Dr Moore on AEs Associated With ADC Treatment in Gynecologic Cancers

“We are still learning how to predict and mitigate [ADC-related toxicities] earlier so that we don’t have deaths. All of these drugs have unfortunately been compromised by deaths, mainly due to ILD, which is the toxicity that we worry most about with ADCs.”

Kathleen N. Moore, MD, MS, professor, Section of Gynecologic Oncology, associate director, Clinical Research, Stephenson Cancer Center, director, Oklahoma TSET Phase I Program, University of Oklahoma College of Medicine, The University of Oklahoma Health Sciences, discusses adverse effects (AEs) associated with the use of antibody-drug conjugates (ADCs) for the treatment of patients with gynecologic cancers.

ADCs are associated with complex toxicity profiles, primarily due to the linker technologies and conjugated toxins used in their design, Moore begins. Although target-specific toxicities occur, much of the AEs stem from how the payloads interact with cells and circulate in the body, she reports, saying that understanding these mechanisms is key to predicting and managing these AEs.

ADCs exhibit on-target, off-tumor effects, as well as off-target, off-tumor toxicities, which contribute to their unique safety concerns, Moore continues. Interstitial lung disease (ILD) is among the most concerning toxicities, she explains. Although this AE can sometimes lead to fatalities, improvements in recognition and management strategies have reduced such outcomes, Moore emphasizes. ILD often goes unrecognized due to the difficulty of interpreting subtle inflammatory changes on CT scans, especially in patients with pre-existing abnormalities, according to Moore. Historically, waxing and waning ground-glass opacities were often dismissed as benign findings, she says. However, education and awareness efforts have emphasized the importance of monitoring these findings, even in asymptomatic patients, to prevent treatment-related complications, she reiterates.

Despite progress in identifying and mitigating ILD, 2 scenarios continue to pose risks, she notes. For example, in some cases, unrecognized early ILD leads to progressive and fatal outcomes, she references. In others, certain patients experience rapid-onset respiratory distress that defies rescue efforts, she notes. Ongoing research into biomarkers aims to identify patients at higher risk for developing severe ILD, she explains. Surveillance protocols and intervention strategies, detailed in recent publications, play an essential role in mitigating these risks and improving patient outcomes, Moore concludes.

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Kathleen N. Moore, MD, MS, discusses adverse effects associated with the use of antibody-drug conjugates for the treatment of gynecologic cancers.

Kathleen N. Moore, MD, MS, associate director, Clinical Research, the Stephenson Cancer Center, director, Oklahoma TSET Phase I Program, professor, Section of Gynecologic Oncology, The University of Oklahoma College of Medicine, discusses the eligibility criteria for the ongoing, first-in-human, phase 1/2 study (NCT03564340) of ubamatamab (REGN4018), a MUC16- and CD3-targeted bispecific antibody, alone or in combination with cemiplimab-rwlc (Libtayo) in patients with recurrent ovarian cancer.

Patients who are eligible for the current trial investigating ubamatamab must have recurrent ovarian cancer, which must be classified as resistant to platinum, Moore says, adding that patients should have had recurrence within 6 months of the date of their last platinum treatment. Moreover, patients’ tumors must be measurable by RECIST v1.1 criteria, as response rate is one of the primary end points investigators will consider, Moore adds. Patients’ cancer antigen 125 plasma levels need to be at least 2 times the upper limit of normal (ULN) because the MUC16 protein has an extracellular tail of cancer antigen 125, which is why these levels are used as biomarkers of response to chemotherapy. Selecting for this elevated marker ensures that the patients enrolled in the study have cancer that expresses MUC16, Moore explains.

In the future, MUC16 may be detected on tumor specimens, and this translational work is ongoing among investigators, Moore continues. However, for now, cancer antigen 125 markers at least 2 times the ULN arerequired to indicate MUC16 expression in patients enrolling in this phase 1/2 trial, Moore says.

All other eligibility criteria are similar to those of most other studies in platinum-resistant ovarian cancer, Moore expands. Patients must have a generally good performance status, and their labwork results need to be within normal limits, she explains. Additionally, patients must have recovered from the adverse effects of other treatments, not including alopecia and low-grade neuropathy, prior to enrolling in this clinical trial, Moore concludes.

Kathleen N. Moore, MD, MS, discusses the eligibility criteria for the ongoing, first-in-human, phase 1/2 study of ubamatamab, a MUC16- and CD3-targeted bispecific antibody, alone or in combination with cemiplimab in patients with recurrent ovarian cancer.


Dr Moore on the Phase 1/2 Study Investigating Ubamatamab in Ovarian Cancer

Kathleen Moore, MD, director, Oklahoma TSET Phase I Clinical Trials Program, associate director, Clinical Research, medical director, the Clinical Trials Office, associate professor, Section of Gynecologic Oncology, Jim and Christy Everest Endowed chair, Cancer Research, director, the Gynecologic Oncology Fellowship Program, Stephenson Cancer Center, discusses current standard of care in treating ovarian cancer.

The requirement for testing or offering testing for germline, somatic 

 mutations, and other high-penetrance genes, has emerged as part of the standard of care in ovarian cancer, Moore says. This testing assists in identifying familial risk to prevent cancer in unaffected family members, along with stratifying patients for prognosis and maintenance therapy with PARP inhibitors, Moore explains. However, some patients may decline that testing when offered, Moore adds.

Moreover, patients can utilize tumor testing for homologous recombination deficiency, Moore continues. Two tests are currently FDA-approved, and others are in development, Moore adds. These tests seek to identify tumors that have an inherent vulnerability to their ability to repair double-stranded DNA breaks, which make them susceptible to platinum-based chemotherapy and PARP inhibitors, Moore concludes.

