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ASCO Gastrointestinal Cancers Symposium 2018
This year’s American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, held from January 18 to 20, hosted more than 3,700 oncology professionals in San Francisco. Our overview of key sessions includes presentations on hepatocellular carcinoma, and colorectal and pancreatic cancers.
KEYNOTE-224: Pembrolizumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib
In patients with advanced hepatocellular carcinoma (HCC) previously treated with sorafenib (Nexavar, Bayer HealthCare Pharmaceuticals), treatment with pembrolizumab (Keytruda, Merck) led to favorable durable responses, progression-free survival (PFS), and overall survival (OS), according to a poster and oral presentation by Dr. Zhu.
He noted that immunotherapy approaches, including immune checkpoint blockade, have demonstrated promising results in advanced HCC. Pembrolizumab, an anti-programmed death-1 monoclonal antibody, has shown antitumor activity with manageable safety in multiple tumor types. The open-label phase 2 KEYNOTE-224 trial (NCT02702414) assessed the efficacy and safety of pembrolizumab 200 mg every three weeks given until progressive disease (PD) or intolerable toxicity in 104 patients (median age, 68 years; 83% male) with HCC previously treated with sorafenib. The primary endpoint was objective response rate (ORR) as determined by RECIST 1.1 criteria, assessed every nine weeks.
Dr. Zhu reported one complete response (CR) (1.0%) and 16 partial responses (PR) (15.4%). The ORR (CR + PR) was 16.3%, with a disease control rate (CR + PR plus stable disease) of 61.5%. The PD rate was 32.7%. In responders, median time to response was 2.1 months (range, 1.8–4.8 months), with responses lasting six months or longer in 94% and with a median duration of 8.2 months (range, 2.3–8.3 months). PFS was 4.8 months (95% confidence interval, 3.4–6.6), and median OS was not yet reached (9.4–not estimable).
Grade 3 or higher adverse events occurred in 25.0% of patients, leading to discontinuation in 6.7% and one death (ulcerative esophagitis). “The safety profile was generally comparable to that established for pembrolizumab monotherapy in other indications,” Dr. Zhu said. No viral flares were observed.
Dr. Zhu concluded, “Pembrolizumab treatment demonstrated efficacy in patients with advanced HCC previously treated with sorafenib.” He also noted that a phase 3 randomized trial (KEYNOTE-240) evaluating pembrolizumab versus placebo as second-line therapy in this population is under way.
Cabozantinib Versus Placebo in Patients With Advanced Hepatocellular Carcinoma Who Have Received Prior Sorafenib: Results From the Randomized Phase 3 CELESTIAL Trial
In patients with advanced hepatocellular carcinoma (HCC) who have had prior systemic therapy with sorafenib (Nexavar, Bayer HealthCare Pharmaceuticals), cabozantinib (Cabometyx, Exelixis, Inc.) significantly improved progression-free survival (PFS) and overall survival (OS), according to results from the randomized phase 3 CELESTIAL trial. Dr. Abou-Alfa underscored that, following systemic therapy, prognosis is often poor for patients with advanced HCC, and treatment options are limited.
Cabozantinib inhibits tyrosine kinases, including vascular endothelial growth factor (VEGF) receptors, MET, and AXL, all of which are implicated in carcinogenesis and in promoting tumor progression and angiogenesis. MET and AXL are associated with resistance to VEGF-receptor–targeted therapy, Dr. Abou-Alfa said. Furthermore, elevated expression of VEGF, MET, or AXL is associated with poor prognosis in HCC. In a phase 2 trial of cabozantinib in patients with advanced HCC, the agent demonstrated preliminary clinical activity with a median PFS of 5.2 months and median OS of 11.5 months.
CELESTIAL investigators randomized 707 patients 2:1 to cabozantinib 60 mg once daily (n = 470) or matched placebo (n = 237). Participants had confirmed HCC with Child–Pugh score A and had been previously treated with sorafenib (up to two lines of prior systemic therapy for HCC, with progression on at least one). Most (71%) had received one prior regimen. Median age was 64 years. About 78% of the patients had extrahepatic disease spread, and 85% had extrahepatic spread and/or macrovascular invasion. The primary endpoint was OS, with secondary endpoints of investigator-assessed PFS and objective response rate (ORR) per RECIST 1.1 criteria.
