On June 1, 2024 Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in developing novel therapies for cancer, chronic hepatitis B (CHB), and age-related diseases, reported that it has released updated data of its novel drug candidate AGP-2449, a FAK/ALK/ROS1 tyrosine kinase inhibitor (TKI), in patients with non-small-cell lung cancer (NSCLC) in a poster presentation at the 60th American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting taking place in Chicago, IL (Press release, Ascentage Pharma, JUN 1, 2024, View Source;ascentage-pharma-releases-updated-data-of-fakalkros1-inhibitor-apg-2449-in-patients-with-nsclc-302161192.html [SID1234643948]). This is the third consecutive year in which clinical data from this study of APG-2449 were selected for presentations at the ASCO (Free ASCO Whitepaper) Annual Meeting.

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The ASCO (Free ASCO Whitepaper) Annual Meeting showcases the most cutting-edge research in clinical oncology and state-of-the-art advanced cancer therapies and is the world’s most influential and prominent scientific gathering of the clinical oncology community. Presenting clinical development progress at the ASCO (Free ASCO Whitepaper) Annual Meeting for the seventh consecutive year, Ascentage had four clinical studies of three of the company’s proprietary drug candidates selected for presentations, including an oral report, at ASCO (Free ASCO Whitepaper) 2024.

Results presented this year reaffirmed the therapeutic potential of APG-2449 in NSCLC, with data demonstrating preliminary efficacy in patients with NSCLC who were TKI naïve and resistant to second-generation ALK TKIs, as well as early antitumor activity in brain metastases. Biomarker analysis showed that, in patients with NSCLC resistant to second-generation ALK TKIs, phosphorylated FAK (pFAK) expression levels in tumor tissue at baseline and reduction in pFAK levels in peripheral blood mononuclear cells (PBMCs) were correlated with responses to APG-2449.

"APG-2449 is an effective multitargeted inhibitor that acts on FAK/ALK/ROS1. Compared to the data released at last year’s ASCO (Free ASCO Whitepaper) Annual Meeting, the latest results presented this year continued to show manageable safety and favorable antitumor activity in patients with NSCLC," said Prof. Li Zhang, the principal investigator of this study from Sun Yat-sen University Cancer Center. "We are very encouraged by the preliminary efficacy observed in patients with resistance to second-generation ALK TKIs, as it suggests that multitargeted inhibition on FAK and ALK may offer a new strategy for the management of patients with NSCLC resistant to second-generation ALK TKIs. We hope that Ascentage Pharma will conduct further studies on APG-2449 and allow more patients to benefit from this novel therapeutic agent as soon as possible."

"These data of APG-2449 in patients with NSCLC revealed a connection between resistance to ALK inhibitors and the FAK pathway, thus suggesting that the multitargeted FAK/ALK/ROS1 TKI APG-2449 may bring renewed hope to patients with NSCLC who are resistant to second-generation ALK inhibitors. This finding is indeed very encouraging," said Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma. "Remaining committed to the mission of addressing unmet clinical needs in China and around the world, we will press forward with this clinical development program in order to bring a safe and effective new treatment option to patients in need."

Highlights of these data presented at ASCO (Free ASCO Whitepaper) 2024 are as follows:

Updated study results of novel FAK/ALK/ROS1 inhibitor APG-2449 in patients (pts) with non-small-cell lung cancer (NSCLC) resistant to second-generation ALK inhibitors.

Abstract#: 3124

Session Title: Developmental Therapeutics—Molecularly Targeted Agents and Tumor Biology

Date and Time: June 1, 2024, Saturday, 9:00 AM – 12:00 PM (Central Time)

First Author: Yuxiang Ma, MD, PhD, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.

Highlights:

Background: ALK inhibitors increase FAK pathway gene expression in ALK+ NSCLC cell lines, with the highest induced expression in drug-tolerant persister cells. This suggests that FAK pathway activation is involved in the mechanism that leads to ALK TKI resistance in ALK+ NSCLC. APG-2449 is an orally active FAK inhibitor and a third-generation ALK/ROS1 TKI that has shown potent antitumor activity in preclinical models. This poster reports further safety and efficacy data of APG-2449.

