October 2020 Edition Vol.11, Issue 10

Five High Profile Trials at ESMO Are Game-Changers

By Ted Bosworth

Five large phase 3 studies presented during the ESMO Virtual Congress 2020 are practice-changing, according to the authors, independent experts, or both.

ASCENT Trial: OS Benefit for Targeted Drug in Metastatic Triple Negative Breast Cancer

The antibody-drug conjugate sacituzumab govitecan provided an overall survival (OS) benefit over standard chemotherapy for patients with advanced metastatic triple-negative breast cancer (TNBC), according to results of the phase 3 ASCENT trial (LBA17). The components of the first-in-class sacituzumab govitecan involve an antibody targeted at Trop2 and an active metabolite of irinotecan called SN-38 that damages the DNA of tumor cells when delivered intracellularly.

The improvement in progression-free survival (PFS), which was the primary endpoint, as well as the large OS benefit “confirms the use of sacituzumab govitecan as a standard therapy for patients with pretreated metastatic triple-negative breast cancer,” reported Aditya Bardia, MD, an assistant professor of medicine at Harvard Medical School, Boston.

In ASCENT, 529 metastatic TNBC patients who had received at least two prior lines of chemotherapy were randomized to sacituzumab govitecan or a physician’s choice of single-agent chemotherapy that included capecitabine, eribulin, vinorelbine, or gemcitabine. Sacituzumab govitecan (10 mg/kg) was delivered intravenously on days 1 and 8 of a 21-day cycle.

PFS was 5.6 months among patients randomized to sacituzumab govitecan versus 1.7 months in those receiving single-agent chemotherapy. By hazard ratio (HR), this represented a 59% relative improvement in this outcome for the antibody-drug conjugate (HR 0.41; P<0.0001). The median OS was almost doubled (12.1 vs. 6.87 months), which was also highly significant (HR 0.48; P<0.0001). The objective response rates (ORR) were 35% and 5% for the experimental and control arms, respectively.

Toxicity was greater in the experimental arm. Grade 3 or higher adverse events that occurred more commonly on sacituzumab govitecan included neutropenia (51% vs. 33%) diarrhea (10.5% vs. <1%), leukopenia (10% vs. 5%), and febrile neutropenia (6% vs. 2%). No treatment-related deaths in either arm were reported.

This is the first time that an OS benefit has been seen over standard chemotherapy, according to Dr. Bardia, who emphasized the very limited treatment options in this disease. Many of the patients were heavily pretreated. About 10% had brain metastases at entry. Outcome data were not presented separately for those with and without brain metastases, but Dr. Bardia said the PFS advantage for sacituzumab govitecan was similar in this subgroup.

Dr. Bardia comments on the practice-changing potential of the ASCENT study data:

monarchE Trial: DFS Benefit with CDK4/6 Inhibitor in High-Risk HR+/HER2- Breast Cancer

The CDK 4/6 inhibitor abemaciclib reduces the risk of recurrence when combined with endocrine therapy in adjuvant treatment of early but high-risk breast cancer, according to results of the phase 3 monarchE trial (LBA5). While most patients with early HR+HER2- breast cancer are cured with front-line therapy, this approach has the potential to improve cure rates in the subset of high risk patients who now relapse.

The significant protection in invasive disease-free survival (IDFS), which was the primary endpoint of monarchE, is the first advance in adjuvant therapy for early HR+/HER- breast cancer “in more than 20 years” and appears to be a new standard of treatment for patients with high-risk features, according to Stephen Johnston, MD, professor of breast cancer medicine, Royal Marsden HS Foundation Trust, London, UK.

In monarchE, 5,367 patients with early but high-risk HR+/HER2- breast cancer were randomized to receive oral abemaciclib in a twice-daily 150 mg dose for two years plus endocrine therapy or endocrine therapy alone. Patients were eligible and defined as high risk if they had four or more positive nodes or one to three positive nodes with a tumor of 5 cm or greater, histologic grade of 3, or central Ki-67 of 20% or greater. Ki-67 expression is a measure of propensity for tumor cell proliferation.

At two years, the higher rate of IDFS in the abemaciclib arm (92.2% vs. 88.7%) translated into a 25% lower risk (HR 0.747; P=0.0096) of recurrence. For abemaciclib there was a nearly 30% advantage for the distant relapse-free survival, which was a secondary endpoint (HR 0.717). The p value was not provided, but the 95% confidence intervals showed statistical significance (95% CI, 0.599 – 0.920).

