NEW YORK – Drugmakers and researchers are looking to the next generation of breast cancer treatments, used alone or in combination with existing therapies, in the hopes of overcoming acquired resistance to CDK4/6 inhibition.
Pfizer, a major player developing next-generation CDK inhibitors, is exploring combination treatment strategies with its blockbuster CDK4/6 inhibitor Ibrance (palbociclib) for the treatment of hormone receptor-positive, HER2-negative breast cancer. The company is studying two next-gen CDK inhibitors in breast cancer and other tumor types: the triple-activity agent targeting CDK2/4/6, dubbed PF-06873600 (or PF3600 for short) and the CDK2 inhibitor PF-07104091.
In its Q4 earnings call in March, Pfizer CSO Mikael Dolsten provided an update on ongoing studies of the two CDK inhibitors and estimated that a Phase II trial of PF3600 would wrap up by year-end and a Phase I/II trial of PF-07104091 would be completed in Q2 2023.
If the studies of these two drugs are successful, Pfizer sees "the potential for breakthrough therapies with significant revenue opportunity," a company spokesperson said over email.
Pfizer is betting that PF3600 and PF-07104091 will bolster its CDK inhibitor franchise, which is currently dominated by the blockbuster Ibrance, the firm's top-selling oncology drug. Ibrance, which has been on the market for seven years, is approved in the US to treat hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer plus an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women or in men and with fulvestrant in patients with disease progression following endocrine therapy. In 2021, the drug earned $5.44 billion in global sales, a 1 percent increase from its sales in 2020 which were $5.39 billion.
"Given strong mechanistic rationale and encouraging preliminary clinical data to date, we believe that the [next-generation] CDK portfolio has the potential to address a broad set of breast cancer patients, both in the first-line HR-positive, HER2-negative metastatic breast cancer setting, as well as expanding to patients in the [second-line or later], post-CDK4/6 inhibitor setting where the unmet need is extremely high," the Pfizer spokesperson said.
In the Phase II study of PF3600, Pfizer is studying the drug as a single agent and in combination with endocrine therapy in several cancer types. The trial involves heavily pretreated patients with HR-positive, HER2-negative breast cancer who have received a CDK4/6 inhibitor; triple-negative breast cancer; platinum-resistant epithelial ovarian cancer; fallopian tube cancer; and primary peritoneal cancer.
In early data from 33 patients with metastatic HR-positive, HER2-negative breast cancer in that study, there were three confirmed partial responses and three patients who maintained stable disease for more than 12 months on treatment, Dolsten noted in the investor call.
In another Phase I/II trial, Pfizer is studying its CDK2 candidate PF-07104091 as a single agent and in several combination regimens, including with endocrine therapy, Ibrance, and aromatase inhibitors. That study involves previously treated patients with HR-positive, HER2-negative breast cancer; triple-negative breast cancer; ovarian cancer; fallopian tube cancer; primary peritoneal cancer; and non-small cell lung cancer.
Early data from that trial, presented in the investor call, showed two patients had confirmed partial responses on PF-07104091 monotherapy. These patients had advanced or metastatic HR-positive, HER2-negative breast cancer and had received or progressed on prior CDK4/6 inhibitors and endocrine therapy.
"Most patients with advanced or metastatic breast cancer eventually develop resistance to both endocrine and CDK4/6 inhibitors despite their transformative efficacy," Dolsten said. "Inhibition of CDK2, delivered with a CDK2 selective activity drug or a triple activity CDK 2/4/6 agent, may prevent, delay, or reverse resistance and prolong survival."
Pfizer researchers developed the CDK2/4/6 drug PF3600 based on findings from a study that delved into the mechanisms of resistance to Ibrance. That research, published in Cancer Cell in October, identified several mechanisms of resistance, including CCNE1 expression, MYC expression, and WNT signaling.
In the study, the researchers zeroed in on CCNE1 expression, which was associated with both resistance to CDK4/6 inhibition with Ibrance and sensitivity to CDK2 inhibition. They developed PF3600 to target the CDK2-CCNE1 complex, alongside targeting CDK4 and CDK6, to interrupt the cell cycle process and slow cancer cell growth even in patients who had acquired resistance to CDK4/6 inhibition.
In an evaluation of PF3600 in HR-positive breast cancer patient-derived xenografts, the researchers found that single-agent PF3600 tumor growth inhibition was equivalent to or greater than that of the Ibrance and fulvestrant combination. PF3600 also showed activity in patient xenografts from triple-negative breast cancer patients with CCNE1 amplification, while Ibrance did not.
