Panagiotis A. Konstantinopoulos is the director of the Mellen and Eisenson Family Center for BRCA and Related Genes, director of Translational Research in the Division of Gynecologic Oncology, and the Velma Eisenson Endowed Chair for Clinical and Translational Research at Dana-Farber Cancer Institute, as well as a professor of medicine at Harvard Medical School.

Dr Konstantinopoulos on the Safety of Letrozole, Abemaciclib, and Metformin in ER+ Recurrent Endometrial Cancer

"We were very happy that the regimen was generally very well tolerated without any new safety signals, compared to what we have seen with previous CDK 4/6 inhibitor studies and hormonal therapy."

Panagiotis A. Konstantinopoulos, MD, PhD, director of the Mellen and Eisenson Family Center for BRCA and Related Genes, director of Translational Research in the Division of Gynecologic Oncology, and the Velma Eisenson Endowed Chair for Clinical and Translational Research at Dana-Farber Cancer Institute, as well as a professor of medicine at Harvard Medical School, discussed safety findings from the phase 2 RESOLVE trial (NCT03675893) evaluating the combination of letrozole, abemaciclib (Verzenio), and metformin in patients with estrogen receptor (ER)–positive, recurrent endometrial cancer.

 showed that the addition of metformin to the combination of letrozole and abemaciclib was feasible and well tolerated with a manageable safety profile consistent with previously reported outcomes for CDK4/6 inhibitors combined with endocrine therapy, Konstantinopoulos reported. No new or unexpected treatment-related adverse effects (TRAEs) were observed with the addition of metformin, he noted.

Among 25 patients enrolled in the trial, the most common grade 3 TRAEs were neutropenia (24%), fatigue (16%), and anemia (8%). No grade 4 or grade 5 toxicities occurred, and no patients discontinued treatment due to toxicity, Konstantinopoulos emphasized. These results suggested that the triplet regimen could be administered safely without requiring dose-limiting modifications or triggering treatment discontinuation.

Konstantinopoulos noted that these toxicity rates were comparable to prior trials, such as a phase 2 study (NCT03675893) of letrozole plus abemaciclib without metformin.

Moreover, the absence of grade 4 or higher toxicities represents a reassuring safety signal for patients with limited treatment options in the recurrent endometrial cancer setting, he concluded.

Videos

Panagiotis A. Konstantinopoulos, MD, PhD, discusses the safety of letrozole, abemaciclib, and metformin in ER-positive, recurrent endometrial cancer.

Dr Konstantinopoulos on Responses With Metformin Plus Letrozole/Abemaciclib in ER+ Endometriod Endometrial Cancer

“In total, there were 3 CRs [among 25] patients. Previously, in all CDK 4/6 inhibitor studies [in endometriod endometrial cancer], no CRs had been observed. This is the first time that we’ve seen CRs [with a CDK 4/6 inhibitor regimen in this patient population.]”

Panagiotis A. Konstantinopoulos, MD, PhD, director of the Mellen and Eisenson Family Center for BRCA and Related Genes, Director of Translational Research in the Division of Gynecologic Oncology and the Velma Eisenson Endowed Chair for Clinical and Translational Research at Dana-Farber Cancer Institute; as well as a professor of medicine at Harvard Medical School, discusses findings from the phase 2 RESOLVE study (NCT03675893) evaluating the combination of letrozole, abemaciclib (Verzenio), and metformin in patients with estrogen receptor (ER)–positive recurrent endometrioid endometrial cancer.

 and showed that the addition of metformin to the combination of letrozole and abemaciclib was feasible, well tolerated, and associated with encouraging clinical activity in 25 patients with recurrent endometrioid endometrial cancer, Konstantinopoulos reported. Notably, the triplet regimen appeared to elicit deeper responses and more durable progression-free survival (PFS) than observed previously with letrozole and abemaciclib alone, he noted. At the time of data cutoff, the objective response rate was 32%, including 3 complete responses (CRs) and 5 partial responses, Konstantinopoulos detailed. These findings mark the first reported CRs in endometrial cancer treated with a CDK4/6 inhibitor–based regimen, which were not observed in earlier CDK4/6 inhibitor studies, he emphasized.

