February 2019 Edition Vol.11, Issue 2

Pembro Shines, Chemo Earns Praise, and a Vaccine Stumbles, All at #GI19

By Christina Bennett, MS

The 2019 Gastrointestinal Cancers Symposium featured several potentially practice-changing studies as well as some disappointing results. In particular, pembrolizumab showed clinical benefit alone and in combination with earlier lines of therapy, and neoadjuvant chemotherapy gained ground as a possible new standard of care for resectable pancreatic cancer. The cancer vaccine tecemotide, however, failed to improve survival in yet another clinical trial, leading to more questions than answers.

KEYNOTE-181: Pembro Beats Chemo in Second-Line Esophageal Cancer

Advanced esophageal cancer patients with high PD-L1–expressing disease showed better survival outcomes with pembrolizumab vs chemotherapy in the second-line setting, according to results from the phase III KEYNOTE-181 study. Pembrolizumab did not significantly extend survival for patients without PD-L1–high disease but did have less toxicity vs chemotherapy, indicating that pembrolizumab may be an option for patients with advanced esophageal cancer, regardless of PD-L1 status.

The trial included patients with advanced or metastatic adenocarcinoma or squamous-cell carcinoma (SCC) of the esophagus or Siewert type I adenocarcinoma of the esophagogastric junction who progressed on or after first-line therapy. Patients were randomly assigned to receive either pembrolizumab alone (n=314) or one of the following standard therapies at the investigator’s discretion: paclitaxel, docetaxel, or irinotecan (n=314).

The trial had 3 primary endpoints: overall survival (OS) in patients with a PD-L1 combined positive score (CPS) of at least 10, OS in patients with SCC, and OS in the intent-to-treat (ITT) population of patients.

A 3-month longer median OS was seen among the subgroup of patients with a PD-L1 CPS of a least 10 who received pembrolizumab vs patients who received chemotherapy (9.3 vs 6.7 months, respectively; HR=0.69; 95% CI, 0.52-0.93; P=0.0074).

Among patients with SCC, a median OS gain of 1 month (8.2 vs 7.1 months) was seen in the pembrolizumab arm compared with the chemotherapy arm, but lacked statistical significance. For the overall ITT population, no gain in median OS was seen (7.1 vs 7.1 months, respectively).

Treatment-related adverse events were reported by 64.3% of patients in the pembrolizumab arm compared with 86% in the chemotherapy arm. Grade 3 through 5 adverse events (AEs) were also lower in the pembrolizumab arm (18.2% vs 40.9%). The pembrolizumab arm did, however, have a higher proportion of immune-mediated and infusion reactions (23.2% vs 7.4%).

“It’s a well-done second-line study and clearly shows that in this PD-L1 CPS greater than or equal to 10 population, that there is clear benefit,” said Veena Shankaran, MD, MS, attending physician in the Gastrointestinal Medical Oncology Program at Seattle Cancer Care Alliance. She added, “I do think it’s practice-changing and should become the standard of care in that group.”

Pembro Combo Dazzles in HER2-Positive Metastatic Esophagogastric Cancer

Pembrolizumab in combination with trastuzumab and chemotherapy showed clinical benefit as a first-line treatment for HER2-positive metastatic esophagogastric cancer. The Memorial Sloan Kettering Cancer Center (MSK) phase II, single-arm trial showed clinical benefit regardless of PD-L1 status. Further study is underway in the KEYNOTE-811 trial.

The MSK phase II trial enrolled 37 patients with stage IV esophageal, gastric, or gastroesophageal junction adenocarcinoma. The primary endpoint was 6-month progression-free survival (PFS), with a target of at least 26 patients progression-free at 6 months. All patients received an induction cycle with trastuzumab and pembrolizumab followed by trastuzumab, pembrolizumab, and a chemotherapy regimen of capecitabine and oxaliplatin. Fourteen patients (40%) had a PD-L1 CPS of at least 1, while 12 (34%) had a PD-L1 CPS less than 1. This information was not available for 9 patients (26%).

Approximately half of patients (12 of 23) had a reduction in tumor size after the pembrolizumab plus trastuzumab induction cycle. Among the evaluable patients, the response rate was 87% (28 of 32), with 3 patients (9%) achieving a complete response and 25 (78%) achieving a partial response. The disease control rate was 100% (32 of 32). Median PFS was 11.4 months and 67% of patients were progression-free at 6 months. Median OS was not reached and the 12-month OS rate 76%.

“What is really impressive about this study is the response rate in the first-line setting is upwards of 80 percent, which is really unprecedented,” said Dr. Shankaran. “Also, the median progression-free survival was eleven months, which is also really unusual for this patient population.”

She added, “[It’s] just a really exciting study.”

Given the small patient population, it’s unclear at this point whether toxicity will be a concern for this combination. Nearly all patients (94%) had treatment-related adverse events, with 2 patients (6%) having a serious event and 1 (3%) discontinuing treatment as a result of treatment.

Standard of Care for Resectable Pancreatic Cancer Is Evolving

Patients with resectable pancreatic cancer who received neoadjuvant gemcitabine before surgery lived a median of 10 months longer than those who received surgery upfront. Findings from the Prep-02/JSAP-05 phase II/III clinical trial contribute to the growing evidence that neoadjuvant chemotherapy improves survival for this patient population.

