New study: UpRi promises to be a better treatment option for platinum-resistant ovarian cancer

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One. Status of treatment of platinum-resistant ovarian cancer:

Platinum-resistant ovarian cancer patients have long been an area of unmet medical need, with standard care such as PEGL liposome doxorubicin and topotecan having a response rate of only 12% and a median progression-free survival (PFS) of about 4 months. When patients respond to platinum chemotherapy, platinum dual liposome doxorubicin, paclitaxel, or gemcitabine plus or without bevacizumab avastine is usually used, and when these regimens are effective, PARP inhibitors (PARP inhibitors are medical agents that can influence the way cancer cells replicate themselves. PARP inhibitors can make breast cancer drugs work effectively, and they can also treat hereditary cancers such as ovarian, prostate, and pancreatic cancer. Nonetheless, these patients will eventually die because of the recurrence of ovarian cancer. The researchers hope to improve the treatment model for platinum-resistant ovarian cancer by developing a first-class antibody drug conjugate (ADC) resoypifiltumab (Upifitamab rilsodotin, XMT-1536, UpRi).

2. The FDA designates UpRi for the treatment of platinum-resistant ovarian cancer:

In August 2020, UpRi received a fast-track designation from the U.S. Food and Drug Administration (FDA) for the treatment of platinum-resistant patients with high-grade serous ovarian cancer who had received 3 previous systemic treatments or 4 previous systemic treatments, regardless of the patient's status with platinum-based drugs.

1. UpRi's mechanism of action:

UpRi targets the sodium-dependent phosphoric acid transporter NaPi2b, which is widely expressed in ovarian cancer but has limited expression in normal tissues, making it a potential therapeutic target. UpRi contains a connectome specifically designed to interact with cancer cells and contains a DolaLock payload, a tubulin inhibitor that, after cleavage in target cells, can penetrate membranes to exert a bystander effect.

NAPI2B is a marker, and some other targeted antigen ADC drugs currently being developed in studies in the treatment of ovarian cancer, such as mirvetuximab soravtansine (IMGN853), which target the folate receptor α, UpRi has a high drug-to-antibody ratio of about 10, and UpRi has an excellent bystander effect, making it a first-class antibody drug conjugate drug.

2. UpRi clinical trial content:

The trial included 100 patients with high NaPi2b-expressing platinum-resistant ovarian cancer and 180 platinum-resistant ovarian cancer patients. Also included was a group of patients with non-small cell lung cancer, for a total of about 444 patients. Patients must have received 1 or 2 platinum-containing chemotherapy treatments for ovarian cancer within 14 days prior to registration and have adequate organ function. Patients who have had a prior allergic reaction to carboplatin, as well as those who have previously received mivituzumab-solavatazin, or other ADCs containing microtubule inhibitors such as meedonin (Maytansinoid, DM1) are excluded. Patients receive intravenous UpRi every 4 weeks until disease progression, unacceptable toxicity, or study aborts. The initial dose of UpRi is 36 mg/m2 and increases to 43 mg/m2. The recommended dose for Phase 2 is 36 mg/m2. The primary endpoint of this trial was ORR (overall response rate). The trial is expected to be completed by the end of 2023.

3. Test results:

Initial safety and efficacy data from trials show that UpRi is well tolerated with consistent safety and antitumor activity in patients with platinum-resistant ovarian cancer. On June 10, 2021, 97 patients in the ovarian cancer cohort were treated with UPRI. Of the 75 patients who could assess efficacy, the ORR was 23%, including 2 patients who achieved a complete response (CR).

Patients in the NaPi2b high subgroup (n=38) (defined as those with a tumor performance score (TPS) of 75 or higher) performed even better than those in the general ovarian cancer population. These patients had an ORR of 34% and a disease control rate of 87%. The median duration of the reaction was approximately 5 months.

The researchers also found that the efficacy of the NaPi2b high subgroup did not depend on taking higher doses of UpRi. The ORR of patients treated at the lowest dose (36 mg/m2) was 50%, compared with 41% and 15%, respectively, in the dose groups of approximately 80 mg/m2 and 43 mg/m2. This trend is also consistent among the population as a whole. The lower the dose, the less the treatment-related dose reduction, but the ORR is similar to the high dose. The lower the dose, the longer the duration of treatment. Patients with high NaPi2b expression stayed longer in the study compared to patients with low NaPi2b expression.

4. Test safety:

In terms of safety, the most common treatment-related adverse effects in the UpRi experiment were fatigue (about 80%), nausea (about 70%), and elevated levels of aspartate aminotransferase (AST) (about 60%). The lowest dose levels resulted in a small number of patients with grade 3 or higher fatigue and AST elevation (both 8%), compared with 13% and 35% in the medium-dose group and 23% and 41% in the high-dose group, respectively. In 44% of patients, dose delays, reductions, and/or discontinuations occurred as a result of adverse reactions. Dose delay due to adverse reactions was reported in 16% of patients, 28% of patients were reduced due to adverse reactions, and 10% of patients withdrew from the trial due to adverse reactions.

5. New plans and prospects for the trial:

Given the current good trial results, Mersana Therapeutics, the manufacturer of UpRi, announced that UpRi's Phase 3 Up-Next trial is expected to start in the second quarter of 2022. It is a maintenance trial of monotherapy that compares UpRi to placebo, and the head-to-head trial is designed to address the lack of effective standards of care and treatment in patients with recurrent platinum-sensitive ovarian cancer.

In the Phase 3 Up-Next trial, UpRi will be evaluated after platinum dual therapy in patients with recurrent platinum-sensitive ovarian cancer. Patients in the Up-Next trial must have high NaPi2b expression and have previously undergone 1 to 3 platinum-based protocols. Patients will receive UpRi 36 mg/m2 randomly, up to a maximum of about 80 mg/m2 or placebo. The primary endpoint of the trial was PFS (progression-free survival).

Under such experimental conditions, PARP inhibitors are not included as maintenance drugs, so only patients with CRs (Complete response, which means that all signs of cancer disappear as a result of treatment and does not necessarily mean that the cancer is cured) or PRs (Partial response, which means that the treatment makes the tumor smaller in diameter or the scope of influence smaller) are eligible to use PARP inhibitors in this case. Assuming that the test results are correct and that UpRi does have accelerated approval from the FDA, the next step of the trial data will hopefully receive full FDA approval of UpRi. If the results are validated, UpRi will provide a new maintenance option for patients with platinum-sensitive recurrent ovarian cancer.