Additionally, 7 patients achieved stable disease (SD) lasting at least 6 months, and 9 patients experienced SD of less than 6 months’ duration, Konstantinopoulos continued, adding that 1 patient had progressive disease as best response. The median PFS exceeded 19.3 months at an estimated follow-up of 27 months. The patient with the longest follow-up experienced progression at 27 months. The 6-month PFS rate was 73.8% (95% CI, 50.7%-87.3%).

These updated findings compare favorably with previous results from a prior phase 2 study (NCT03675893) of letrozole plus abemaciclib without metformin in 30 patients with ER-positive recurrent endometrial cancer, in which the median PFS was 9.1 months (95% CI, 3.5 to 16.5), Konstantinopoulos noted. In other CDK4/6 inhibitor studies in endometrial cancer, the median PFS has typically ranged from 8 to 9 months, with shorter median follow-up durations, he concluded.

Konstantinopoulos reported participating in advisory boards with AstraZeneca, GSK, Merck, Immunogen, EMD Serono, Scorpion, Schrodinger, Nimbus, and Mural Oncology; participating in scientific steering committees with AstraZeneca; participating in data monitoring committees with Gilead; and receiving institutional funding as the principal investigator from AstraZeneca, Bayer, Eli Lilly and Company, GSK, Merck, Merck KGaA, and Pfizer.

Panagiotis A. Konstantinopoulos, MD, PhD, discusses CRs achieved with letrozole, abemaciclib, and metformin in ER–positive endometriod endometrial cancer.

Panagiotis A. Konstantinopoulos, MD, PhD, director of Translational Research, Gynecologic Oncology, Dana-Farber Cancer Institute, associate professor of medicine, Harvard Medical School, discusses the role of immunotherapy in the treatment of patients with ovarian cancer.

Unlike cervical and uterine cancers where there are FDA-approved indications for pembrolizumab (Keytruda), there are not yet any approved uses for immunotherapy in ovarian cancer. With that being said, it is important to note that pembrolizumab is still a reasonable treatment strategy for the rare subset of patients whose tumors are microsatellite instability—high (MSI–H).

The incidence of MSI—H is very low in high-grade serous ovarian cancer, Konstantinopoulos explains, appearing in just 1% to 2% of cases. MSI–H is also observed in the low-grade endometrioid subtype of ovarian cancer, as well as in clear cell ovarian cancer, which is a highly aggressive and unique subtype of the disease.

In a study conducted at Dana-Farber Cancer Institute, investigators found that in 30 patients with clear cell disease, 3 of them had MSI—H tumors, which was also associated with high PD-L1 expression. There is rationale to test every patient with clear cell ovarian cancer for MSI–H using immunohistochemistry, Konstantinopoulos notes. Although these tumors are very rare, they can be matched with effective therapies.

Dr. Konstantinopoulos on Immunotherapy in Ovarian Cancer

Panagiotis A. Konstantinopoulos, MD, director, Translational Research, Gynecologic Oncology, Dana-Farber Cancer Institute, associate professor of medicine, Harvard Medical School, discusses the role of immunotherapy in the treatment of gynecologic cancers.

Although immunotherapy has not made much headway in this space overall, there are 2 types of gynecologic malignancies for which there have been FDA approved agents, namely checkpoint inhibitors. In endometrial cancer, about 28% of tumors express microsatellite instability (MSI), and a tumor agnostic has been approved by the FDA for pembrolizumab (Keytruda) for use in gynecologic cancers that express MSI. This is very applicable for patients with endometrial cancer who relapse on standard chemotherapy, Konstantinopoulos notes.