The side effects of abemaciclib in the adjuvant setting were similar to the prior experience with this drug in advanced HR+HER2- for which it already has an indication. Specifically, 82% of patients on abemaciclib experience diarrhea of which 7.6% was grade 3 or higher. Diarrhea of grade 3 or higher was seen inly 0.1% of controls. Neutropenia and fatigue were also more common among those who received abemaciclib than endocrine therapy alone.

There was a trend for a greater risk of relatively uncommon adverse events in the abemaciclib-treated patients, including venous thromboembolism (2.5% vs. 0.5%) and interstitial lung disease (2.7% vs. 1.2%). Conversely, the addition of abemaciclib resulted in a lower incidence of arthralgia and hot flush relative to endocrine therapy alone, according to Dr. Johnston.

HR+/HER- breast cancer is the commonest subtype with a high rate of cure when diagnosed early. There has been an unmet need to improve therapies in patients with high-risk features, according to Giuseppe Curigliano, MD, associate professor of medical oncology, University of Milan, Italy.

“This is a very important trial and the findings will change practice,” Dr. Curigliano said.

Erika Hamilton, MD, Sarah Cannon Research Institute, considers the impact of the monarchE trial:

PROfound Trial: OS Benefit for PARP Inhibitor in Metastatic Prostate Cancer

Relative to a physician’s choice of enzalutamide or abiraterone, the PARP inhibitor olaparib improves OS in men with metastatic castration-resistant prostate cancer (mCRPC) who have mutations in genes involved in homologous recombination repair (HRR), according to results of the phase 3 PROfound trial (Abstract 6100). The presence of any of 15 such genes permitted enrollment in the PROfound trial, but most patients had mutations in the BRCA1, BRCA2, or the ATM genes.

PROfound is the “first randomized trial to prospectively demonstrate an OS improvement” in mCRPC patients with DNA repair gene mutations and “can now be considered a standard” in these patients, according to Joaquin Mateo, MD, PhD, Prostate Cancer Translational Research Group. Vall d’Hebron Institute of Oncology, Barcelona, Spain.

In PROfound, 387 mCRPC patients who had progressed on a prior hormonal agent were randomized in a 2:1 ratio to receive daily oral olaparib or a physician’s choice of enzalutamide or abiraterone. Data were assessed in two cohorts. One cohort of 256 patients had mutations in BRCA1, BRCA2, or ATM genes. The remaining 142 patients had a mutation in at least one of 12 other genes, such as Bripo1, CHEK1, or RAD51B, that are known to be involved directly or indirectly in regulating HRR.

The significant improvement in PFS among those randomized to olaparib was reported at the ESMO Congress 2019. Now, with longer followup, the OS benefit has become significant in cohort A (HR 0.69; P=0.0175) and has reached borderline significance in the overall population that combines cohorts A and B (HR 0.79; P=0.0515). This advantage was achieved despite a study design that permitted patients in the control arm to crossover to olaparib at radiographic progression. Sixty-six percent did so.

Based on these data, the FDA has already granted an indication for olaparib for patients with HRR gene-mutated mCRPC who have progressed following enzalutamide or abiraterone treatment.

Maha Hussain, MD, of Lurie Comprehensive Cancer Center, Northwestern Medicine, provides perspective on the PROfound phase 3 data:

CheckMate 9ER Trial: OS Benefit for Nivolumab plus TKI in Advanced Renal Cell Carcinoma

The combination of the CPI nivolumab and the tyrosine kinase inhibitor (TKI) cabozantinib improved overall survival relative to sunitinib in the first-line treatment of advanced renal cell carcinoma (aRCC), according to results of the CheckMate 9ER trial (Abstract 6960). This benefit, as well as improvement in PFS, was consistent across multiple subgroup stratifications.

The evidence of an OS benefit over the previous standard “support this combination as a new option for advanced renal cell carcinoma patients,” reported Toni K. Choueri, MD, Director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston.

In CheckMate 9ER, 651 patients with aRCC were randomized. Nivolumab was administered in a flat dose of 240 mg every two weeks. The oral TKIs, taken daily, and the CPI were administered until disease progression, unacceptable toxicity, or, in the case of the CPI, for two years.