Patient enrollment and methods:

This study comprises dose-escalation and dose-expansion portions. 1,200 mg daily (QD) was determined as the RP2D. There were two cohorts in the dose-expansion portion: Cohort 1 included patients with NSCLC who were resistant to second-generation ALK TKIs; Cohort 2 included patients with NSCLC who were ALK or ROS1 TKI naïve.
As of April 2, 2024, a total of 144 patients with NSCLC, mesothelioma, or ovarian cancer were treated with APG-2449 at doses ranging from 150 – 1,500 mg. The median (range) age of patients was 53 (21-78) years, and 53.5% were female.
Efficacy results:

The ORRs of APG-2449 in patients with ROS1+ and ALK+ TKI-naïve NSCLC (n=36) were 68.2% (15/22) and 78.6% (11/14), respectively. Of the 22 patients with NSCLC resistant to second-generation ALK inhibitors and without targetable bypass gene mutations (e.g., KRAS G12C, BRAF V600E), 10 achieved PRs (10/22; 45.5%). Among the patients treated at RP2D, 12 had brain metastasis at baseline, 9 of whom achieved intracranial PR, resulting in an intracranial ORR of 75.0%.
Biomarker analysis found that, in patients with NSCLC that was resistant to second-generation ALK TKIs, responses to APG-2449 were correlated with pFAK levels in tumor tissues at baseline and reductions in pFAK levels in PBMCs.
Safety results: A total of 129 (89.6%) patients had treatment‑related adverse events (TRAEs), the most frequent (≥10%) of which were elevated serum creatinine (49.3%), increase in alanine aminotransferase (42.4%), increase in aspartate aminotransferase (36.1%); nausea (28.5%); vomiting (23.6%); diarrhea (22.9%); decreased leukocyte count (22.2%), decreased neutrophil count (17.4%) and rash (13.2%). In all, 20 (13.9%) TRAEs were grade ≥ 3.

Conclusions: APG-2449 demonstrated preliminary efficacy in patients with NSCLC whose disease was TKI naïve and resistant to second-generation ALK inhibitors, especially in brain metastases. Biomarker analysis showed that, in patients with NSCLC resistant to second-generation ALK TKIs, responses to APG-2449 PFS were correlated with pFAK levels in tumor tissues at baseline and reductions in pFAK levels in PBMCs.

*APG-2449 is an investigational drug that has not been approved in any country and region.

Appendix: The four clinical studies of Ascentage Pharma’s three drug candidates, including lisaftoclax, presented at this year’s ASCO (Free ASCO Whitepaper) Annual Meeting.

Drug Candidates

Abstract Title

Abstract #

Format

Olverembatinib
(HQP1351)

Updated efficacy results of
olverembatinib (HQP1351) in patients
withtyrosinekinase inhibitor (TKI)-
resistantsuccinatedehydrogenas
e (SDH)-deficientgastrointestinal
stromal tumor (GIST)and
paraganglioma

#11502

Oral
Report

Lisaftoclax
(APG-2575）

Safety and efficacy of lisaftoclax, a
novel BCL-2 inhibitor, in combination
withazacitidine in patients with
treatment-naïve or relapsed
or refractory acute myeloid leukemia

#6541

Poster
Presentation

Updated efficacy and safety results of
BCL-2 inhibitorlisaftoclax (APG-2575)
alone or combinedwithibrutinibor
rituximab in patients (pts)with
Waldenströmmacroglobulinemia
(WM)

#7078

Poster
Presentation

APG-2449

Updated study results of novel
FAK/ALK/ROS1 inhibitor APG-2449 in
patients (pts) with non-small-cell lung
cancer (NSCLC) resistant tosecond-
generationALK inhibitors

