The pipeline includes next-in-class treatments for melanoma, NSCLC, breast cancer, and multiple myeloma.
According to Sandra Cuellar, PharmD, we’re currently living in the golden age of oncology.1
“If you look at the past decade of FDA oncology approvals, we have made remarkable progress with immune checkpoint inhibitors, with sophisticated biologic agents such as antibody drug conjugates, bispecific monoclonal antibodies, [and] targeted therapies,” said Cuellar, a clinical associate professor and clinical oncology pharmacist at UI Health/University of Illinois at Chicago College of Pharmacy, during her presentation at the 2022 American Society of Health-System Pharmacists Summer Meetings and Exhibition.1 “In the past decade or so…the number of drug approvals in oncology is over 330.”
The majority of these approvals—59%— are for label expansion. The poster child, she added, is prembrolizumab, which is has 33 indications over 13 individual disease states. Twenty-five percent of approvals were the first approval of a next-in-class drug, and 16% were for drugs with a new mechanism of action, with 7 such drugs approved in 2020.
Check out our coverage of the 2022 ASHP Summer Meetings and Exhibition to learn more about the latest in the specialty drug pipeline.
According to Cuellar, melanoma was one of the first cancers that saw the efficacy of immune checkpoint inhibitors (ICIs). “In this particular cancer, we had very poor outcomes,” she said. “The approval of [ICIs] really did improve outcomes.” To build on that success, researchers turned to lymphocyte activation gene 3 (LAG-3), an immune checkpoint protein that is upregulated in melanoma.
Preclinical data support the idea of using nivolumab and relatlimab-rmbw, 2 dual ICIs that have demonstrated synergistic activity. Results of the RELATIVITY-047 trial (NCT03470922), which evaluated the efficacy of nivolumab and relatlimab -rmbw combination therapy in a global, randomized, double-blind phase 3 trial. Results demonstrated that in a population of 694 patients with untreated unrescetable or metastatic melanoma, the median progression free survival rate in was 10.12 months vs 4.63 months with nivolumab therapy alone.
Nivolumab and relatlimab -rmbw (Opdulag) is a first-in-class therapy approved by the FDA on March 18, 2022, for the frontline treatment of adult and pediatric patients 12 years or older with unresectable or metastatic melanoma. It is formulated as an injection of 240 mg nivolumab and 80 mg relatlimab per 20 mL (12 mg and 4 mg per mL) and administered in adults and pediatric patients weighing at least 40 kg as 480 mg nivolumab and 160 mg relatlimab intravenously over a 30-minute period every 4 weeks.
“As an oncology pharmacist…this has been probably the most remarkable progress I have witnessed,” said Cueller. “Why is that? We started out 20-plus years ago treating [NSCLC] as one disease,” typically with CarboTaxol. However, Cueller explained, patients were frequently experiencing negative outcomes, leading to a shift in thinking around the disease and an understanding that different histologies of NSCLC require different therapies, including squamous cell and adenocarcinoma. Today, patients with NSCLC undergo tissue or liquid biopsy and next generation tumor sequencing to determine which oncogenic mutation is driving their disease.
Over time, researchers have continued to identify mutations responsible for driving NSCLC, including HER2. Between 2% and 3% of patients with NSCLC have a HER2 mutation, most commonly exon 20 insertion, representing an unmet need in cancer therapy.
Enter poziotinib, a potent, irreversible EGFR and HER2 inhibitor with exon 20 mutations. The phase 2 ZENITH20 clinical trial (NCT03318939) included 7 cohorts of patients with either EGFR or HER2 exon mutations. Cueller focused on patients in cohort 2, which included those with HER2 exon 20 insertion mutations who were previously treated and received an oral, once-daily dose of poziotinib 16 mg. In total, 27.8% of patients met the primary endpoint of overall response rate; duration of response was 5.1 months, and median progression-free survival was 5.5 months.
Poziotinib is a next-in-class investigational therapy with a likely indication for metastatic NSCLC with HER2 exon 20 insertion mutations with an anticipated PDUFA date of November 24, 2022. Tentative dosing is oral, 16 mg once daily until progression or unacceptable toxicity.
Up to 30% of [patients with NSCLC] have an [epidermal growth factor receptor] EGFR-activating mutation,” said Cuellar. “Of these EGFR mutations, about 83% express HER3 protein,” which is associated with increased metastases, decreased survival, and increased resistance. Cuellar noted that although there are several approved treatments for patients with EGFR mutations, there are limited treatments available for those who progress or have resistance to first-line EGFR tyrosine kinase inhibitor agents.
Patritumab deruxtecan, an investigational first-in-class HER3 directed antibody drug conjugate, may one day be an option for this group of patients. In a multicenter, open-label, multicohort phase 1 trial (NCT03260491), researchers identified a dose of 5.6 mg/kg administered intravenously every 3 weeks as the correct dose for a dose expansion trial. Efficacy of this dose was evaluated in 57 patients, while safety and tolerability of all doses, ranging from 3.2 mg/kg to 6.4 mg/kg, were evaluated in 81 patients.
Within the cohort, median time to response was 2.6 months; median duration of response was 6.9 months, and median progression-free survival was 8.2 months. “This is very early preliminary data, but [this is] very promising, especially in a patient population that’s heavily pre-treated.” Adverse events were common; 11% led to treatment discontinuation, 21% led to dose reduction and 37% led to dose interruption.
