered into a collaboration and license agreement for the research and development of chimeric antigen receptor (CAR) T-cell therapeutics.

The terms of the multi-year agreement will allow AbbVie to utilize Caribou’s next-generation Cas12a clusters of regularly interspaced short palindromic repeats (CRISPR) hybrid RNA-DNA (chRDNA) genome editing and cell therapy technologies to research and develop 2 new CAR T-cell therapies. AbbVie will be given exclusive rights to Cas12a for the targets of their choosing. Caribou will perform certain pre-clinical research, development, and manufacturing activities for the collaboration programs, while AbbVie will handle development, commercialization, and other manufacturing efforts.

A $40 million upfront cash payment and equity investment will be directed to Caribou, as well as up to $300 million in future development, regulatory, and launch milestones. Additionally, there will be the potential for Caribou to receive additional payments for commercial milestones and global tiered royalties. AbbVie has the option to expand the collaboration to include an additional 2 CAR T -cell therapies for a fee.1

“Caribou’s next-generation CRISPR genome editing technologies hold broad promise for new therapy development,” Rachel Haurwitz, PhD, president and CEO of Caribou said in an interview with 

®. “A partnership with AbbVie allows Caribou to increase the number of targets and diseases addressable by these technologies. It’s an important opportunity to expand upon what we hope to do for patients. The collaboration is also an important validation of Caribou’s differentiated next-generation CRISPR genome editing technologies.”

CRISPR gene editing technology utilizes modular, biological tools to induce DNA changes in living cells. The 2 basic components of CRISPR systems are the nuclease proteins and the RNA molecules. The nuclease proteins cut DNA while the RNA molecules guide the nuclease to generate a site-specific, double-stranded break, which result in editing at the targeted genomic site. CRISPR systems are differentiated by the presence of a class 1 multiprotein effector complex or a class 2 single effector protein.

CRISPR systems have been shown to achieve several different types of genetic modifications in different types of cells. CRISPR techniques have achieved recombination, engineered immunity, mutagenesis, and donor-mediated gene disruption in bacteria, yeast, and filamentous fungi cells. The technique has also been used to achieve RNA-guided gene editing in multiple human cell lines with high specify and efficiencies of up to approximately 50%.

CRISPR systems can sometimes unintentionally edit certain genomic sites, leading to harmful effects on cellular function. Caribou’s chRDNAs are highly specific RNA-DNA hybrid guides that are used in combination with CRISPR to direct more precise genome editing.

“Caribou utilizes CRISPR hybrid RNA-DNA guides that contain both DNA and RNA nucleotides,” Haurwitz explained. “These hybrid guides drive much more specific genome editing than all RNA guides. Caribou uses chRDNA guides in concert with a CRISPR enzyme to develop complex immune cell therapies.”

By using CRISPR technology to engineer CAR T-cells to withstand host immune attack, Caribou hopes to develop “off-the-shelf” cellular therapies aimed at benefitting a broad patient population. The company is currently focusing on genome-edited off-the-shelf allogenic CAR T-cell and natural killer cell therapies for the treatment of patients with intractable malignancies.

Current programs in the discovery phase include CB-011 and CB-012 which use T cells to target BCMA and CD371 for patients with hematologic malignancies, respectively. Another product, CB-020, focuses on using natural killer cells therapies for an undisclosed target for patients with solid tumors. The CB-010 program, currently in phase 1 exploration, uses T cells to target CD19 and for patients with relapsed/refractory B-cell non-Hodgkin lymphoma.

“I am excited about the opportunity for our companies to collaboratively develop 2 additional CAR T- [cell products], expanding upon the total number of therapies Caribou’s technologies underpin,” Haurwitz concluded.

AbbVie and Caribou Biosciences announce collaboration and license agreement for CAR-T cell products. News release. February 10, 2021. Accessed February 21, 2021. 

https://www.prnewswire.com/news-releases/abbvie-and-caribou-biosciences-announce-collaboration-and-license-agreement-for-car-t-cell-products-301225509.html

Pioneering chRDNA guides. Caribou Biosciences. Accessed February 21, 2021. 

Donohue PD, Barrangou R, May AP. Advances in industrial biotechnology using CRISPR-cas systems. 

2018;36(2):134-136. doi:10.1016/j.tibtech.2017.07.007

Cameron P, Coons MM, Stenberg SH, et al. Harnessing type I CRISPR-Cas systems for genome engineering in human cells. 

2019;37:1471-1477. doi:10.1038/s41587-019-0310-0

Pipeline. Caribou Biosciences. Accessed February 21, 2020. 

February 23, 2021 - AbbVie and Caribou Biosciences, Inc have entered into a collaboration and license agreement for the research and development of chimeric antigen receptory T-cell therapeutics. 

Pipeline Report: February 2021

Articles

Patritumab Deruxtecan Under Exploration in Phase 2 HERTHENA-Lung01 Trial for EGFR+ NSCLC

Camidanlumab Tesirine Under Investigation in Relapsed/Refractory Hodgkin Lymphoma