ESMO 2024: Potential Practice-changing Outcomes are Changing Patients’ Lives

During the upcoming European Society for Medical Oncology (ESMO) Congress 2024, being held September 13-17, 2024 in Barcelona, Spain, Pfizer is presenting two late-breaking presentations include longer-term results from the phase 2 PHAROS study (NCT03915951), the first clinical trial of encorafenib (Braftovi®; Pfizer) plus binimetinib (Mektovi®; Pfizer) in patients with BRAF^V600E-mutated metastatic non-small cell lung cancer (NSCLC), new data from a phase 2 study of ponsegromab in cancer cachexia (NCT05546476) and encouraging early results for preliminary efficacy and safety data for disitamab vedotin * in combination with pembrolizumab (Keytruda®; Merck & Co), and results from an additional analysis from the pivotal EV-302 trial supporting the combination of enfortumab vedotin (Padcev®; Astellas/Pfizer) and pembrolizumab (Keytruda®; Merck & Co) as a new standard of care for patients with previously untreated la/mUC, and a novel combination of CDK4 + CDK2 inhibitors.

Overall, data from more than 50 company-sponsored, investigator-sponsored and collaborative research abstracts, including more than 10 oral and mini-oral presentations, will be presented across the Pfizer’s tumor areas and core scientific modalities, as well as a potential treatment for a cancer-related condition.

“At this year’s ESMO, we are looking forward to demonstrating our progress toward delivering next-generation biologics and novel combinations that have the potential to be new standards of care for patients,” noted Chris Boshoff, Chief Oncology Officer and Executive Vice President, Pfizer.

“Our key data presentations highlight our scientific leadership in developing targeted therapies, including small molecules and antibody-drug conjugates, across our core tumor areas, including breast, bladder and thoracic cancers.”

Transforming outcomes
“At ESMO, Pfizer will share important data highlighting our commitment to transforming outcomes for patients living with lung cancer, including longer-term follow-up results from the PHAROS study of encorafenib + binimetinib in BRAF V600E-mutated metastatic non-small cell lung cancer,” said Karin Tollefson, Chief Oncology Medical Officer, Pfizer.

“We are also looking forward to sharing progress on our industry-leading pipeline of new molecules, including encouraging early results for two novel, investigational antibody-drug conjugates and preliminary data on a novel combination of Pfizer’s next-generation CDK inhibitors.”

Updated results
Key research includes a late-breaking presentation of updated results from the pivotal Phase 2 PHAROS** study of encorafenib in combination with binimetinib in patients with BRAF^V600E-mutated metastatic non-small cell lung cancer (mNSCLC). Longer-term efficacy and safety data will be presented, following the initial primary overall response results (ORR) that supported the FDA approval for encorafenib + binimetinibin this indication in 2023 and the recent approval by the European Commission in August 2024.

The Pfizer-team is also expected to  share updated data from the safety lead-in of the ongoing Phase 3 BREAKWATER trial (NCT04607421) , showing antitumor activity of encorafenib + cetuximab + FOLFIRI in patients with untreated BRAF^V600E-mutated metastatic colorectal cancer (mCRC) in a mini-oral presentation.

Additionally, expect late-breaking Proffered Paper Presentation on the Phase 2 efficacy and safety results for its GDF-15 inhibitor, ponsegromab (PF-06946860), in patients with cancer-associated cachexia, highlighting the company’s commitment to improving the treatment journey for people living with cancer.

Cancer cachexia is a complex, but common, life-threatening wasting condition characterized by severe weight loss. In contrast to weight loss resulting from inadequate caloric intake, cachexia causes mostly muscle loss instead of fat loss. The condition affects patients with advanced cancers and can greatly impact a patient’s ability to tolerate cancer treatment as a result of increased side effects, leading to treatment interruptions, reducing the overall health related Quality of Life (hrQoL). Cancer cachexia is also linked to poorer survival. Despite its severity, there are no FDA-approved treatments for cachexia. [1][2][3]

Pfizer will also present early clinical-stage research for a number of priority pipeline areas, including encouraging Phase 1 results of the potential first-in-class antibody-drug conjugate (ADC) candidate SGN-PDL1V (PF-08046054) in NSCLC and head and neck squamous cell carcinoma (HNSCC). SGN-PDL1V is a novel, investigational ADC directed to PD-L1 (programmed death ligand 1) with multiple proposed mechanisms of action including monomethyl auristatin E (MMAE)-directed cytotoxicity, bystander effect, and immunogenic cell death (ICD). The investigational drug contains an antibody directed to PD-L1 in which a protease-cleavable mc-vc (maleimidocaproyl-valine-citrulline) linker covalently attaches the microtubule-disrupting agent MMAE to the antibody, enabling preferential release of MMAE within target cells. Based on pre-clinical studies, it is believed that SGN-PDL1V (PF-08046054) may have the potential to drive antitumor T-cell responses through inhibition of the PD-1/PD-L1 immune checkpoint.[4]

Finally, Pfizer will presents initial data for the investigational ADC disitamab vedotin in combination with pembrolizumab in human epidermal growth factor receptor 2 (HER2)-expressing locally advanced or metastatic urothelial cancer (la/mUC) and the first data combining atirmociclib, a highly-selective cyclin-dependent kinase 4 (CDK4) inhibitor (CDK4i), with a novel CDK2 inhibitor (CDK2i) in hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer (MBC) from a Phase 1 dose-escalation study.