The primary endpoint was not met at the first interim analysis (52% of required events), but was met at the second interim analysis (78% of required events; 317/470 deaths with cabozantinib, 167/237 deaths with placebo; hazard ratio [HR], 0.76; P = 0.0049). Median OS was 10.2 months with cabozantinib and 8.0 months with placebo. PFS was 5.2 months with cabozantinib and 1.9 months with placebo (HR, 0.44; 95% confidence interval, 0.36–0.52; P < 0.0001).
For the secondary endpoints, ORR was 4.0% with cabozantinib and 0.4% with placebo (P = 0.0086). Median time to first subsequent systemic anticancer therapy was 6.6 months for cabozantinib and 3.3 months for placebo. Disease control (partial response or stable disease) was achieved by 64% of the cabozantinib group compared with 33% of the placebo group.
Dose reductions were reported in 62% of patients receiving cabozantinib and in 13% of those receiving placebo. Treatment-related adverse events led to discontinuation in 16% of cabozantinib patients and in 3% of placebo patients. Grade 3–4 adverse event rates were 68% and 36% for cabozantinib and placebo, respectively, with hand–foot syndrome (17%) and hypertension (16%) most common in the cabozantinib group. Treatment-related grade 5 adverse events occurred in six patients in the cabozantinib group (hepatic failure, esophagobronchial fistula, portal vein thrombosis, upper gastrointestinal hemorrhage, pulmonary embolism, and hepatorenal syndrome) and in one patient in the placebo group (hepatic failure). Dr. Abou-Alfa noted that adverse events were consistent with the known safety profile of cabozantinib.
“If approved, cabozantinib represents a new treatment option for advanced HCC patients after prior systemic anticancer therapy,” he concluded.
Prospective Clinical Study of Circulating Tumor Cells for Colorectal Cancer Screening
A novel circulating tumor cell (CTC) assay (CMx, CellMax Life) based on a simple blood draw has demonstrated high accuracy for detecting colorectal cancer (CRC). The accuracy, which extends to detection of precancerous CRC lesions, is a first for “liquid biopsy” trials, Dr. Tsai said in an oral presentation.
“Colorectal cancer can be preventable because it is a slow-growing disease and can take five to 15 years to develop from polyp to cancer,” he said. Most CRCs, however, are diagnosed late, with 61% of diagnoses taking place when the disease is already regional or distant. While five-year survival rates are 91% when the disease is localized at diagnosis, the rates are 71% with regional disease and 14% with distant disease. Because colonoscopy is invasive, uncomfortable, and inconvenient for people, about one-third of individuals are never screened.
Prior research had shown that the assay was able to detect minute numbers of CTCs (one per one billion blood cells) found in polyps. Detachment of CTCs from the primary tumor and their subsequent circulation through the bloodstream is the fundamental mechanism of metatstasis, Dr. Tsai said. His analysis focused particularly on the assay’s specificity because low specificity (which entails a high rate of false-positives) would discourage its routine use.
Participants in the study (N = 620) were older than 20 years of age and had presented for routine colonoscopy or had been diagnosed already with CRC. Colonoscopy and biopsy showed 438 patients had adenomatous polyps or early- to late-stage CRC. The remaining participants were free of precancerous growths or CRC. Investigators then took 2-mL blood samples from all enrollees, processing them with the CMx platform, which includes a lipid-coated chip that captures CTCs.
Dr. Tsai reported that the assay’s sensitivity ranged from 77% for detecting precancerous lesions to 87% for cancer at stages I–IV. Specificity ranged from 84% to 88% for precancerous and cancerous samples. The false-positive rate in the healthy control group was 3.3%, and the false-negative rate in the group with disease was 15.8%. He emphasized that the accuracy was superior to that of the fecal occult blood testing recommended by guidelines. Dr. Tsai also noted that noncompliant individuals prefer blood testing to both stool-based testing and colonoscopy by wide margins. Greater compliance, he suggested, can lead to better outcomes.