#3124

Poster
Presentation

On June 1, 2024 Molecular Partners AG (SIX: MOLN; NASDAQ: MOLN), a clinical-stage biotech company pioneering the design and development of a new class of custom-built protein drugs known as DARPin therapeutics, reported it had presented the final data from its Phase 1 dose-escalation study of MP0317 at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting 2024, held in Chicago, IL, USA (Press release, Molecular Partners, JUN 1, 2024, View Source [SID1234643939]). MP0317 is a CD40 agonist designed to activate immune cells specifically within the tumor microenvironment (TME) by anchoring to fibroblast activation protein (FAP) which is expressed in high amounts around tumors. This tumor-localized approach has the potential to deliver greater efficacy with fewer side effects compared to systemic CD40-targeting therapies.

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"The Phase 1 data for MP0317 demonstrate the ability of the FAP x CD40 DARPin to avoid the systemic toxicities of CD40 agonists while showcasing truly promising modulation of the tumor microenvironment," said Philippe Legenne, MD, MBA, Molecular Partners’ acting Chief Medical Officer. "This further deepens the clinical evidence supporting DARPins’ ability to deliver multi-specific candidates with enhanced capabilities in oncology including localized activation of powerful immunostimulatory molecules. We will continue discussions with potential partners towards clinical evaluation of MP0317 in combination with complementary approaches."

Mechanistic data & clinical response
The final analysis of this phase 1 dose-escalation study included 46 patients with advanced solid tumors and confirms earlier reported interim analysis findings. MP0317 treatment resulted in target occupancy in tumor biopsies with evidence of TME remodeling as characterized by increases in dendritic cells (DC), T follicular helper cells and plasma cells, as well as IFNγ downstream activation and DC maturation gene signature score increases. These findings were further supported by observed elevation of serum levels of CXCL10, a pro-inflammatory downstream effector of the IFNγ signaling.

In terms of clinical response, one patient achieved an unconfirmed partial response and stable disease was observed in 14 additional patients. The data support further clinical evaluation of MP0317 in combination with complementary anticancer therapies. Dose-response analyses of the final trial data propose MP0317 at dosages of 1.5mg/kg or above as providing an optimal benefit-risk profile, with adjustable dosing frequency to match a combination dosing scheme.

Safety & tolerability
MP0317 displayed a favorable and manageable safety profile across all nine planned dosing cohorts (0.03–10 mg/kg administered intravenously weekly (Q1W) or every 3 weeks (Q3W). The most frequently observed adverse reactions were fatigue and lower grade infusion-related reactions (grade 1–2). Dose-limiting toxicity was reported in one patient (transient asymptomatic grade 3 elevation of liver enzymes) at the highest planned dose of 10 mg/kg administered Q3W.

Details of the poster presenting the final results from the MP0317 Phase 1 study at the 2024 ASCO (Free ASCO Whitepaper) Annual Meeting can be found below. The poster will be made available on Molecular Partners’ website after the presentation.

Title: Effect of MP0317, a FAP x CD40 DARPin, on safety profile and tumor-localized CD40 activation in a phase 1 study in patients with advanced solid tumors

Abstract number (poster board): 2573 (52)

Timing: 1 June 2024; 9:00 am – 12:00 pm PST

On June 1, 2024 Purple Biotech Ltd. ("Purple Biotech" or "the Company") (NASDAQ/TASE: PPBT), a clinical-stage company developing first-in-class therapies that harness the power of the tumor microenvironment and immune system to overcome tumor immune evasion and drug resistance, reported positive interim data from its randomized, controlled, open label, multicenter Phase 2 study of CM24 in second-line metastatic pancreatic ductal adenocarcinoma (PDAC) presented at a late-breaking abstract poster presentation at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, Purple Biotech, JUN 1, 2024, View Source;id=308199&p=2326565&I=1206939-c7Z3G6f3m8 [SID1234643938]).