Kathleen Moore, MD, discusses current standard of care in treating ovarian cancer.


Dr. Moore on BCMA-Mutation Testing in Ovarian Cancer

Kathleen N. Moore, MD, associate director for clinical research, gynecologic oncologist at The Stephenson Cancer Center, The University of Oklahoma, explores the impact of the SOLO-1 trial in the field of ovarian cancer, in particular, the benefits olaparib (Lynparza) provides and the light it shines on the importance of using genetic testing to inform treatment decisions.

In the phase III SOLO-1 trial, treatment with olaparib led to a 70% reduction in the risk of disease progression or death in patients with 

-mutant advanced ovarian cancer who were in complete or partial response to platinum-based chemotherapy (HR, 0.30; 95% CI, 0.23-0.41; 

 <.0001) versus placebo following platinum-based chemotherapy.

The impact of the SOLO-1 trial is still being felt internationally, Moore explains, as the efficacy with olaparib was above and beyond what was expected in this patient population. The median progression-free survival with olaparib was not reached at a median 41-month follow-up.

It has been known that all patients with ovarian cancer should be offered genetic testing, and should be beyond germline 

 mutations. However, following these findings, there is a push for patients to have this testing much earlier, she adds.

Research is ongoing that is reflecting the challenges of how physicians should test for germline or somatic 

 mutations, what sort of test should be conducted, and what is done first. Globally, Moore says, the challenges to testing are even greater outside of the United States. The impact of SOLO-1 is first and foremost, to the efficacy with olaparib, but secondly, it will push physicians to standardize testing, she concludes.

Based on the SOLO-1 findings, the FDA approved olaparib as a maintenance treatment for patients with deleterious or suspected deleterious germline or somatic 

-mutated advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to frontline platinum-based chemotherapy, as approved by an FDA-approved companion diagnostic assay, in December 2018.

Kathleen N. Moore, MD, associate director for clinical research, gynecologic oncologist at The Stephenson Cancer Center, The University of Oklahoma, explores the impact of the SOLO-1 trial in the field of ovarian cancer, in particular, the benefits olaparib provides and the light it shines on the importance of using genetic testing to inform treatment decisions.

Dr. Moore on the Impact of the SOLO-1 Trial in Ovarian Cancer

Kathleen N. Moore, MD, assistant professor, Stephenson Cancer Center, The University of Oklahoma, discusses challenges with immunotherapy agents in the treatment of patients with ovarian cancer.

Overall, immunotherapy is well tolerated. However, there are significant toxicities that occur that providers need to be mindful of because they differ from other targeted agents, says Moore. There are ongoing studies with immune checkpoint inhibitors, which should inform physicians on how to meet the safety bar. It is important to manage the safety for patients, which is true across all solid tumors.

The biggest challenge is identifying whether this a class of drugs that belongs in the treatment paradigm. Physicians are using PD-1/PD-L1 and CTLA-4 inhibitors, but there is a pipeline of agents that are not checkpoint modulators. There are even different ways to target different parts of the immune system. According to Moore, checkpoint inhibitors may not be the way that physicians should be targeting ovarian cancer for immune response, but there could be other effective ways to do it.

Dr. Moore on Challenges With Immunotherapy in Ovarian Cancer

Kathleen N. Moore, MD, assistant professor, Stephenson Cancer Center, The University of Oklahoma, discusses combinations in the treatment of patients with ovarian cancer.

There is a lot of basic and translational science that supports the use of combinations of immunotherapy and VEGF inhibitors, says Moore. VEGF is a proangiogenic molecule, but it is immuno-suppressive, so it directly and indirectly inhibits the immune response to cancer, Moore says. Combining a VEGF-targeted agent with an anti—PD-1/PD-L1 agent may prevent the tumor from evading immune response.

Additionally, there are several combinations that are of interest in ovarian cancer and other solid tumors. These combinations include immune agents plus antiangiogenic agents, PARP inhibitors or other DNA-damaged response inhibitors, cytotoxic chemotherapy, and immune agents in combinations with other immune agents. Moore says that investigators are capitalizing on different aspects of the immune system with these combinations.

Kathleen N. Moore, MD, assistant professor, The Stephenson Cancer Center, The University of Oklahoma, discusses combinations in the treatment of patients with ovarian cancer.
 

Dr. Moore Discusses Combinations in Ovarian Cancer

Kathleen N. Moore, MD, assistant professor, The Stephenson Cancer Center, The University of Oklahoma, discusses combinations of immunotherapy with PARP inhibitors for patients with 

There is evidence for combining PARP inhibitors with immune agents in patients with 

 mutations, explains Moore. In ovarian cancer, there is a lot of inherent DNA damage-response abnormalities that result in mutations that could be neoantigens. Hopefully, 50% or more of patients will respond to the use of a PARP inhibitor that will increase the neoantigen load and then bring in an immune checkpoint inhibitor, says Moore.

There are many ongoing trials investigating this. For example, the TOPACIO/KEYNOTE-162 trial investigating niriparib (Zejula) plus pembrolizumab (Keytruda) in breast and ovarian cancer in 

-mutated patients. That trial has only been presented in abstract form thus far, but has shown efficacy. There are planned studies in frontline ovarian cancer looking at combinations of PARP inhibitors and immunotherapy.

Kathleen N. Moore, MD, assistant professor, The Stephenson Cancer Center, The University of Oklahoma, discusses combinations of immunotherapy with PARP inhibitors for patients with BRCA-mutated ovarian cancer.

Kathleen N. Moore, MD

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