Antibody-drug Conjugate XMT-1536 Shows Promise for Ovarian Cancer in Phase 1 Trial

Antibody-drug Conjugate XMT-1536 Shows Promise for Ovarian Cancer in Phase 1 Trial
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Treatment with XMT-1536 appears to be safe, with promising responses shown in heavily pretreated patients with ovarian cancer and non-small cell lung cancer (NSCLC) adenocarcinoma in a Phase 1 clinical trial.

Mersana Therapeutics’ XMT-1536 is an antibody-drug conjugate that works by delivering a toxic compound specifically to cancer cells containing a protein called sodium-dependent phosphate transport protein 2b (NaPi2b).

It is based on the company’s Dolaflexin platform,which has been designed to increase the safety, tolerability, and efficacy of antibody-drug-conjugates. Dolaflexin uses Fleximer, a biodegradable polymer (a large molecule made of repeated subunits) that links the antibody to the toxic compound. The polymer is intended to carry high amounts of this compound to kill cancer cells more efficiently.

Mersana launched the Phase 1 trial (NCT03319628) in 2017 to test the experimental therapy. The trial, which is still recruiting patients at several sites across the U.S., is evaluating the safety and preliminary efficacy of XMT-1536 in adults with ovarian cancer or NSCLC adenocarcinoma, whose tumors likely contain NaPi2b.

An initial dose-escalation phase is intended to determine the maximum tolerated or optimal recommended dose of XMT-1536. Then, an expansion phase will divide participants into two groups (one for those with ovarian cancer and another for those with NSCLC adenocarcinoma). XMT-1536 will be given at the dose determined previously to evaluate treatment response.

XMT-1536 isadministered by intravenous (into-the-vein) infusion once every 28 days, until disease progression, unacceptable toxicity, or the patient or study physician decides to stop treatment.

Of the 59 patients enrolled so far, 37 were diagnosed with ovarian cancer, 11 with NSCLC adenocarcinoma, and 11 with other types of tumors. All participants were heavily pretreated, and had received a median of five prior lines of treatment.

Most women with ovarian cancer had previously been treated with the anti-cancer agent bevacizumab or PARP inhibitors — medications that block the activity of PARP enzymes, preventing cancer cells from repairing their DNA and eventually killing them. All patients with NSCLC adenocarcinoma had previously received platinum-based chemotherapy and immunotherapy.

As of Feb. 3, 2020, new data from the first part of the study showed that the safety profile of XMT-1536 in patients on higher doses of the medication remained consistent with previous findings from those treated with lower doses.

The most common treatment-related adverse events were only mild or moderate in severity, and included nausea, fatigue, and headaches. The most common severe adverse event was a temporary elevation of liver aspartate aminotransferase (an indicator of liver inflammation or damage).

No dose-limiting toxicities were reported among those receiving the highest dose of XMT-1536 (43 mg/m2), and no severe episodes of neutropenia (low white blood cell counts), peripheral neuropathy, or eye toxicity were reported.

Regarding treatment response, two of seven patients (29%) receiving XMT-1536 at 43 mg/m2 achieved a partial response (tumor size reduction), and four (57%) achieved stable disease, which corresponds to a disease control rate of 86%.

Among the 15 patients receiving XMT-1536 at 30 mg/m2  or higher, and whose tumors contained high levels of NaPi2b, 33% achieved partial response and 40% stable disease, for a disease control rate of 73%.

In contrast, none of the nine patients receiving XMT-1536 at similar doses but whose tumors contained low levels of NaPi2b achieved a partial response. Still, most (55%) achieved stable disease.

“These data demonstrate that XMT-1536, our first-in-class Dolaflexin ADC targeting NaPi2b, delivers confirmed responses and durable stable disease in heavily pretreated ovarian cancer and NSCLC adenocarcinoma patients who have exhausted all other treatment options,” Anna Protopapas, Mersana’s president and CEO, said in a press release.

“These data also show that XMT-1536 is well tolerated without the severe toxicities of other ADC platforms such as neutropenia, neuropathy and ocular toxicity. Moreover, these data establish the potential for a biomarker-response relationship to identify patients most likely to benefit from XMT-1536,” she added.

In January, Mersana announced that the dose to be used during the expansion portion of the study would be amended from 36 mg/m2 to 43 mg/m2 for newly enrolled participants.

The company is now planning to enroll about 45 patients in each of the two groups in the expansion phase. Early data from this part of the study is expected later this year.

“We look forward to advancing XMT-1536 for both ovarian cancer and NSCLC adenocarcinoma patients. Having already accumulated meaningful patient experience in the expansion cohorts, we remain on track to provide an interim update in the second quarter of 2020,” Protopapas said.

Joana holds a BSc in Biology, a MSc in Evolutionary and Developmental Biology and a PhD in Biomedical Sciences from Universidade de Lisboa, Portugal. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that made up the lining of blood vessels — found in the umbilical cord of newborns.
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José is a science news writer with a PhD in Neuroscience from Universidade of Porto, in Portugal. He has also studied Biochemistry at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario in London, Ontario, Canada. His work has ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease.
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Joana holds a BSc in Biology, a MSc in Evolutionary and Developmental Biology and a PhD in Biomedical Sciences from Universidade de Lisboa, Portugal. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that made up the lining of blood vessels — found in the umbilical cord of newborns.
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