With a median followup of 18.1 months, the combination of nivolumab and cabozantinib doubled the PFS relative to sunitinib (16.6 vs. 8.3 months), providing a highly significant advantage (HR 0.51; P<0001). The advantage of the combination for OS, a secondary endpoint, was nearly as great and also highly significant (HR0.60; P<0.001). Other outcomes, such as ORR (55.7% vs. 27.1%) also supported the greater activity of the combination. The median durations or response for the combination and for sunitinib were 20.2 and 11.5 months, respectively.

Grade 3 or higher adverse events occurred more frequently on the combination than single-agent sunitinib (60.6% vs. 50.9%). Treatment discontinuations as a result of adverse events were reported in 15.3% of those on the combination versus 8.8% of those randomized to sunitinib. There was one treatment-related death attributed to the combination and two to sunitinib.

Both nivolumab and cabozantinib have demonstrated activity as monotherapies in aRCC. The potential of the immunomodulatory properties of cabozantinib to enhance the efficacy of nivolumab provided a rationale for the combination, according to Dr. Choueri.

The followup of this trial “is still quite short,” and other combinations, including CPI and an anti-angiogenic agent, have also shown an OS advantage over sunitinib alone, according to Dominik Berthold, MD, Department of Oncology, Lausanne University Hospital, Switzerland.

As a result, he said there is not yet a consensus about which combination is best in aRCC even if the current evidence does suggest combination therapies are superior to the previous standard of sunitinib alone. Nonetheless, he said this combination of nivolumab and cabozantinib “can be considered a new first-line treatment option” in aRCC.

Eleni Efstathiou, MD, PhD, of MD Anderson Cancer Center, discusses the CheckMate 9ER clinical trial:

KEYNOTE 590 Trial: OS Benefit Provided by CPI Plus Chemotherapy in Esophageal Cancer

The combination of the CPI pembrolizumab plus cisplatin and 5-fluorouracil provide an OS advantage over chemotherapy alone in patients with advanced esophageal cancer, according to results of the KEYNOTE 590 trial (Abstract LBA8). Patients were eligible if they had locally advanced unresectable or metastatic esophageal adenocarcinoma or squamous cell carcinoma (ESCC) or Siewert type 1 esophagogastric unction adenocarcinoma (EGJ).

“Pembrolizumab plus chemotherapy should be a new standard of care as first-line therapy in patients with locally advanced unresectable or metastatic esophageal cancer, including cancer of the gastroesophageal junction,” reported Peter Enzinger, MD, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston.

In KEYNOTE 590, 749 treatment-naïve patients with ESCC (73%) or EGJ (27%) were randomized to pembrolizumab plus chemotherapy or chemotherapy alone. Pembrolizumab (or placebo) was administered every three weeks. Cisplatin in a dose of 80 mg/m2 was administered on the first day and 5-FU in a dose of 800 mg/m2 was administered on days one to five of an every-three-week schedule. Treatment was continued until progression, unacceptable toxicity, or a maximum of two years.

After a median followup of 10.8 months, the addition of pembrolizumab provided an OS advantage (HR 0.73; P<0.0001) regardless of histology. The advantage was greater in ESCC patients with a relatively elevated score of PD-L1 expression, defined as a combined positive score (CPS) ≥10 (HR 0.62; P0.0001). There was a median PFS advantage for the whole population (HR 0.65; P0.0001) that was also greater in patients with CPS ≥10 (HR 0.51; P<0.0001). The ORR rates, favoring the addition of pembrolizumab, were 45.0% versus 29.3% (P<0.0001).

Adverse events were similar, according to Dr. Enzinger. The rates of grade 3 or greater adverse events were 71.9% in the group receiving pembrolizumab versus 67.5% in those receiving chemotherapy alone. There were no major differences in individual toxicities, but discontinuation for drug-related adverse events was higher in the pembrolizumab arm (19% vs. 12%).

Despite the greater advantage in patients with tumors showing elevated PD-L1 expression, the advantage of adding pembrolizumab to chemotherapy was observed “regardless of biomarker status,” according to Dr. Enzinger. The benefit, which was similar in ESCC and EGJ patients, was also observed across histologies.

Geoffrey Y. Ku, MD, Memorial Sloan Cancer Center, talks about treating squamous cell carcinoma versus adenocarcinoma of the esophagus and the KEYNOTE 590 data:

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