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"These exciting interim data demonstrate the potential of CM24 in combination with nivolumab plus the standard-of-care chemotherapy regimen Nal-IRI/5FU/LV to improve clinical outcomes for advanced metastatic PDAC patients. We are highly encouraged by the meaningful results of our primary endpoint, Overall Survival, as well as by the concordant and consistent improvement in all secondary endpoints including PFS, ORR, DCR and CA19-9" stated Gil Efron, Chief Executive Officer of Purple Biotech.

Michael Cecchini, MD Assistant Professor of Medicine at the Yale Cancer Center, a principal investigator in this study, commented, "As a clinician, it is encouraging to see these interim data in the Nal-IRI arm suggesting the potential for improved clinical outcomes for patients with late-stage metastatic PDAC who are in dire need of new effective therapies. These patients face very limited time with their families, and the prospect of potentially lengthening their lives while delaying their disease progression by approximately two months overall is clinically meaningful. These data justify further investigation of CM24 in combination with nivolumab together with standard-of-care chemotherapy to potentially improve outcomes for patients facing a very poor prognosis from this type of tumor".

The Phase 2 study is evaluating CM24, a novel first-in-class multi-functional anti-CEACAM1 antibody, in combination with Bristol Myers Squibb’s immune checkpoint inhibitor nivolumab plus SoC chemotherapy in second-line PDAC patients versus SoC chemotherapy alone. CM24 is a humanized monoclonal antibody that blocks CEACAM1, an immune checkpoint protein responsible for tumor immune evasion and poor tumor response and/or resistance to immune checkpoint inhibitors. The primary endpoint of the study is OS and the secondary endpoints include PFS, ORR and DCR. A Bayesian methodology was used to estimate the magnitude of effect of the experimental arm versus the SoC arm and the study is not powered for hypothesis testing. A total of 63 patients have been enrolled, across 18 centers in the U.S., Spain, and Israel in 2 parallel independent randomized study cohorts (total of 2 arms per cohort). The experimental arms administered patients with CM24 plus nivolumab and a choice of one of two SoC chemotherapies for second-line PDAC, dependent on prior first line therapy regimen; either gemcitabine/nab-paclitaxel or liposomal irinotecan (Nal-IRI)/5-fluorouracil (5-FU) and leucovorin (LV) (Nal-IRI/5FU/LV), while the control arms administered either respective chemotherapy alone. CA19-9 as well as additional exploratory biomarkers are also being evaluated. Of the 63 patients enrolled, 32 were in the gemcitabine/nab-paclitaxel study (experimental and control) and 31 were in the Nal-IRI/5FU/LV study (experimental and control). An analysis of the gemcitabine/nab-paclitaxel study will be performed when the data are sufficiently mature. Topline final data are expected by the end of 2024.

The study interim efficacy results as of the cutoff date of May 8, 2024, are summarized in the following table:

Metric CM24 + Nivolumab + Nal/IRI/5FU/LV Arm
(n = 16) Nal/IRI/5FU/LV Arm
(n = 15)
Hazard ratio for OS 0.74 (95% CI: 0.31-1.77)
Median OS 7.72 months 5.62 months
6 months OS rate 53% 39%
Hazard Ratio for PFS 0.72 (95% CI: 0.33-1.60)
Median PFS 3.8 months 1.9 months
3 months PFS rate 60% 47%
6 months PFS rate 19% 10%
ORR 25% 7%
DCR 63% 40%
A consistent and continuous decrease of CA19-9, a validated and clinically predictive PDAC biomarker, was observed in the experimental arm (61% on average) vs. an increase in the control arm (34% on average).

The CM24+nivolumab+Nal/IRI/5FU/LV regimen was well tolerated, with the most frequent treatment emergent Grade 3 or higher adverse events being diarrhea (19%), fatigue (19%) and anemia (6%).

