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Pfizer Pursuing Multiple Biomarker-Defined Cancer Indications in Coming Years

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NEW YORK – During a webcast presentation on Tuesday, executives from Pfizer updated market analysts on its oncology R&D pipeline, which includes several drugs for biomarker-defined populations headed for pivotal registration studies, as well as first-in-class agents in preclinical or early-phase clinical studies. 

Among drugs in late-phase development, Pfizer's Oncology Chief Development Officer Chris Boshoff highlighted data on the BRAF- and MEK-targeting agents encorafenib (Braftovi) and binimetinib (Mektovi), as well as the PARP inhibitor talazoparib (Talzenna). 

For encorafenib and binimetinib, Pfizer plans to expand their indications into various BRAF-driven cancers, including in earlier disease settings and in combination with other drugs. The encorafenib-binimetinib combination has US Food and Drug Administration approval in unresectable or metastatic melanoma with BRAF V600E/K mutations, while encorafenib plus cetuximab (Lilly's Erbitux) has approval in metastatic colorectal cancer with BRAF V600E mutations. 

Boschoff provided an early view of the data from the Phase II ANCHOR study evaluating encorafenib, binimetinib, and cetuximab as a first-line treatment for patients with BRAFV600E-mutated colorectal cancer. The objective response rate of the three-drug combination was 50 percent and the disease control rate was 85 percent. 

Though the data are preliminary, they have provided Pfizer with sufficient proof of activity to begin evaluating the three-drug regimen in a three-arm, Phase III study, dubbed BREAKWATER, slated to begin later this year in first-line BRAF-mutated colorectal cancer. "We believe that Braftovi is a best-in-class BRAF inhibitor," Boshoff said during the presentation. "And we have a comprehensive development plan for Braftovi-Mektovi that we are rapidly advancing across BRAF-driven cancers." 

Beyond colorectal cancer, Pfizer has an ongoing Phase II open-label study of encorafenib-binimetinib in metastatic BRAFV600E-mutated lung cancer. The drug giant will also begin evaluating the encorafenib-binimetinib combination plus the immune checkpoint inhibitor pembrolizumab (Merck's Keytruda) as a first-line treatment for BRAFV600E-muated melanoma in 2021. 

For the PARP inhibitor talazoparib, currently approved for germline BRCA-mutated, HER2-negative breast cancer, Pfizer is also exploring other markets, such as prostate cancer. Boshoff presented interim data from the Phase II TALAPRO-1 study of talazoparib in patients with heavily pretreated, metastatic, castration-resistant prostate cancer with DNA damage response (DDR) mutations, which so far has yielded an objective response rate of 27 percent in the overall population of patients with a variety of DDR mutations and a response rate of 42 percent in patients specifically harboring BRCA1 or BRCA2 mutations.

Boshoff pointed out that patients with BRCA1 mutations did respond to talazoparib in this study, which may potentially differentiate the drug from the activity seen with other PARP inhibitors in prostate cancer. 

Based on interim TALAPRO-1 data, Pfizer is moving ahead with TALAPRO-2, a Phase III clinical trial comparing talazoparib plus enzalutamide (Pfizer/Astellas Oncology's Xtandi) versus enzalutamide alone in patients with mCRPC. As of now, that trial has completed enrollment of the all-comer cohort and Pfizer expects to read out primary results in 2021. Prostate cancer patients' DDR mutation status will be evaluated in the second part of this two-part study. 

"TALAPRO-2 will be the first study to read out for a PARP inhibitor in combination with a next-generation androgen receptor inhibitor," Boshoff said. "We anticipate that this investigational combination has the potential to become a new standard of care in this setting if successful."

At the European Society of Medical Oncology's Virtual Congress this weekend, Pfizer will present data from its Phase III CROWN study comparing its third-generation ALK inhibitor lorlatinib (Lorbrena) against its first-generation drug crizotinib (Xalkori) in first-line ALK-positive non-small cell lung cancer. 

"We believe that the CROWN results will position Lorbrena to be highly competitive with second-generation ALK inhibitors in the first-line setting, assuming regulatory approval," Boshoff said. 

In addition to the updates on late-phase clinical trials, Pfizer executives discussed several agents researchers are currently exploring in preclinical and early-phase studies. 

Among these, Jeff Settleman, Pfizer's head of oncology R&D, highlighted an investigational CDK2/4/6 inhibitor that may be able to overcome patients' resistance to the company's CDK4/6 inhibitor palbociclib (Ibrance), which is approved for hormone receptor-positive, HER2-negative, metastatic breast cancer. This agent is currently in Phase I development, and Pfizer expects to share its proof-of-mechanism evidence in 2021. 

In addition to the CDK2/4/6 inhibitor, Pfizer is also developing a selective CDK4 inhibitor that it is betting will improve upon palbociclib's activity. The first-in-patient clinical trial for this agent is slated to begin later this year, as well as for a selective CDK2 inhibitor, which has been shown in preclinical models to overcome resistance to palbociclib in estrogen receptor-positive breast cancer.

Pfizer is also developing a HER2-directed antibody-drug conjugate for the treatment of patients with breast cancer and other HER2-expressing cancers. The agent, which Pfizer began studying in a Phase I clinical trial in 2017, has demonstrated activity in both HER2-positive breast cancer and HER2-positive gastrointestinal cancers. This study included patients who previously received and progressed on Genentech's HER2-directed antibody-drug conjugate TDM1 (Kadcyla). 

According to Settleman, Pfizer also has encouraging preclinical data for this molecule in NSCLC tumor models with low HER2 expression, with complete regressions observed in TDM1-refractory xenografts. The company plans to expand testing for the agent in HER2-expressing lung cancer, accordingly. 

Finally, Pfizer executives discussed several targeted next-generation therapy programs that are expected to enter the clinic either this year or next. One is a potentially first-in-class, brain-penetrant BRAFV600E inhibitor for patients with BRAF-driven cancers, including melanoma. The first-in-human clinical trials for this agent will begin by the end of this month. Other clinical trial candidates include one agent that targets HER2 exon20 and another that targets C-Met EXON14. Both of these candidates are designed to interrogate the amplified wildtype protein and known drug resistance mutations, as well as treat or forestall intracranial disease.