2016 ASCO Gastrointestinal Cancers Symposium Kicks Off; NETs in the Spotlight

The 2016 Gastrointestinal Cancers Symposium, being held January 21-23 in San Francisco, will attract cancer researchers and clinicians from around the world to hear the latest in colorectal, pancreatic, liver, esophageal, gastric and other GI malignancies. Three studies were previewed ahead of the meeting in a presscast.

Two support new treatments for neuroendocrine tumors (NETs) of the GI tract. NETs are a group of cancers that originate in hormone-producing (ie, neuroendocrine) cells of various organs in the body, with 60% being gastrointestinal. While they are diagnosed in the US each year in only about 8,000 people, their incidence is increasing and there are few treatment options after patients progress on somatostatin analogs (SSAs), according to presscast moderator and ASCO Spokesperson Smitha Krishnamurthi MD, of Seidman Cancer Center and the Case Comprehensive Cancer Center in Cleveland, Ohio.

Results of a third study suggest that preoperative treatment of locally advanced rectal cancer can be delivered more conveniently.

Everolimus Effective in NETs of GI Origin

The mTOR inhibitor everolimus, which is approved for the treatment of pancreatic NETs, has demonstrated efficacy against NETs in the GI tract and those of unknown origin, according to a subgroup analysis of the international phase IIII RADIANT-4 trial (Abstract 315).

Patients randomized to receive everolimus (10 mg/day) had approximately a doubling in progression-free survival (PFS) versus placebo in this post-hoc analysis. In the primary analysis of RADIANT-4, presented at the European Cancer Congress, everolimus reduced the risk of progression by 52% among patients with advanced GI and lung NETs (P < 0.00001).

“This was quite a stunning finding—a 7-month improvement in PFS. We are now looking in detail at the GI subgroup,” said Simron Singh, MD, MPH of Sunnybrook’s Odette Cancer Centre in Toronto, Canada, who presented the latest findings to the media.

The current analysis included 175 patients with previously treated advanced GI NETs and 36 patients with NETs from an unknown site. All patients had non-functional tumors, meaning the tumors were causing few or no symptoms initially.

In the overall population of this subanalysis, everolimus reduced the risk of disease progression by 40% or more, compared to placebo. Median PFS was 13.1 months versus 5.4 months among patients with GI tumors (HR =0.56) and 13.6 versus 7.5 months, respectively, among those with tumors of unknown origin (HR = 0.60).

“This was clearly a significant improvement in stopping tumors from growing with everolimus,” Dr. Singh commented.

When the researchers examined the findings in the midgut (ileum, jejunum, cecum, duodenum, appendix and small intestine) versus non-midgut (stomach, colon, rectum) locations, they found relative risk reductions of 29% and 73%, respectively, favoring everolimus, he said.

Additionally, prior treatment with an SSA did not reduce the benefit of everolimus, as the relative risk reduction was approximately 50% in groups with and without prior treatment. “Patients appeared to benefit from everolimus across the board,” he said.

The most common adverse effects with everolimus were those familiar to the drug—stomatitis, diarrhea, peripheral edema, and fatigue.

“This study in advanced progressive NETs suggests everolimus is a new, effective, exciting treatment option,” Dr. Singh concluded.

Dr. Krishnamurthi commented on the results. “While everolimus is already approved for treating pancreatic NETs, these results demonstrate that it may also be effective for a broader group of patients. The findings are important, showing an improvement in the risk of progression by more than 40%, without severe toxicity. This is a welcomed finding for patients with limited systemic treatment options.”

NETs in Midgut Benefit from Radiolabeled SSA

A novel radiolabeled SSA, 177Lu-DOTA0-Tyr3-Octreotate (177Lu-Dotatate) (Lutathera), reduced the risk of disease progression or death by 79% in an international phase III study of previously treated, advanced NETs of midgut origin (Abstract 194).

177Lu-Dotatate belongs to a fairly new therapeutic class known as peptide receptor radionuclide therapy (PRRT). With 177Lu-Dotatate, an SSA is attached to a radioactive molecule, enabling targeted delivery of radiation to tumors, explained Jonathan R. Strosberg, MD, of Moffitt Cancer Center, Tampa, Florida.

“There have been several generations of PRRTs. 177Lu-Dotatate is the latest, and it has a relatively favorable therapeutic index compared to previous generations,” Dr. Strosberg indicated.

“NETTER-1 is the first trial to test a PRRT in a randomized, prospective fashion,” he said.

NETTER-1 randomized 230 patients who progressed after SSA therapy to 177Lu-Dotatate or to more SSA treatment with high-dose octreotide LAR 60 mg. Patients in the experimental arm were treated once every 8 weeks for a total of 4 administrations of 177Lu-Dotatate.

