June 2019 Edition Vol.11, Issue 6

Four Big Trials at ASCO Yield Practice-Changing Data

By Ted Bosworth

For subsets of patients with pancreatic cancer, head-and-neck cancer, urothelial cancer, or prostate cancer, new data from the 2019 annual meeting of the American Society of Clinical Oncology (ASCO) have redefined optimal therapy.

Patients with Pancreatic Cancer

The change in the standard of care for patients with pancreatic cancer involves those with a germline BRCA1 or 2 mutation. For these individuals, olaparib maintenance therapy following standard chemotherapy doubled the progression-free survival (PFS). Although an improvement on overall survival (OS) has not yet been shown, the median duration of response has already surpassed expected survival, making an OS benefit an almost certain result of additional follow up.

Based on benefit observed in patients with BRCA mutations, the data from the trial indicate that all patients with pancreatic cancer undergo blood testing for this marker, which is not now standard practice. Although only identified in 4% to 7% of patients, the presence of these mutations predict a median 24.9-month duration of response on olaparib, or approximately double that of the expected survival in those not treated.

“I am quite sure this will change the face of treatment,” said the principal investigator Hedy L. Kindler, MD, associate vice chair for clinical research, University of Chicago, Chicago, Illinois. An expert discussant invited by ASCO to comment, Suzanne Cole, MD, director of the Simmons Cancer Clinic, UT Southwestern Medical Center, Richardson/Plano, Texas, agreed. She called these data “a fantastic step forward.”

In this multicenter trial, called POLO, 154 patients with metastatic pancreatic cancer and a confirmed germline BRCA1 or 2 mutation were eligible for enrollment if they had received at least 16 weeks of first-line platinum-based chemotherapy (ASCO Abstract LBA4). They were randomized in a 3:2 ratio to receive maintenance therapy with the PARP inhibitor olaparib, an oral therapy given twice daily, or placebo until progression or unacceptable toxicity.

Median PFS, which was the primary endpoint, was 3.8 months for those randomized to placebo and 7.4 months for those randomized to olaparib, producing a 47% reduction in progression or death (HR 0.53; P=0.0038) (Figure 1). According to Dr. Kindler, there was no difference in health-related quality of life for those receiving olaparib relative to placebo, another reason cited for introducing this as a new standard of care in patients with germline BRCA mutations.

Immunotherapy for Advanced Head and Neck Cancer

In patients with recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC), pembrolizumab alone or in combination with chemotherapy should be considered a new first-line choice based on results of the KEYNOTE-048 trial (ASCO abstract 6000).

“For the majority of these patients, pembrolizumab or pembrolizumab combined with chemotherapy represent a new standard of care,” reported Danny Rischin, MD, Head, Department of Medical Oncology, Peter McCallum Cancer Centre, Melbourne, Australia.

In KEYNOTE-048, 882 R/M HNSCC patients with no previous systemic therapy in the R/M setting were randomized in a 1:1:1 ratio to pembrolizumab monotherapy administered every three weeks for up to 35 cycles, to the same regimen of pembrolizumab administered with six cycles of carboplatin or cisplatin with 5-FU, or to EXTREME, a standard chemotherapy regimen for R/M HNSCC consisting of cetuximab carboplatin, and 5-FU.

PD-L1 expression, evaluated by comparing patients with a Combined Positive Score (CPS) of greater than 20, greater than 1, and less than one, was a preplanned stratification. Eighty-five percent had a CPS score of 1 or greater and 43% had a score of 20 or greater.

Pembrolizumab plus chemotherapy was superior to EXTREME for OS for the total population without regard to CPS score (HR 0.77; P=0.0034).

Pembrolizumab did not show superiority to EXTREME for OS prior to stratification by CPS score. Rather, it was non-inferior. However, it was superior to EXTREME for those with CPS scores of 1 or greater (HR 0.78; P=0.0086) or for scores of 20 or greater (HR 0.61; P=0.0007). Based on these results, the authors concluded that PD-L1 expression should be measured in order to guide the decision to consider pembrolizumab alone or in combination with chemotherapy.

Grade 3 or higher adverse events were lower on pembrolizumab monotherapy (54.7%) compared with pembrolizumab plus chemotherapy (85.1%) or to EXTREME (83.3%)

Although Dan P. Zandberg, MD, Director of the head and neck cancer disease section at the Hillman Cancer Center, University of Pittsburgh, is among experts who agreed that the results of KEYNOTE-048 change the standard of care, he believes testing for the PD-L1 biomarker should be required for guiding the use of immunotherapy in this population.