Patritumab deruxtecan was granted an FDA Breakthrough Therapy Designation on December 23, 2021. Tentative dosing is 5.6 mg/kg intravenously every 3 weeks until progression or unacceptable toxicity.
The KRASG12c mutation occurs in approximately 13% of cases of NSCLC. Adagrasib is an investigational drug that irreversibly and selectively binds to KRASG12c in its inactive state, blocking both cell growth and proliferation.
The nonrandomized, open-label, phase 1/2 KRYSTAL-1 study (NCT03785249) evaluated adagrasib in patients with KRASG12c-mutated solid tumors or unresectable or metastatic disease who had progressed on standard treatment. “The phase 1 study demonstrated that the dose that was going to be further investigated was 600 mg twice a day,” Cuellar explained. “In the phase 2 component, they looked at monotherapy in [NSCLC], colon cancer, and other solid tumors.”
In a NSCLC cohort of 79 patients, adagrasib demonstrated an overall response rate of 58% with a 9.5-month median duration of treatment, 12.6-month median duration of response, and 8.3-month progression-free survival; 36% of participants experienced grade 3/4 adverse events.
As a next-in-class drug, adagrasib received an FDA Breakthrough Therapy Designation on June 25, 2021, and has an anticipated PDUFA date of December 14, 2022. The drug is administered orally with a tentative dosing of 600 mg twice daily until progression or unacceptable toxicity.
According to Cuellar, the most common type of breast cancer—both in her practice and in the United States—is hormone positive breast cancer. “Endocrine therapy is the backbone in the treatment of hormone positive breast cancer,” she said. “And unfortunately, although we do have good efficacy outcomes with endocrine therapy, we do see up to 42% of patients do [become resistant] to endocrine therapies.”
Mutations in the membrane-localized estrogen receptor 1 gene (mESR1) is one of the “primary culprits” of endocrine therapy resistance. “We do have selective estrogen receptor degraders, or SERDs, that are indicated in the metastatic setting and have demonstrated some efficacy in patients with mESR1 metastatic breast cancer,” Cuellar explained, including fulvestrant, administered via intramuscular injection.
Data from the EMERALD trial (NCT03778931), initially presented at the 2021 San Antonio Breast Cancer Symposium, highlighted elacestrant, an investigational, nonsteroidal, orally bioavailable SERD. The global, open-label, randomized, phase 3 trial included patients (men and postmenopausal women) with estrogen receptor positive, HER2 negative advanced or metastatic breast cancer who had progressed after 1 or 2 lines of endocrine therapy treatment, one of which included a CDK4/6 inhibtor. Patients received elacestrant or standard of care, either fulvestrant or an aromatase inhibitor.
“This is a very resistant patient population,” Cuellar said. “Unless [patients] have visceral crisis or symptomatic visceral disease, the standard of care in treating these patients is exhausting these endocrine options.”
Median progression free survival among all patients was 2.79 months in the elacestrant group vs 1.91 months with standard of care therapy. In the mESR1 group, median progression free survival was 3.78 months compared with 1.87 in standard of care.
Other oral SERDs in development include giredestrant and amcenestrant, both in phase 2 and phase 3 trials; rintodestrant, currently in phase 1 research; and camizestrant, currently being evaluated in two phase 3 and one phase 2 trial.
Elacestrant is a next-in-class investigational therapy that has received an FDA Fast Track Designation. Tentative dosing is 400 mg orally daily until progression or unacceptable toxicity.
In today’s treatment landscape, there are limited treatments for patients with relapsed/refractory multiple myeloma who fail standard of care therapeutic options. However, Cuellar explained, “There’s a lot of exciting and emerging data [around] B-cell maturation antigen or BCMA.”
“BCMA is almost universally expressed in myeloma cells, and because it’s universally expressed…it has become a target for drug development,” she said. “We already have some CAR-T therapies looking at BCMA, we have an antibody drug conjugate that targets BCMA, and we have teclistamab.”
Teclastimab is a T-cell redirecting, bispecific antibody targeting both BCMA and CD3, engineered to have the dual specificity to facilitate cell-to-cell interactions between a patient’s T-cells and malignant cells expressing tumor-specific antigens. The MajesTEC-1 study (NCT) was a first-in-human, open-label, dose escalation/dose expansion phase 1/2 trial of patients with relapsed/refractory multiple myeloma who received 3 or more previous lines of therapy and had been triple exposed to these classes.
After dose escalation, patients received teclistamab 1.5 mg/kg subcutaneously once weekly until progression or unacceptable toxicity. Overall response rate was 62%. “Why is that exciting? Because this is something that’s off the shelf that I can administer to my patients,” Cuellar said. “A lot of people are excited about CAR-T, but CAR-T takes time to coordinate. I think this is a preliminary promising efficacy.”
Cuellar cautioned that when treating patients with an antibody drug conjugate or bispecific antibody—“really, any time we’re engaging [the patient’s] T-cells”—2 adverse events should be top of mind: cytokine release syndrome (CRS) and neurotoxicity. In MajesTEC-1, 49.7% and 21.2% of patients had grade 1 or grade 2 CRS events, confined to the dose step-up and first cycle of therapy, and all resolved without the need for treatment discontinuation. Neurotoxicity was noted in 21% of patients, but no treatment discontinued therapy or reduced their dose.
Teclistamab is a first-in-class investigational therapy with a PDUFA date slated for the third quarter of 2022. It is administered subcutaneously at a dose of 1.5 mg/kg once per week.