publication date: Apr. 24, 2020

Clinical Roundup

Phase III CheckMate-743 study of Opdivo and Yervoy meets primary OS endpoint in mesothelioma

CheckMate -743, a phase III trial evaluating Opdivo (nivolumab) in combination with Yervoy  (ipilimumab) in previously untreated malignant pleural mesothelioma met its primary endpoint of overall survival.

Bristol-Myers Squibb sponsors both drugs.

Based on a prespecified interim analysis conducted by the independent data monitoring committee, Opdivo in combination with Yervoy resulted in a statistically significant and clinically meaningful improvement in OS compared to chemotherapy (pemetrexed and cisplatin or carboplatin).

The safety profile of Opdivo plus Yervoy observed in the trial reflects the known safety profile of the combination.

“These topline results from the CheckMate-743 trial demonstrate the potential of Opdivo plus Yervoy in previously untreated patients with malignant pleural mesothelioma, and is another example of the established efficacy and safety of the dual immunotherapy combination seen in multiple tumor types,” Sabine Maier, development lead of Thoracic Cancers at BMS, said in a statement.

CheckMate-743 is an open-label, multi-center, randomized phase III trial evaluating Opdivo plus Yervoy compared to chemotherapy (pemetrexed and cisplatin or carboplatin) in patients with previously untreated malignant pleural mesothelioma. The primary endpoint of the trial was OS. Secondary endpoints included objective response rate, disease control rate, progression-free survival, and efficacy measures according to PD-L1 expression level.


Phase III CheckMate -9ER meets primary PFS endpoint in RCC

The phase III CheckMate-9ER trial evaluating Opdivo (nivolumab) in combination with Cabometyx (cabozantinib) compared to sunitinib in previously untreated advanced or metastatic renal cell carcinoma met its primary endpoint of progression-free survival at final analysis.

CheckMate-9ER has also met secondary endpoints of overall survival at a prespecified interim analysis, and objective response rate.

Opdivo is sponsored by Bristol-Myers Squibb, and Cabometyx is sponsored by Exelixis. The trial is sponsored by BMS and Ono Pharmaceutical Co. and co-funded by Exelixis, Ipsen and Takeda Pharmaceutical Company Ltd.

CheckMate-9ER is an open-label, randomized, multi-national phase III trial evaluating patients with previously untreated advanced or metastatic renal cell carcinoma. Patients are randomized 1:1 to Opdivo and Cabometyx or sunitinib. The primary endpoint is progression-free survival. Secondary endpoints include overall survival and objective response rate. The primary efficacy analysis is comparing the doublet combination versus sunitinib in all randomized patients.

The safety profiles of Opdivo and Cabometyx observed in the trial reflect the known safety profiles of the immunotherapy and tyrosine kinase inhibitor components in first-line RCC.

“The results from the pivotal CheckMate-9ER trial clearly demonstrate the combination of cabozantinib plus nivolumab provides a clinically meaningful benefit in the key efficacy measures of progression-free survival and overall survival for previously untreated kidney cancer patients,” Toni Choueiri, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute and Jerome and Nancy Kohlberg Professor of Medicine at Harvard Medical School, said in a statement.


New targeted agent produces responses in trial with patients with uterine serous carcinoma

In its first clinical trial in patients with a hard-to-treat form of uterine cancer, a targeted drug that subjects tumor cells to staggering levels of DNA damage caused tumors to shrink in nearly one-third of patients, investigators at Dana-Farber Cancer Institute report.

The preliminary results, presented online April 23 at the virtual session of the Society for Gynecologic Oncology Annual Meeting on Women’s Cancer, demonstrated strong activity of WEE1-directed therapy in uterine serous carcinoma (USC), which accounts for about 10% of uterine cancers but up to 40% of deaths from the disease, trial leaders say.

The drug tested in the study—adavosertib—takes advantage of an inherent weakness in the relentless growth of some cancer cells. Their non-stop proliferation creates a condition known as replication stress, where their ability to duplicate their DNA effectively is significantly impaired.

In USC, more than 90% of cases are marked by a mutation or other abnormality in the TP53 gene, which plays a critical role in the checkpoint between the first phase of cell growth and the DNA-duplication phase. Without a working TP53 gene, cells can barrel into the DNA-duplication phase with extensive DNA damage on board.

The absence of functional TP53 places enormous strain on a checkpoint further on in the cell cycle called G2/M. Providing a final quality check, G2/M, guards the entry to mitosis, the act of dividing into two daughter cells. Hobbling G2/M by blocking one of the proteins involved in it could burden tumor cells with so much DNA damage that they cannot survive.