On June 1, 2024 Affimed N.V. (Nasdaq: AFMD), a clinical-stage immuno-oncology company committed to giving patients back their innate ability to fight cancer, reported longer follow-up data from the EGFRwt cohort and initial clinical efficacy data from the EGFRmut cohort from the on-going AFM24-102 study in NSCLC (Press release, Affimed, JUN 1, 2024, https://www.affimed.com/affimed-provides-follow-up-data-of-afm24-plus-atezolizumab-showing-durable-responses-in-heavily-pretreated-nsclc-egfr-wild-type-patients-and-positive-initial-data-from-the-nsclc-egfr-mutant-cohort/ [SID1234643937]).

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As of the updated data cutoff on May 13, 2024 for the 17 EGFRwt patients previously reported on, 15 patients were response-evaluable. Four confirmed objective responses were seen: 1 complete response (CR) and 3 partial responses (PR). In addition, 8 patients achieved stable disease (SD), resulting in a disease control rate of 71%. Median progression-free survival was 5.9 months with median follow-up of 7.4 months. Importantly 3 of 4 responses were ongoing for more than 7 months. All responders were resistant to checkpoint inhibitor treatment prior to the study, which supports the hypothesis that combining AFM24 with atezolizumab may provide an alternative strategy to overcome resistance to existing therapies.

As of May 21, 2024, 21 heavily pretreated EGFRmut patients (median of 3 prior therapies) had received the combination therapy of which 13 were response-evaluable. The combination of AFM24 with atezolizumab showed encouraging signals of clinical activity including 1 CR, 3 PRs and 6 patients with SD. As of the data cut-off, all responses were on-going. EGFRmut NSCLC is considered an immunogenically weak subtype where single-agent therapy with immune checkpoint inhibitors have exhibited poor response rates. The data suggests that the combination of AFM24 and atezolizumab could be acting synergistically to improve efficacy outcomes.

AFM24 and atezolizumab combination therapy demonstrated a manageable safety profile. Side effects were consistent with the known safety profiles of these agents. The most frequent side effects observed were mild to moderate infusion related reactions and transient mild to moderate increase in liver enzymes.

"The efficacy of the combination of AFM24 and atezolizumab in these heavily pretreated NSCLC patients is encouraging and supports our hypothesis of a synergistic activity of AFM24 with PD-1/PD-L1 blockade. We believe the durability of the responses in EGFRwt tumors is remarkable and is unlikely driven by PD-1/PD-L1 blockade alone, as all patients with responses had documented progression on their previous PD-1/PD-L1 therapy. In addition, median PFS of atezolizumab, even in checkpoint naïve patients, is only 2.8 months," said Dr. Andreas Harstrick, Chief Medical and acting Chief Executive Officer of Affimed. "This growing body of evidence reinforces our belief that AFM24 in combination with check point targeting can address pressing unmet medical needs in refractory NSCLC patients."

The EGFRwt NSCLC cohort of the study will enroll up to 40 patients and the EGFRmut NSCLC cohort will enroll up to 25 patients. Recruitment in both cohorts is ongoing, and further updates are expected in H2 2024.

Conference Call and Webcast Information

Affimed will host a conference call and webcast for the financial community on June 1, 2024, at 6:00 p.m. CDT / 7:00 p.m. EDT. Dr. Harstrick and Dr. Hye Ryun Kim, Professor at Yonsei University College of Medicine, Seoul, Korea, will review the latest clinical findings and address questions.

The conference call will be available via phone and webcast. The live audio webcast of the call will be available in the "Webcasts" section on the "Investors" page of the Affimed website at View Source To access the call by phone, please use link:

https://register.vevent.com/register/BIff607338e5d247f99b548240be2ad413, and you will be provided with dial-in details and a pin number.

About AFM24
AFM24 is a tetravalent, bispecific ICE that activates the innate immune system by binding to CD16A on innate immune cells and epidermal growth factor receptors (EGFR), a protein widely expressed on solid tumors, to kill cancer cells. Generated by Affimed’s fit-for-purpose ROCK platform, AFM24 represents a distinctive mechanism of action that uses EGFR as a docking site to engage innate immune cells for tumor cell killing through antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis.