The trial enrolled patients with treatment-naïve, resectable pancreatic cancer without distant metastases. Patients were randomly assigned to receive surgery upfront followed by adjuvant treatment with S-1, an oral 5-fluorouracil prodrug, for 6 months (n=182) or neoadjuvant gemcitabine followed by surgery and adjuvant treatment with S-1 (n=182).

The median OS was 36.72 months for the neoadjuvant chemotherapy arm and 26.65 months for the surgery upfront arm, with a hazard ratio of 0.72 (95% CI, 0.55 – 0.94; P=0.015). The 2-year OS rate was 63.7% for the neoadjuvant chemotherapy arm and 52.5% for the surgery upfront arm.

Nearly three-quarters of patients who received neoadjuvant gemcitabine had grade 3 (48.8%) or grade 4 (23.8%) AEs. The most common AEs were hematologic and included grade 3 leukopenia (26.7%) and neutrophilia (34.9%). The most common grade 4 event was neutrophilia (22.7%).

Currently, S-1 is not available in the United States, but the findings still have merit. “At this point what remains to be seen for those of us who practice in the United States is a similar randomized study that looks at our current standard of care, which is FOLFIRINOX or gemcitabine with nab-paclitaxel, in this same patient cohort,” said Rohit Chandwani, MD, PhD, surgical oncologist at Weill Cornell Medicine and NewYork-Presbyterian.

Cancer Vaccine Tecemotide Yields Questions, Not Answers

The randomized, double-blinded, placebo-controlled phase II LICC trial that evaluated tecemotide, a cancer vaccine, as an adjuvant treatment after metastasectomy for patients with colorectal cancer failed to meet its primary endpoint of improved survival and did not show an association between MUC1 expression and outcomes.

Tecemotide is a long-peptide vaccine that targets MUC1, a cell membrane glycoprotein that is overexpressed and aberrantly underglycosylated.

Carl Christoph Schimanski, MD, PhD, Klinikum Darmstadt, the study presenter pointed out that the OS was “unexpectedly high” in both arms; the median OS was 62.8 months for the tecemotide arm and not yet reached for the placebo arm. He offered a possible explanation, that perhaps the “careful” staging of patients and “very tight” surveillance program lead to a study population with less disease than typically seen in other studies.

About the negative trial results and lack of association between MUC1 expression and outcomes, study discussant Michael J. Overman, MD, professor of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center, said, “Whether [MUC1 is] the wrong target, or whether it was the wrong formulation in regards to cancer vaccine, I think we do not know.”

In summary, he said, “There’s many unanswered questions in regards to the LICC study, and in regards to cancer vaccines in general.”

SIDEBAR: Proteus Launches “Digital” Chemotherapy, Plans to
Expand Underway

Proteus Digital Health made a big splash at the 2019 Gastrointestinal Cancers Symposium, but not with a coveted presentation slot. Instead, a well-timed announcement: They had begun treating stage III and IV colorectal cancer patients with their “digital” capecitabine. Reportedly, this is the first time cancer patients have been treated with an oncolytic that has an imbedded sensor to track medication adherence, among other metrics. The idea is that such a medication could improve patient outcomes.

The digital medication consists of the oral chemotherapeutic itself and a sensor, which Proteus manufactures. A pharmacist must physically assemble the sensor and the chemotherapeutic into a capsule for the patient to take. The patient also wears a patch on their skin so that when the digital medication is ingested, the sensor can relay information to the patch about the time, dose, and type of oral chemotherapeutic taken.

In addition, data on a patient’s rest, activity, and resting heart rate can be gathered and, with the patient’s consent, shared with their physician, pharmacist, or caretaker. Although a patient’s activity can be tracked, a person’s geographic location cannot be. The patient can then view this information on a tablet device and the physician, pharmacist, or caretaker can intervene as necessary.

The debut of digital capecitabine is not in the form of a clinical trial, because regulatory approval is currently not needed for this type of dispensing arrangement, but instead described as a “learning launch” by a Proteus spokeswoman. The launch is being carried out with Fairview Health Services and University of Minnesota Health, which is where pharmacists assemble and patients pick up the digital capecitabine.

“I think there’s a lot of benefit,” said Paul Morales, PharmD, BCOP, Fairview Infusion Pharmacy manager at the University of Minnesota Health Clinics and Surgery Center. He explained that the regimens tend to be complex and have a lot of nuances. For example, patients may need to take three tablets in the morning and four at night or be on treatment for two weeks with a one-week break.

“It would be very helpful as far as adherence would go,” agreed Eric Dallara, RPh, pharmacist at New England Cancer Specialists. He has not dispensed the medication. He too cited the complexity of treatment regimens as a reason in favor of digital medications. “Right now, we’re taking the patient’s word for it.”

Currently, the University of Minnesota Health and Fairview is the only health system dispensing digital capecitabine, but that could change soon. Proteus is currently in discussions with other health systems to begin dispensing their digital capecitabine through medication registries, and New England Cancer Specialists is one of them.

Steven D’Amato, RPh, BSPharm, New England Cancer Specialists’ CEO, told OBR they “have talked with the company about the possibility of working together in the future. Those discussions are continuing, and no timeline has been set.”

Editor’s Note: On February 5, 2019, shortly after Proteus made their announcement, the U.S. FDA issued draft premarket guidance for combination products, such as Proteus’ digital capecitabine. The regulatory guidance would create a submission pathway for digital medicines and ensure the products are safe and effective. See the FDA statement here: https://www.fda.gov/NewsEvents/Newsroom/FDAInBrief/ucm630720.htm

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