That is the strategy behind adavosertib, which targets a protein called WEE1 that helps regulate the G2/M checkpoint. The new trial marked the first time the drug, which has been tested in patients with other cancers, including breast and ovarian cancer, was tested in patients with USC.

The trial involved 35 patients, all of whom had previously been treated with platinum-based chemotherapy.  They took adavosertib orally on a set schedule.  At a median follow-up of 3.8 months, 10 of 34 patients who could be evaluated, had shrinkage of their tumors – a response rate of almost 30%. In some cases, the responses were exceptionally durable, with some patients still responding more than a year after undergoing treatment, study leaders say.


RVD Therapy shows substantial benefit in large myeloma study

A team of investigators from Winship Cancer Institute of Emory University has shown outstanding long term survival results for multiple myeloma patients from a 3-drug induction regimen in a study published in the Journal of Clinical Oncology

The study describes the largest cohort of patients treated with a combination of lenalidomide, bortezomib, and dexamethasone (RVD) with the longest follow up reported to date.

The study followed 1,000 consecutive patients with newly diagnosed myeloma, both transplantation-eligible and -ineligible, who were treated with RVD induction therapy from January 2007 until August 2016.

“Looking at a large cohort of patients over a long period of time, we were able to provide a more comprehensive picture of the overall treatment course with RVD as induction therapy,” senior author and Winship hematologist, Ajay K. Nooka, said in a statement..  “We have seen our patients attain excellent results from RVD, so it’s gratifying to corroborate those results in this study.”

The study describes the RVD induction regimen as part of the significant therapeutic advances in myeloma over the past few decades that have led to an improved survival benefit for patients.

“Our study demonstrates not only the efficacy of the RVD induction regimen in attaining deep responses, but also the benefit of risk-stratified and continuous maintenance therapy in positively impacting long-term survival,” first author and Winship hematologist Nisha S. Joseph, said in a statement.

The study’s outcomes are based on genetic risk at diagnosis, progression-free survival, overall survival, and the impact of genetics on the quality and depth of response. African American patients made up 35.2% of study participants, which is consistent with the demographics of the myeloma population served by Winship.

“Large data sets like ours with 352 African-American patients receiving uniform therapy help to reassure that AA patients derive a similar benefit as their white counterparts if offered the same therapeutic care,” Nooka and Joseph said.


Cue Biopharma and Merck to evaluate CUE-101 + Keytruda in head and neck indication

Cue Biopharma Inc. and Merck are evaluating the combination of Cue Biopharma’s investigational product candidate CUE-101, a first-in-class biologic, with Merck’s Keytruda in patients with advanced head and neck cancer.

Cue Biopharma is a clinical-stage biopharmaceutical company engineering a novel class of injectable biologics to selectively engage and modulate targeted T cells within the body.

Under the terms of the agreement, Cue Biopharma will conduct a phase I study, KEYNOTE-A78, evaluating CUE-101 in combination with Kekytruda in first-line HPV+ advanced head and neck cancer.

KEYNOTE-A78 will be conducted alongside the ongoing phase I monotherapy study of CUE-101 post first-line treatment. The early monotherapy PK data from the first two dosing cohorts demonstrates dose-related drug exposure consistent with preclinical modeling. Subsequent to the respective dose escalations, expansion cohorts evaluating CUE-101 as a monotherapy and in combination with Keytruda will be conducted at optimized dosing regimens.

“Through the monotherapy and combination studies, we believe we will be able to demonstrate the mechanistic advantages of our approach and platform for modulating disease-relevant T cells directly in the patient’s body to safely enhance efficacy over current standards of care,” Daniel Passeri, chief executive officer of Cue Biopharma, said in a statement.

“Based on a novel mechanism of action designed to induce and expand tumor-specific T cells in the patient’s body, we believe CUE-101 may lead to enhanced anti-tumor activity in combination with KEYTRUDA,” Ken Pienta, acting chief medical officer of Cue Biopharma, said in a statement.

CUE-101 is a fusion protein comprised of a human leukocyte antigen complex, an HPV16 E7 peptide epitope, reduced affinity human interleukin-2 molecules, and an effector attenuated human immunoglobulin G (IgG1) Fc domain. In preclinical studies, CUE-101 has demonstrated selective induction and expansion of HPV16 E7-specific cytotoxic T cells with both in vitro and in vivo evidence supporting its potential for clinical efficacy both as a monotherapy and in combination with anti-PD1 checkpoint blockade.

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