A session held at the HOPA Annual Meeting 2021 discussed investigational cancer drugs in clinical trials.
Amid fluctuating pharmacy trends and persistent pandemic changes, keeping pace with the latest clinical trial data for investigational oncology drugs can be a challenge.
In a session held virtually on April 14, during the Hematology/Oncology Pharmacy Association (HOPA) Annual Meeting 2021, Heidi D. Finnes, PharmD, BCOP, senior manager, Pharmacy Cancer Center Research, Mayo Clinic Cancer Center in Rochester, Minnesota, dove into the details of investigational medications currently under clinical development in the oncology space, including pertinent clinical trial data, potential impacts on current clinical practice, adverse events (AEs), and interventions for managing toxicity.
Finnes discussed investigational cancer medications in these categories:
Oral paclitaxel plus encequidar
In the intestine, paclitaxel causes apoptosis to cancer cells. However, when intracellular paclitaxel is given orally, it has poor bioavailability due to binding to the P-glycoprotein Efflux Pump. Therefore, a P-glycoprotein inhibitor – encequidar – is necessary.
Oral paclitaxel plus encequidar was evaluated in a trial that included 402 female patients with metastatic breast cancer who were randomized 2:1 to receive either paclitaxel 205 mg/m2 plus encequidar 15 mg (n=235) once daily prior to each paclitaxel dose 3 times of week for a total of 3 weeks, or paclitaxel 175 mg/m2 (n=125)intravenously (IV).
Finnes emphasized that oral paclitaxel treatment can be cumbersome for patients. “Many patients had more than 10 or 11 pills that needed to be taken per day with varying times of fasting that had to occur,” she said.
Key end points were overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) and all 3 factors were higher in the paclitaxel plus encequidar when compared with the IV paclitaxel arms. Responses were maintained past 100 days in 75% of patients and beyond 200 days in 34% of patients. In regard to OS, there was a 26.5% reduction in the risk of death in patients treated with paclitaxel plus encequidar.
Finnes also described the toxicities associated with the combination drug treatment. Among these were increases in gastrointestinal-related AEs, including diarrhea, nausea, and vomiting. “One of the surprising toxicities associated with this was the increase of neutropenia in some of these patients,” Finnes explained.
“One of the great things about giving paclitaxel orally is there is decreased risk of neuropathy,” Finnes added. Treatment with oral paclitaxel showed an 8% risk in grade 3 total incidents and 2% risk for grade 4 compared with a 31% and 15% risk for IV paclitaxel, respectively.
“So as pharmacists, I think some of the things that we can intervene on is being sure that patients are prepared for diarrhea symptoms and adequate intake of fluids, as well as prophylactic loperamide, or 5-HT3 receptor antagonists if patients have nausea and vomiting,” Finnes said.
The FDA has reviewed the trial data and cited concerns surrounding the primary end point of ORR at 19 weeks by blinded independent central review. The FDA explained that the reread of the data may have introduced unmeasured bias influenced by the blinded independent review committee. The agency additionally had concerns about the high rates of neutropenia with the oral paclitaxel combination.
Finnes described tesetaxel as being “unlike any other oral taxane medication, in that it's not effluxed by P-glycoprotein. Because of this, it's actually orally bioavailable and more soluble with a longer half-life compared to other taxanes,” Finnes explained.
The phase 3 CONTESSA trial randomized 685 patients with metastatic breast cancer to receive tesetaxel 27 mg/m2 on day 1 only plus capecitabine at a reduced dose of 1650 mg/m2 per day on days 1 through 14. Patients were administered capecitabine at the FDA-approved dose of 2500 mg/m2 on days 1 through 14.
PFS and ORR were primary end points of the study, both of which were higher in the tesetaxel arms. Finnes called attention to the significantly higher risk of neutropenia and febrile neutropenia in patients receiving the tesetaxel plus capecitabine combination. “So, monitoring will be required for our patients receiving this type of therapy,” Finnes said.
There are currently several phase 2 clinical trials investigating tesetaxel in various cancer types. “The practice implications for oral taxanes, I think, are interesting,” Finnes said. “We were very excited about the results of oral paclitaxel and encequidar…However, the FDA has concerns and would like further studies.”
Investigators hypothesize that oral taxanes may be less toxic than IV paclitaxel, especially for the risk of neuropathies. “However, the increased risk of neutropenia is very concerning,” Finnes said. “I think we await…more mature results from the tesetaxel clinical trial to see where these drugs end up.”
Wee1 is a protein kinase that regulates the G2/M checkpoint and prevents entry into mitosis in response to cellular DNA damage, Finnes explained.
Cyclin-dependent kinases (CDKs) that control the progression from G2 to mitosis are called CDK1 or cyclin B. Prior to mitosis, CDK1 is maintained in an inactive state by Wee1, thus allowing time for damaged DNA to be repaired. Inhibition of Wee1 prevents the dephosphorylation of CDK1 and allows for continued cell cycle progression while still harboring unrepaired damaged DNA. The inability to repair damaged DNA results in death to the cancer cell.
Finnes explained that somatic mutations in TP53 are often present in almost every cancer. They are also greatest in patients with cancers in advanced stages and with more aggressive cancers. Up to 50% of patients with ovarian, esophageal, colorectal, head and neck, and lung cancers can have a TP53 mutation.
“One of those more aggressive cancers is uterine serous carcinoma [USC]. Uterine serous carcinoma has a TP53 mutation in greater than 90% of patients,” Finnes said.
A phase 2, single-arm, open label clinical trial evaluated 35 female patients with recurrent USC. Patients were treated with adavosertib 300 mg orally once daily during days 1 to 5 and 8 to 12 within a 21-day treatment cycle. The dual end points were ORR and PFS at 6 months.