Estimates place the likely cost of the assay at about $100, he said. Ongoing studies are evaluating the assay’s utility for other solid tumors (e.g., prostate, breast, lung).
Nivolumab/Ipilimumab Combination In Patients With DNA Mismatch Repair-Deficient/Microsatellite Instability-High Metastatic Colorectal Cancer: First Report Of the Full Cohort From CheckMate-142
In previously treated patients with DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC), the combination of nivolumab (Opdivo, Bristol-Myers Squibb) and ipilimumab (Yervoy, Bristol-Myers Squibb) provided durable clinical benefit with meaningful quality-of-life improvements, according to results of the Checkmate-142 trial. Earlier findings from this trial had shown a one-year overall survival rate of 85% in patients receiving the combination.
Approximately 4% of patients with mCRC have a deficiency in the DNA mismatch repair system that leads to high microsatellite instability and a concomitant predisposition to mutation. Metastatic DNA dMMR/MSI-H CRC exhibits high levels of tumor neoantigens, tumor-infiltrating lymphocytes, and checkpoint regulators. It has a poor prognosis after treatment with conventional chemotherapy, Dr. André said. In the nivolumab monotherapy cohort of Checkmate-142, nivolumab demonstrated durable responses, sustained disease control, and encouraging survival. Because nivolumab and ipilimumab act synergistically to promote T cell antitumor activity, it was hypothesized that combination therapy could further improve results. Checkmate-142, a nonrandomized, phase 2 investigation, is the largest single study of the combination in this population.
Investigators enrolled 119 patients (median age, 58 years [range, 21–88 years]; 59% male), assigning them to either nivolumab as a single agent (3 mg/kg every two weeks) or nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every three weeks for four doses, followed by nivolumab (3 mg/kg) every two weeks. Forty percent of the patients had three or more prior lines of therapy, and 76% had two or more.
After a median follow-up of 13.4 months, the objective response rate (ORR) for the combination was 55%. The complete response rate was 3.4%, and the disease control rate (DCR) (complete response plus partial response plus stable disease) was 80%. The DCR for nivolumab alone was 69%. Seventy-eight percent of patients had some degree of tumor reduction. In addition, responses were observed regardless of tumor programmed death ligand-1 expression, BRAF or KRAS mutation status, or clinical history of Lynch syndrome. The median time to response was 2.8 months. Median duration of response has not been reached, Dr. André said.
At the time of the presentation, 94% of responders had ongoing responses, and 63% of patients were continuing treatment (37% have discontinued, 19% for disease progression and 13% for study drug-related adverse events). Progression-free survival among patients receiving the nivolumab/ipilimumab combination was 76% and 71% at nine and 12 months, respectively. Overall survival rates for the same periods were 87% and 85%, respectively.
Dr. André noted that quality-of-life measures (European Organization for Research and Treatment of Cancer’s QLQ-C30 and EuroQol’s EQ-5D VAS) showed significant and sustained improvements. No new safety signals or deaths attributable to treatment were reported. The grade 3–4 treatment-related adverse event rate of 32% (versus 20% for monotherapy) was deemed “acceptable.”
Dr. André concluded, “Nivolumab plus ipilimumab represents a promising new treatment for patients with previously treated dMMR/MSI-H metastatic colorectal cancer.”
SCOT: Tumor Sidedness and the Influence of Chemotherapy Duration on Disease-Free Survival
For the first time in a clinical trial, prognosis in unselected patients with cancer of the colon or rectum was shown to be influenced primarily by the higher rates of recurrence in those with right-sided tumors, Dr. Saunders said.
He noted that patients with right-sided tumors who develop metastatic disease have a worse prognosis compared with patients with left-sided tumors. In general, registry studies and meta-analyses have shown that patients with locoregional right-sided tumors have worse overall survival. The PETACC8 study confirmed this, but only in patients who had relapsed. Disease-free survival (DFS) was similar for patients with right- and left-sided tumors.