Pfizer has not published any research on the development of its CDK2 candidate, PF-07104091.
In the CDK2 space, Pfizer's two candidates are some of the furthest along in clinical development, according to Rinath Jeselsohn, an assistant professor of medicine at the Dana-Farber Cancer Institute who studies treatment resistance and tumor progression in HR-positive breast cancer. Jeselsohn is not involved with Pfizer's CDK2 research.
She noted that CDK4/6 inhibitors work by blocking the repression of RB1, a tumor suppressor gene that regulates the cell cycle. If RB1 is suppressed, the cell cycle can reach the restriction point, when cells no longer need external signals to proliferate, allowing tumor cells to grow.
"What we're seeing is some clinical studies of HR-positive breast cancer is that higher levels of cyclin E, the partner of CDK2, are associated with resistance to CDK 4/6 inhibition," Jeselsohn said, describing this downstream bypass mechanism. "If you have more activity of CDK2-cyclin E, it further phosphorylates and inactivates RB1 and allows pathways through the cell cycle. If you could block CDK2, 4, and 6, you're essentially fully targeting RB1 suppression."
Currently, breast cancer patients who have developed resistance to CDK4/6 inhibitors have limited treatment options, Jeselsohn added. Standard treatments include endocrine therapies plus mTOR inhibitors, such as Novartis' Afinitor (everolimus); or PI3K inhibitor Piqray (alpelisib) for patients with PIK3CA mutations.
CDK2, however, is only one mechanism of resistance to CDK4/6 inhibitors. Patients can also develop resistance through acquired PI3K or MAPK pathway mutations, which could be overcome by PI3K inhibitors and MEK inhibitors, respectively, Jeselsohn said. RB1 loss or RB1 mutations are also a mechanism that emerges with resistance to CDK4/6, but these are found in a relatively small number of patients, she added.
Some drugmakers are also exploring other CDK receptors, such as CDK7. Carrick Therapeutics, for example, is advancing a CDK7 inhibitor samuraciclib in breast cancer. Initial data the firm presented last year from a study of HR-positive, HER2-negative breast cancer patients showed that 71 percent of those who previously received CDK4/6 inhibitor treatment and then got samuraciclib experienced tumor shrinkage. Out of 24 evaluable patients in this assessment, two patients had a partial response and 13 patients reached stable disease.
While Pfizer's next-generation CDK inhibitors are perhaps the furthest along in clinical development, other pharma companies are hot on its heels with CDK2 and CDK2/4/6 inhibitors in late-preclinical or early clinical development.
Blueprint Medicines is developing a candidate targeting CDK2, BLU-222, and is exploring that drug in CDK4/6-resistant, estrogen receptor-positive, HER2-negative breast cancer; and in tumors that overexpress CCNE1. This year, Incyclix Bio is moving its CDK2 inhibitor candidate, INX-315, into a proof-of-concept Phase I/II study in CDK4/6-resistant and cyclin E-overexpressed cancers, including breast and ovarian cancer.
In the CDK2/4/6 inhibitor space, Regor Therapeutics is planning a Phase I trial of RGT-419B in advanced, HR-positive, HER2-negative breast cancer patients who are resistant to CDK4/6 inhibitors.
Meanwhile, researchers are also looking for biomarkers to better select breast cancer patients for CDK4/6 treatment combinations. One study, which researchers presented at a conference in December, monitored the circulating tumor DNA (ctDNA) of breast cancer patients being treated with Ibrance and an aromatase inhibitor. They found that if ESR1 mutations were detected in ctDNA, which are associated with aromatase inhibitor resistance, they could switch patients to Ibrance and selective estrogen receptor degrader fulvestrant to avoid the aromatase inhibitor resistance.
Another study, also presented in December, monitored ctDNA to determine which patients would respond to Novartis' CDK4/6 inhibitor Kisqali (ribociclib) and aromatase inhibitor letrozole. That study found patients who had baseline tumor mutations but achieved variant allele frequency clearance at day 15 of the first treatment cycle were more likely to respond to the combination therapy than those who did not achieve clearance.
As these biomarker strategies and next-generation CDK inhibitors continue to be studied in clinical trials, researchers are hopeful that they will lead to new precision treatment opportunities for advanced breast cancer patients and help them overcome or avoid acquired resistance to currently available CDK inhibitors.