At the time of analysis, 23 patients in the experimental group had disease progression, compared to 67 in the octreotide group. Median PFS was not reached with 177Lu-Dotatate but was 8 months with octreotide LAR (HR = 0.21; P < 0.0001).

“The study met its primary endpoint in extremely impressive fashion,” Dr. Strosberg commented in the presscast. “With roughly a year and a half of follow-up, the expected median PFS is likely to be longer than 3 years.”

Response rates were also higher with 177Lu-Dotatate, 19% versus 3% (P < 0.0004). While this rate may sound low, he explained that NET patients are very resistant to systemic therapy, and response rates to other treatments “are in the single digits.”

“This is the only large study showing double-digit response rates in midgut NETs, and the difference is highly significant,” he said.

Serious adverse events were reported in 26% of the experimental arm and 24% of the control arm. At the Symposium, Dr. Strosberg will provide more detail on these.

To date, 13 patients in the experimental arm have died, versus 22 in the control arm (P < 0.019), a numerical trend that does not yet meet statistical significance for this interim analysis, he said, “but is suggestive of an improvement” in overall survival.

Dr. Krishnamurthi commented that NETTER-1 shows 177Lu-Dotatate to have “an impressive ability to slow the growth of midgut tumors progressing on an SSA.” She was further impressed with the response rate in a population typically unresponsive to systemic treatments. “It’s exciting to see this novel therapy,” she said.

Shorter Radiation Course Benefits Locally Advanced Rectal Cancer

For preoperative treatment of locally advanced rectal cancer, a short, 5-day course of radiation followed by chemotherapy may be as effective as standard chemoradiation, which delivers radiation over about 5 weeks, with concurrent chemotherapy typically given in the 1st and 5th weeks, Polish investigators are reporting at the Symposium (Abstract 489).

The phase III study by the Polish Colorectal Study Group found that 5 days of radiation followed by 3 cycles of chemotherapy prior to surgery achieved similar outcomes with less toxicity.

“The new regimen has similar efficacy but causes fewer side effects and is more convenient for patients. It is also less costly compared to standard chemoradiation, so it may be especially valuable in limited-resource settings,” said Lucjan Wyrwicz, MD, PhD, of the Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology in Warsaw.

The study enrolled 515 patients with stage cT3 or cT4 rectal cancer, assigning them to standard chemoradiation or to the short-course radiation regimen. All patients received FOLFOX4 (5-FU, leucovorin, oxaliplatin). In the experimental arm, 3 cycles of chemotherapy followed 5 days of radiation (5 x 500 cGy), while in the control arm chemotherapy was given concurrently with radiation, which was delivered over about 5 weeks. The protocol was amended partway through the study to state that the use of oxaliplatin (which is relatively toxic) was by physician discretion and was not mandated. Both groups underwent surgery approximately 12 weeks after starting radiotherapy.

The short-course approach achieved outcomes that were as good as, or better than, those of the conventional arm. The treatments conveyed the same ability to perform radical surgery and achieved similar disease-free survival, but the short-course was associated with less toxicity, Dr. Wyrwicz reported.

R0 resection (negative surgical margins), the primary endpoint, was achieved in 77% of the experimental arm and 71% of the control arm (P = 0.081), indicating a trend in favor of the short-course approach. Pathologic complete responses were achieved by 16% and 12%, respectively (P = 0.17).

Rates of disease-free survival and local failure at 3 years were, for the experimental and control arms respectively, 53% versus 52% (P = 0.85) ad 22% versus 21% (P = 0.82). Acute toxicities were observed in 75% and 83%, respectively (P = 0006), though rates of grade 3+ toxicities were similar at 23% and 21%, he reported.

While those endpoints were not significantly different, the Kaplan-Meier curves for overall survival separated at about 2 years and plateaued afterward, with 3-year survival rates of 73% with the short-course radiation modality and 65% with chemoradiation (P = 0.046).

This preliminary observation of an 8% absolute survival benefit warrants a closer look for factors that may be contributing to a survival benefit, he added.

“Despite the fact that the trial was negative—it did not show superiority of the short-course for radical resection rate—we showed for the first time that there is an alternative to standard chemoradiation lasting more than 5 weeks,” Dr. Wyrwicz commented.

According to Dr. Krishnamurthi, short-course radiotherapy has been more widely used in Europe than in the US, largely because of conflicting results of studies that have compared it to standard treatment. “But these results may lead to increased use of this method here,” she said. “We’re trying to fine-tune how we deliver treatment to patients prior to surgery, to maximize efficacy and convenience and minimize side effects.”

by Caroline Helwick

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