The SCOT trial included 6,088 patients with high-risk stage II or III cancer of the colon or rectum from 244 centers in six countries. The investigators compared three months and six months of treatment with adjuvant capecitabine and oxaliplatin or leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin (patient/physician choice) and found that DFS for the shorter treatment (76.7%) was noninferior to the longer treatment (77.1%) (noninferiority P = 0.012) in results presented last year.
The present analysis was designed to see if stratification according to tumor sidedness would reveal differences in DFS. Dr. Saunders explained that right-sided tumors included those arising in the caecum and ascending and transverse colon, and left-sided tumors included all cancers distal to and including the splenic flexure.
Patients with right-sided tumors tended to be older (median age, 66 years versus 64 years; P < 0.001), were less likely to be male (53% versus 66%; P < 0.001), were more likely to have T4 tumors (41% versus 24%; P < 0.001), and were less likely to have stage II disease (17% versus 21%; P = 0.001). DFS was significantly worse at three years in patients with right-sided tumors (73% versus 80% for left-sided; hazard ratio, 1.401; 95% confidence interval, 1.216–1.615; P < 0.0001). No correlation was found between chemotherapy duration/sidedness and DFS.
The findings underscore that there must be inherent differences between right- and left-sided tumors, Dr. Saunders said. To identify these differences and find effective treatment strategies for right-sided tumors requires stratification by tumor side of patients in future trials.
BEACON CRC Study Safety Lead-In in Patients With BRAF V600E Metastatic Colorectal Cancer: Efficacy and Tumor Markers
Updated results of the BEACON CRC safety lead-in study showed that the triple combination of the BRAF inhibitor encorafenib (investigational, Array BioPharma) 300 mg once daily plus the MEK inhibitor binimetinib (investigational, Array BioPharma) 45 mg twice daily plus standard weekly cetuximab (Erbitux, Lilly) at 400 mg/m2 initially and then 250 mg/m2 once weekly in 28-day cycles continues to be generally well tolerated with promising antitumor activity.
BRAF mutations are detected in 10% to 15% of metastatic colorectal cancer (mCRC) cases and confer a poor prognosis, according to Dr. Van Cutsem’s poster presentation. Progression-free survival (PFS) is about two months with objective response rates (ORRs) generally below 10%. After failure of first-line therapy, overall survival (OS) is less than six months. In a recent prospective trial of patients with BRAF V600E mCRC who had received one or two prior regimens in the metastatic setting and then standard-of-care irinotecan plus cetuximab, tumor shrinkage was observed in only 21%, and 60% of the patients had 100% or greater increases in tumor volume. Dr. Van Cutsem cited low efficacy in this population in 11 clinical trials with ORRs from 4% to 8.3%, PFS from 1.8–2.8 months, and OS from 4.1–6.2 months.
A phase 2 study of cetuximab and encorafenib in this population led to a median PFS of 4.2 months, an ORR of 22%, and median OS greater than one year. In addition, adding a MEK inhibitor to BRAF inhibition has demonstrated improved efficacy over BRAF inhibition alone. These results led to the BEACON CRC phase 3 study, a three-armed multicenter investigation in patients with BRAF V600E mCRC whose disease has progressed after one or two prior regimens in the metastatic setting. They are to receive either the triplet of encorafenib, binimetinib, and cetuximab compared with investigator’s choice of an irinotecan standard biweekly dose plus cetuximab or leucovorin calcium (folinic acid), fluorouracil, irinotecan plus cetuximab, or the doublet choice of encorafenib plus cetuximab.
Because the triplet combination of binimetinib plus encorafenib plus cetuximab had not been studied previously, a lead-in study to test safety and activity was designed. Among 30 patients enrolled, 29 had the BRAF V600E mutation (median age, 59 years; 43% male). Median time on treatment was 7.9 months, with one-third of the patients remaining on study treatment at the time of data cut-off.