Study investigators reported favorable results, with 29.4% ORR (95% CI 15.1-47.5) and 47% PFS. Toxicities of grade 3 or higher included neutropenia (32%), anemia (21%), and fatigue (24%).
Adavosertib was also studied with gemcitabine and radiation therapy in patients with locally advanced pancreatic cancer. Thirty-four patients received gemcitabine 1000 mg/m2 IV once daily on days 1 and 8 every 21 days, plus adavosertib orally once daily on days 1, 2, 8, and 9, 3 to 4 hours and 24 hours after gemcitabine treatment. Radiation occurred during cycles 2 and 3.
The trial’s primary objective was maximum tolerated dose (MTD), which investigators reported as 150 mg/day. Median OS was 21.7 months and medical PFS was 9.4 months.
“Knowledge of TP53 mutations will be very important in the efficacy and incidence of use of Wee1 inhibitors,” Finnes said. Although Wee1 inhibitors may be effective as monotherapy or in combination with DNA altering agents, pharmacists should expect increased toxicity when the treatment is given in combination with chemotherapy.
“Cancers with high expression of Wee1 or cancers with TP53 mutations may have potential future treatment options with the use of Wee1 inhibitors. I think time will tell as we accrue more patients to these exciting new mechanism of action medications,” Finnes said.
Approximately 35% of all triple negative breast cancers have a PIK3CA/AKT/PTEN alteration. As such, ipatasertib is a highly selective AKT inhibitor that was administered to patients with PIK3CA/AKT/PTEN altered triple negative breast cancer in a phase 3 double blind placebo controlled IPATunity130 clinical trial.
The primary end point of the trial was PFS investigator assessed, which was 7.4 months in the ipatasertib plus paclitaxel treatment arm and 6.1 months in the placebo plus paclitaxel arm of the study (HR 1.02, 95% CI 0.71-1.45, P=0.9237).
“What I think is interesting about this clinical trial is there may be potential subgroups for which PIK3CA/AKT/PTEN alterations with ipatasertib may have better efficacy or derive better benefit,” Finnes said. “But it was not based on these results.”
Capivasertib is a potent selective pan inhibitor of AKT.
A phase 2, randomized, double-blind and placebo controlled clinical trial included 140 patients that had metastatic hormone receptor positive breast cancer who had received a prior aromatase inhibitor. With PFS as the primary end point, investigators reported statistically significant differences between the 2 treatment arms: 10.3 months in the capivasertib plus fulvestrant group and 4.8 months in the placebo plus fulvestrant group (HR 0.58, 95% CI 0.39-0.84 P=0.0044 two-sided).
“Now, the results of this clinical trial are still very early, so, at the time of this publication, median OS was not statistically different.” Finnes said.
As for AKT inhibitor practice implications, Finnes said that they are still yet to be determined. Combinations of AKT inhibitors and paclitaxel did not improve response rates or PFS. “I think looking at potentially targetable mutations and specifics of those alterations may be important,” Finnes said.
T-cell immunoglobulin ITIM domain (TIGIT) “has emerged as a key target for antitumor responses as it has efficacy in our immunity cycle,” according to Finnes.
Cancer types with the highest TIGIT are those with diffuse large B-cell lymphoma, testicular cancers, lung adenocarcinoma, head and neck, and cutaneous melanomas, according to Finnes.
A clinical trial investigated tiragolumab plus atezolizumab in patients with PD-L1+ non-small cell lung cancer (n=135). Patients received either tiragolumab or placebo 600 mg on day 1 with atezolizumab 1200 mg IV every 21 days. Primary end point was ORR, with PFS as another key endpoint. ORR was 31.3% in the combination arm and 16.2% in the placebo arm (OR 2.57, 95% CI 1.07-6.14). PFS was 5.4 months in the combination arm and 3.6 months with placebo (HR 0.57, 95% CI 0.37-0.9).
“What was interesting in this trial was that all toxicities - specifically grade 3 and grade 4 toxicities - did not appear to be any different when looking at the combination compared to atezolizumab alone. So, fairly well tolerated with expected toxicities regarding PD1 and PDL1 inhibitors,” Finnes summarized.
Finnes explained that TIGIT inhibitor practice is an attractive target in the treatment of various cancer types due to the broad expression of TIGIT on lymphocytes. The treatment is likely most efficient in combination with other immunotherapies, particularly with PD1 and PDL1. “I’m really excited for the data to mature with TIGIT inhibitors. This is very early data, but I think this may be another innovative immunotherapy that can add to our control of cancer,” Finnes said.
CD25 directed therapies
Antibody drug conjugates (ADCs) are monoclonal antibodies that are conjugated with a pyrrolobenzodiazepine, and this targets the CD25.
A phase 2 clinical trial evaluated camidanlumab tesirine for the treatment of relapsed/refractory Hodgkin lymphoma in patients who had received at least 3 prior therapies and who were ineligible for hematopoietic stem cell transplant (HSCT). Patients also had to have received a prior PD-1 inhibitor and brentuximab therapy.
Patients received camidanlumab tesirine 45 mcg/kg on day 1 and every 21 days for 2 cycles, then 30 mcg/kg on day 1 and every 21 days thereafter. The primary end point was ORR, which “was very impressive, in my opinion, of 83% in this clinical trial,” Finnes said.
The most common treatment-related AEs were fatigue, which was present in more than 50% of patients, pyrexia, nausea, rash, and headache, among others.
“Toxicities occurred in almost 100% of patients and 63% experienced grade 3/4 toxicity, including hypophosphatemia and liver function test elevations,” Finnes explained. “I think it's exciting to see continued enrollments and we will continue to look for updates on the CD25 directed therapy and its place in our actual Hodgkin lymphoma treatment paradigm,” Finnes said.