On June 1, 2024 Pfizer Inc. (NYSE: PFE) reported detailed overall survival (OS) results from the Phase 3 ECHELON-3 study of ADCETRIS (brentuximab vedotin) in combination with lenalidomide and rituximab for the treatment of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) (Press release, Seagen, JUN 1, 2024, View Source [SID1234643931]). The study showed that the ADCETRIS combination reduced patients’ risk of death by 37% compared to placebo in combination with lenalidomide and rituximab (HR 0.63 [95% CI: 0.445-0.891] p=0.0085). The overall survival benefit was consistent across levels of CD30 expression.

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The ECHELON-3 results will be presented as a late-breaker (LBA7005) in an oral session at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting along with four-year results from the Phase 3 HD21 trial in advanced classical Hodgkin lymphoma (cHL) (LBA7000).

"ECHELON-3 is one of the first randomized, placebo-controlled Phase 3 studies to demonstrate an overall survival benefit in patients with relapsed/refractory DLBCL after two or more prior lines of systemic therapy," said principal investigator Dr. Jeung-A Kim, College of Medicine, The Catholic University of Korea. "The clinically meaningful improvement in survival demonstrates the potential benefit of this ADCETRIS regimen in relapsed/refractory DLBCL, particularly for patients whose disease has progressed after CAR-T therapy or bispecific antibody treatment or individuals who are not able to receive these treatments."

ADCETRIS is approved in the U.S. as monotherapy or in combination with chemotherapy for seven lymphomas including certain types of cHL, anaplastic large cell lymphoma and peripheral T-cell lymphoma. Seven-year survival data for an ADCETRIS regimen for patients with advanced stage cHL will be shared in a poster presentation (7053) at the ASCO (Free ASCO Whitepaper) Meeting on June 3.

"Three Phase 3 trials in three different types of lymphoma have now demonstrated that an ADCETRIS-containing regimen improved overall survival," said Roger Dansey, M.D., Chief Development Officer, Oncology, Pfizer. "ADCETRIS is a standard of care medicine in its approved indications today, and these impressive results from an interim analysis highlight its potential to benefit people with relapsed/refractory DLBCL regardless of CD30 expression."

DLBCL is the most common lymphoma and is aggressive and difficult to treat, with up to 40 percent of patients experiencing disease progression after initial therapy.1,2

Among 230 randomized patients in the trial, the interim analysis showed that median OS in patients randomized to receive ADCETRIS, lenalidomide and rituximab was 13.8 months (95% CI: 10.3-18.8) compared to 8.5 months (95% CI: 5.4-11.7) in patients randomized to lenalidomide and rituximab plus placebo.

Median progression-free survival (PFS) was 4.2 months (95% CI: 2.9-7.1) in the ADCETRIS arm versus 2.6 months (95% CI: 1.4-3.1) in the lenalidomide and rituximab plus placebo arm (HR 0.527 [95% CI: 0.380-0.729] p<0.0001). The overall response rate for patients treated with the ADCETRIS regimen was 64.3% (95% CI: 54.7-73.1) versus 41.5% (95% CI: 32.5-51.0) in the lenalidomide and rituximab plus placebo arm. The complete response rate was 40.2% in ADCETRIS-treated patients (95% CI: 31.0%, 49.9%) compared to 18.6% (95% CI:12.1%, 26.9%) in the lenalidomide and rituximab plus placebo arm.

The most frequently reported treatment-emergent adverse events (TEAEs) Grade 3 or higher for the ADCETRIS versus placebo arms were: neutropenia (43% vs 28%), thrombocytopenia (25% vs 19%) and anemia (22% vs 21%). Peripheral sensory neuropathy was infrequent and low grade for each arm with Grade 3 events of 4% vs 0%.