Key Presentations

Genitourinary Cancer

• Enfortumab vedotin (Padcev®; Astellas/Pfizer) and pembrolizumab (Keytruda®; Merck & Co)***: Additional analysis from the pivotal EV-302 trial continues to support the combination as a new standard of care for patients with previously untreated la/mUC. An exploratory analysis shows Enfortumab vedotin + pembrolizumab showed consistent progression free survival (PFS), overall survival (OS), and ORR versus chemotherapy regardless of Nectin-4 or PD-L1 expression.
• Disitamab Vedotin: preliminary efficacy and safety data for disitamab vedotin in combination with pembrolizumab highlights Pfizer’s continued commitment to developing novel therapeutics to meet the needs of patients with bladder cancer. Results from the safety run-in of the ongoing Phase 2 trial showed encouraging early efficacy and a safety profile consistent with previously presented data in treatment-naive patients with HER2-expressing la/mUC.

Thoracic Cancer

• SGN-PDL1V (PF-08046054): encouraging Phase 1 results will be presented for PDL1V, a novel, investigational vedotin ADC directed to PD-L1-expressing solid tumors. Data from the dose-escalation and dose optimization cohorts of the ongoing Phase 1 study show PDL1V as monotherapy was generally well tolerated with no unexpected adverse events, and encouraging antitumor activity was observed in patients with heavily pretreated NSCLC and HNSCC.

Breast Cancer

• Atirmociclib (PF-07220060) + PF-07104091: initial data from a dose-escalation study evaluating the innovative combination of atirmociclib, a potential first-in-class CDK4-selective inhibitor, with PF-07104091, a novel CDK2-selective inhibitor, showed a manageable safety profile and encouraging efficacy in patients with heavily pretreated HR+/HER2- breast cancer. These early results highlight the potential of Pfizer’s strategy to advance atirmociclib as a future CDK inhibitor backbone therapy that may address treatment resistance with first generation CDK4/6i, subject to clinical success and regulatory approval. The CDK4i+2i combination is continuing to be explored in an ongoing Phase 1b/2 dose escalation and dose expansion study (NCT05262400).

Additional information on the Pfizer-sponsored abstracts, including date and time of presentation, follow in the chart below.

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Note: * Disitamab vedotin (Aidixi®; RemeGen) is an antibody-drug conjugate (ADC) comprising a monoclonal antibody against human epidermal growth factor receptor 2 (HER2) conjugated via a cleavable linker to the cytotoxic agent monomethyl auristatin E (MMAE).  The drug, approved in China for the treatment of patients with HER2-overexpressing (defined as IHC2+ or 3+) locally advanced or metastatic gastric cancer (including gastroesophageal junction adenocarcinoma) who have received at least two systemic chemotherapy regimens. Pfizer is developing disitamab vedotin globally outside of RemeGen’s territory.
** The PHAROS trial is conducted with support from Pierre Fabre.
*** Pfizer and Astellas have a clinical collaboration agreement with Merck to evaluate the combination of PADCEV ^® and KEYTRUDA ^® in patients with previously untreated metastatic urothelial cancer.

Clinical trials
An Open-label Study of Encorafenib + Binimetinib in Patients With BRAFV600-mutant Non-small Cell Lung Cancer – ClinicalTrials.gov ID NCT03915951
Study of the Efficacy and Safety of Ponsegromab in Patients With Cancer, Cachexia and Elevated GDF-15 (PROACC-1) – ClinicalTrials.gov ID NCT05546476
A Study of Encorafenib Plus Cetuximab With or Without Chemotherapy in People With Previously Untreated Metastatic Colorectal Cancer – ClinicalTrials.gov ID NCT04607421
A Study of PF-08046054/​SGN-PDL1V in Advanced Solid Tumors – ClinicalTrials.gov ID NCT05208762

Highlights of prescribing Information
Encorafenib (Braftovi®; Pfizer) [Prescribing Information]
Binimetinib (Mektovi®; Pfizer) [Prescribing Information]
Enfortumab vedotin (Padcev®; Astellas/Pfizer)[Prescribing information]
Pembrolizumab (Keytruda®; Merck & Co)[Prescribing Information]

References
[1] Cleveland Clinic. Cachexia (Wasting Syndrome). Cachexia (Wasting Syndrome): Symptoms & Treatment (clevelandclinic.org). Online. last accessed on September 3, 2024.
[2] Martin L, Sawyer MB. Cancer Cachexia: Emerging pre-clinical evidence and the pathway forward to clinical trials. J Natl Cancer Inst. 2015 Oct 9;107(12):djv322. doi: 10.1093/jnci/djv322. PMID: 26453482.
[3] Nishikawa H, Goto M, Fukunishi S, Asai A, Nishiguchi S, Higuchi K. Cancer Cachexia: Its Mechanism and Clinical Significance. Int J Mol Sci. 2021 Aug 6;22(16):8491. doi: 10.3390/ijms22168491. PMID: 34445197; PMCID: PMC8395185.
[4] Kwan B, Ramirez M, Jin S, Yu C, Wo S, Gupta P, Allred S, Simmons J, et al. SGN-PDL1V, a Novel, investigational PD-L1-directed Antibody-drug Conjugates for the Treatment of Solid Tumors .J Immunother Cancer 2021;9(Suppl 2):A1–A1054 | DOI 10.1136/jitc-2021-SITC2021.783

Featured image: General images of ESMO 2019 Congress being held in Barcelona, Spain, September 27 – October 1, 2019. Courtesy European Society for Medical Oncology (ESMO). Used with Permission.

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