Urothelial Cancer

In the phase 2 EV-201 trial, enfortumab vedotin, a novel monoclonal antibody that is not yet approved, produced a median OS of 11.7 months in locally advanced or metastatic urothelial cancer that had advanced after treatment with a platinum-based therapy and a checkpoint inhibitor. There was no control group, but the OS was impressive in a setting where there are no approved treatment options.

If granted accelerated approval, enfortumab vedotin “has the potential to become a new standard of care in the third-line setting for advanced and metastatic urothelial carcinoma,” reported Daniel P. Petrylak, MD, professor of urology, Yale School of Medicine, New Haven, Connecticut.

Results were presented from the first of two cohorts in the EV-201 trial. In a second on-going cohort, enfortumab vedotin is being tested in patients previously treated with a checkpoint inhibitor but who are platinum naïve and cisplatin ineligible.

The objective response rate in this first cohort, of which 90% had metastatic disease, was 44% with a complete response rate of 12%. An objective response of 38% was seen in liver metastases. The median PFS was 5.8 months and the median duration of response was 7.6 months.

The drug had a manageable side effect profile with low rates of grade 3 or higher adverse events, according to Dr. Petrylak, who reported a 12% discontinuation rate for toxicity.

The ASCO-invited expert, Andrea Nicchi, MD, Istituto Nazionale dei Tumori, Milan, Italy, agreed that enfortumab vedotin is “the next-in-line standard of care” for metastatic urothelial cancer. Although he said other drugs in development, such as sacituzumab govitecan, are also promising in this setting, he considers these data the most impressive so far in a challenging disease.

Anti-Androgen Therapies Moved Forward in Metastatic Prostate Cancer

In patients with metastatic hormone sensitive prostate cancer (mHSPC) two large trials demonstrated that adding on a new generation androgen receptor (AR) blocker to testosterone suppression improves OS. The results of these trials, using different agents from the same drug class, are considered mutually reinforcing.

In the multinational ENZAMET trial, 1125 mHSPC patients on testosterone suppression were randomized to receive a first-generation nonsteroidal androgen antagonist (NSAA), such as bicalutamide or flutamide, or the anti-androgen therapy enzalutamide (ASCO Abstract LBA2). Concurrent docetaxel was allowed and patients were stratified by high versus low volume of disease.

At three years 80% of those randomized to enzalutamide versus 72% of those in the control group were alive, (HR 0.67; P=0.002), reported Christopher Sweeney, MBBS, Dana-Farber Cancer Center, Boston (Figure 2). Enzalutamide was also associated with superior PFS (HR 0.39; P<0.001) and time to clinical progression (HR 0.40; P<0.001).

The OS benefit of enzalutamide was concentrated in the subgroup not taking docetaxel (OR 0.53). In the 45% of the study patients who were taking docetaxel, the small numerical OS improvement (OR 0.90) did not reach statistical significance. The advantage of enzalutamide was similar in those with low- and high-volume disease.

In the TITAN trial, 525 mHSPC patients on androgen deprivation therapy were randomized to receive the anti-androgen therapy apalutamide or placebo (ASCO abstract 5006). When compared at an interim analysis, there was a large advantage for apalutamide for the co-primary endpoints of radiographic progression-free survival (HR 0.48; P<0.0001) and OS (HR0.67; P=0.0053).

This benefit was considered sufficiently compelling that the TITAN data monitoring committee recommended unblinding the trial to allow placebo patients to crossover, reported Kim N. Chi, MD, BC Cancer Agency, Vancouver, Canada.

“With two large study showing similar results with next-generation androgen receptor inhibitors, this increases my confidence that earlier introduction of these drugs is warranted,” reported ASCO-invited expert Neeraj Agarwal, MD, Huntsman Cancer Institute, University of Utah, Salt Lake City.

Without comparative data, the choice between enzalutamide and apalutamide might best be made on the basis of the modest differences in the side effect profiles, according to Dr. Sweeney. He further suggested the timing of docetaxel is now uncertain given the lack of OS benefit among patients receiving both enzalutamide and this chemotherapy in the ENZAMET study.

 

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