About ECHELON-3

ECHELON-3 is an ongoing, randomized, double-blind, multicenter Phase 3 study evaluating ADCETRIS plus lenalidomide and rituximab versus lenalidomide and rituximab plus placebo in adult patients with relapsed/refractory DLBCL, regardless of CD30 expression, who have received two or more prior lines of therapy and are ineligible for stem cell transplant or CAR-T therapy. In this global study, 230 patients were randomized across North America, Europe and Asia-Pacific. The primary endpoint is OS in the intent to treat population, with key secondary endpoints of PFS and ORR as assessed by investigator. Other secondary endpoints include complete response rate, duration of response, safety and tolerability.

About Diffuse Large B-cell Lymphoma

DLBCL is the most frequent type of lymphoma and is aggressive and difficult to treat.1,2 More than 25,000 cases of DLBCL are diagnosed each year in the United States, accounting for more than 25 percent of all lymphoma cases.2 DLBCL can develop spontaneously or as a result of diseases such as chronic lymphocytic lymphoma/small lymphocytic lymphoma, follicular lymphoma, or marginal zone lymphoma.1 Up to 40 percent of patients relapse or have refractory disease after frontline treatment.2

About ADCETRIS

More than 55,000 patients have been treated with ADCETRIS in the U.S. since its first U.S. approval in 2011, and more than 140,000 patients have been treated with ADCETRIS globally.

ADCETRIS is an antibody-drug conjugate (ADC) comprised of a CD30-directed monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Pfizer’s proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-positive tumor cells.

ADCETRIS is approved in seven indications in the U.S.:

Adult patients with previously untreated Stage III/IV classical Hodgkin lymphoma (cHL) in combination with doxorubicin, vinblastine, and dacarbazine (2018)
Pediatric patients 2 years and older with previously untreated high risk cHL in combination with doxorubicin, vincristine, etoposide, prednisone and cyclophosphamide (2022)
Adult patients with cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation (2015)
Adult patients with cHL after failure of auto-HSCT or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates (2011)
Adult patients with previously untreated systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified, in combination with cyclophosphamide, doxorubicin, and prednisone (2018)
Adult patients with sALCL after failure of at least one prior multi-agent chemotherapy regimen. (2011)
Adult patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) after prior systemic therapy (2017)
Pfizer and Takeda jointly develop ADCETRIS. Under the terms of the collaboration agreement, Pfizer has U.S. and Canadian commercialization rights, and Takeda has rights to commercialize ADCETRIS in the rest of the world. Pfizer and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.

ADCETRIS (brentuximab vedotin) for injection U.S. Important Safety Information

BOXED WARNING

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML): JC virus infection resulting in PML, and death can occur in ADCETRIS-treated patients.

CONTRAINDICATION

Contraindicated with concomitant bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation).

WARNINGS AND PRECAUTIONS

Peripheral neuropathy (PN): ADCETRIS causes PN that is predominantly sensory. Cases of motor PN have also been reported. ADCETRIS-induced PN is cumulative. Monitor for symptoms such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Patients experiencing new or worsening PN may require a delay, change in dose, or discontinuation of ADCETRIS.

Anaphylaxis and infusion reactions: Infusion-related reactions (IRR), including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an IRR occurs, interrupt the infusion and institute appropriate medical management. If anaphylaxis occurs, immediately and permanently discontinue the infusion and administer appropriate medical therapy. Premedicate patients with a prior IRR before subsequent infusions. Premedication may include acetaminophen, an antihistamine, and a corticosteroid.

Hematologic toxicities: Fatal and serious cases of febrile neutropenia have been reported with ADCETRIS. Prolonged (≥1 week) severe neutropenia and Grade 3 or 4 thrombocytopenia or anemia can occur with ADCETRIS.

Administer G-CSF primary prophylaxis beginning with Cycle 1 for adult patients who receive ADCETRIS in combination with chemotherapy for previously untreated Stage III/IV cHL or previously untreated PTCL, and pediatric patients who receive ADCETRIS in combination with chemotherapy for previously untreated high risk cHL.