The confirmed ORR (complete responses [CRs] plus partial responses [PRs]) was 48% with CRs in three patients. Among patients with one prior line of therapy, the ORR was 62% (two CRs and eight PRs). Among those with two prior lines of therapy, the ORR was 31% (four of 13 patients), including three PRs and one CR. Responses were ongoing in six of 14 responding patients (43%). The remaining 15 patients all achieved stable disease as their best response, with nine patients (60%) having stable disease for six months or longer. The preliminary estimate of median PFS is 8.0 months, with seven of 29 patients still progression free. Dr. Van Cutsem noted that evidence of tumor regression was observed in all but one evaluable patient. The number of prior regimens did not affect outcome.
Common adverse events were consistent with those previously reported for BRAF, MEK, and EGFR inhibitors, and included gastrointestinal and skin toxicities.
“Safety and preliminary efficacy data support the initiation of the phase 3 portion of the BEACON CRC trial,” he concluded. Enrollment is currently ongoing.
Phase 2 LAPACT Trial of Nab-Paclitaxel Plus Gemcitabine for Patients With Locally Advanced Pancreatic Cancer
Thirty percent of patients with pancreatic cancer have unresectable locally advanced tumors (LAPC) for which induction chemotherapy is recommended. The phase 3 MPACT trial in metastatic pancreatic cancer showed that nab-paclitaxel (nab-P) plus gemcitabine reduced primary pancreatic cancer burden threefold compared with gemcitabine alone, suggesting the potential for activity against LAPC, Dr. Hammel said.
The international, multicenter, phase 2 LAPACT trial prospectively evaluated the safety and efficacy of six cycles of nab-P plus gemcitabine induction (125 mg/m2 nab-P plus 1,000 mg/m2 gemcitabine on days 1, 8, and 15 of each 28-day cycle) in newly diagnosed, untreated patients. After induction, patients without progressive disease or unacceptable adverse events were eligible for continued treatment with nab-P plus gemcitabine, chemoradiation, or surgery per investigator’s choice (IC). If tumor response was deemed adequate, surgery could occur before completion of the induction cycles. Time to treatment failure (TTF) was the primary endpoint.
Of 107 enrolled patients, 61 completed induction, with 20 discontinuations attributed to adverse events. Mean patient age was 65 years, and 55% were women. Forty-six patients (43%) received IC treatment after induction: 13 (12%) continued nab-P plus gemcitabine, 17 (16%) received chemoradiation, and 16 (15%) underwent surgical resection. Median duration of treatment exposure was 20.7 weeks. Approximately 63% of patients had one or more dose reductions and about half had one or more dose delays.
Grade 3 or higher adverse events were reported in 80% of patients. Nonhematologic adverse events included fatigue, asthenia, hyperglycemia, and alanine aminotransferase increases, with events of grade 3 or higher occurring in 5.7% to 10.4% of patients. Grade 3 or higher neutropenia occurred in 41.5% of patients, but febrile neutropenia of grade 3 or higher was low at 3.8%. Induction therapy with nab-P plus gemcitabine was tolerable and consistent with known safety profiles, Dr. Hammel commented. He noted that, overall, patients’ global health status was maintained through day 1 of cycle 6.
Reporting on efficacy during induction, Dr. Hammel said there were partial responses in 32.7% and stable disease in 57.9% of patients, with the latter persisting at 16 weeks or longer and at 24 weeks or longer in 44.9% and 32.7%, respectively. Disease control rates at 16 weeks or longer and at 24 weeks or longer were 77.6% and 65.4%, respectively. Progressive disease occurred in 4.7%.
TTF, the primary endpoint, was 8.8 months (90% confidence interval, 6.67–9.82), meeting the protocol-specified target of 6.6 months. Median progression-free survival was 10.8 months, and estimated overall survival was 72% at 12 months.
Dr. Hammel concluded that “Nab-P plus gemcitabine has promising antitumor activity.” He also noted that quality of life was maintained in most patients and that nab-P plus gemcitabine induction allowed for conversion to tumor resection in 15% of patients.