Pembrolizumab is also FDA approved for the treatment of patients with cervical cancer, specifically those who have a combined tumor proportion score of at least 1. This score takes into account PD-L1 expression in the tumor cells as well as the immune cells.

Panagiotis A. Konstantinopoulos, MD, PhD, director, Translational Research, Gynecologic Oncology, Dana-Farber Cancer Institute, associate professor of medicine, Harvard Medical School, discusses immunotherapy in gynecologic cancers.

Dr. Konstantinopoulos on Immunotherapy in Gynecologic Cancers

Panagiotis A. Konstantinopoulos, MD, PhD, director, Translational Research, Gynecologic Oncology, Dana-Farber Cancer Institute, associate professor of medicine, Harvard Medical School, discusses the combination of PARP inhibitors and immunotherapy.

Konstantinopoulos explains that PARP inhibitors can induce double-strand breaks, which can lead to activation of the immune system either through increased neoantigens or activation of the STING pathway. The STING pathway is involved in innate immunity, he adds. Additionally, PARP inhibitors can also upregulate PD-L1 through the activation of a double-strand break in ATM- and ATR-Chk1.

Immune activation as a result of PARP inhibition paired with PD-L1 overexpression provides necessary immune priming for the cancer cells to respond to immunotherapy, according to Konstantinopoulos. This was the preclinical evidence for the phase I/II TOPACIO/KEYNOTE-162 study (NCT02657889), which is evaluating the combination of the PARP inhibitor niraparib (Zejula) and the PD-1 inhibitor pembrolizumab (Keytruda) in patients with recurrent ovarian cancer.

Panagiotis A. Konstantinopoulos, MD, PhD, director, Translational Research, Gynecologic Oncology, Dana-Farber Cancer Institute, associate professor of medicine, Harvard Medical School, discusses the combination of PARP inhibitors and immunotherapy.
 

Dr. Konstantinopoulos Discusses PARP Plus Immunotherapy

Panagiotis A. Konstantinopoulos, MD, PhD, director, Translational Research, Gynecologic Oncology, Dana-Farber Cancer Institute, associate professor of medicine, Harvard Medical School, discusses the rationale behind the TOPACIO trial for the treatment of patients with recurrent ovarian cancer (ROC).

Treatment for patients with platinum-resistant or platinum-refractory ovarian cancer is an important unmet need as these patients have very limited treatment options, says Konstantinopoulos. Bevacizumab (Avastin) paired with chemotherapy is currently FDA approved for the treatment of patients who have had up to two prior lines of chemotherapy.

At the 2018 ASCO Annual Meeting, Konstantinopoulos presented data from the TOPACIO trial which focused on a difficult-to-treat patient population. The trial combined the PD-1 inhibitor pembrolizumab (Keytruda) with the PARP inhibitor niraparib (Zejula). Data indicated the immunotherapy combination resulted in a 25% objective response rate (ORR) for all patients with platinum-resistant ovarian cancer and an ORR of 45% in the subgroup with 

Panagiotis A. Konstantinopoulos, MD, PhD, director, Translational Research, Gynecologic Oncology, Dana-Farber Cancer Institute, associate professor of medicine, Harvard Medical School, discusses the rationale behind the TOPACIO trial for the treatment of patients with recurrent ovarian cancer.

Panagiotis A. Konstantinopoulos, MD, PhD

Articles

Dr Konstantinopoulos on the Safety of Letrozole, Abemaciclib, and Metformin in ER+ Recurrent Endometrial Cancer

Dr Konstantinopoulos on Responses With Metformin Plus Letrozole/Abemaciclib in ER+ Endometriod Endometrial Cancer

Dr. Konstantinopoulos on Immunotherapy in Ovarian Cancer

Dr. Konstantinopoulos on Immunotherapy in Gynecologic Cancers

Dr. Konstantinopoulos Discusses PARP Plus Immunotherapy

Dr. Konstantinopoulos on Rationale for TOPACIO Trial in Ovarian Cancer