Monitor complete blood counts prior to each ADCETRIS dose. Monitor more frequently for patients with Grade 3 or 4 neutropenia. Monitor patients for fever. If Grade 3 or 4 neutropenia develops, consider dose delays, reductions, discontinuation, or G-CSF prophylaxis with subsequent doses.

Serious infections and opportunistic infections: Infections such as pneumonia, bacteremia, and sepsis or septic shock (including fatal outcomes) have been reported in ADCETRIS-treated patients. Closely monitor patients during treatment for infections.

Tumor lysis syndrome: Patients with rapidly proliferating tumor and high tumor burden may be at increased risk. Monitor closely and take appropriate measures.

Increased toxicity in the presence of severe renal impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with severe renal impairment. Avoid use in patients with severe renal impairment.

Increased toxicity in the presence of moderate or severe hepatic impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with moderate or severe hepatic impairment. Avoid use in patients with moderate or severe hepatic impairment.

Hepatotoxicity: Fatal and serious cases have occurred in ADCETRIS-treated patients. Cases were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, and occurred after the first ADCETRIS dose or rechallenge. Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may increase the risk. Monitor liver enzymes and bilirubin. Patients with new, worsening, or recurrent hepatotoxicity may require a delay, change in dose, or discontinuation of ADCETRIS.

PML: Fatal cases of JC virus infection resulting in PML have been reported in ADCETRIS-treated patients. First onset of symptoms occurred at various times from initiation of ADCETRIS, with some cases occurring within 3 months of initial exposure. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider PML diagnosis in patients with new-onset signs and symptoms of central nervous system abnormalities. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed.

Pulmonary toxicity: Fatal and serious events of noninfectious pulmonary toxicity, including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome, have been reported. Monitor patients for signs and symptoms, including cough and dyspnea. In the event of new or worsening pulmonary symptoms, hold ADCETRIS dosing during evaluation and until symptomatic improvement.

Serious dermatologic reactions: Fatal and serious cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate medical therapy.

Gastrointestinal (GI) complications: Fatal and serious cases of acute pancreatitis have been reported. Other fatal and serious GI complications include perforation, hemorrhage, erosion, ulcer, intestinal obstruction, enterocolitis, neutropenic colitis, and ileus. Lymphoma with pre-existing GI involvement may increase the risk of perforation. In the event of new or worsening GI symptoms, including severe abdominal pain, perform a prompt diagnostic evaluation and treat appropriately.

Hyperglycemia: Serious cases, such as new-onset hyperglycemia, exacerbation of pre-existing diabetes mellitus, and ketoacidosis (including fatal outcomes) have been reported with ADCETRIS. Hyperglycemia occurred more frequently in patients with high body mass index or diabetes. Monitor serum glucose and if hyperglycemia develops, administer anti-hyperglycemic medications as clinically indicated.

Embryo-fetal toxicity: Based on the mechanism of action and animal studies, ADCETRIS can cause fetal harm. Advise females of reproductive potential of this potential risk, and to use effective contraception during ADCETRIS treatment and for 2 months after the last dose of ADCETRIS. Advise male patients with female partners of reproductive potential to use effective contraception during ADCETRIS treatment and for 4 months after the last dose of ADCETRIS.

ADVERSE REACTIONS

The most common adverse reactions (≥20% in any study) are peripheral neuropathy, fatigue, nausea, diarrhea, neutropenia, upper respiratory tract infection, pyrexia, constipation, vomiting, alopecia, decreased weight, abdominal pain, anemia, stomatitis, lymphopenia, mucositis, thrombocytopenia, and febrile neutropenia.

DRUG INTERACTIONS

Concomitant use of strong CYP3A4 inhibitors has the potential to affect the exposure to monomethyl auristatin E (MMAE). Closely monitor adverse reactions.

USE IN SPECIAL POPULATIONS

L actation: Breastfeeding is not recommended during ADCETRIS treatment.

Please see the full Prescribing Information, including BOXED WARNING, for ADCETRIS here.