Meeting Highlights

European Society of Medical Oncology 17th World Congress on Gastrointestinal Cancer Walter Alexander The European Society of Medical Oncology (ESMO) gastrointestinal cancer meeting encompasses malignan­ cies affecting every component of the gastrointestinal tract and aspects related to patient care, screening, diag­ nosis, and the latest management options. This year’s meeting, held from July 1 to July 4 in Barcelona, Spain, attracted 3,200 oncologists and other medical profes­ sionals. We review major sessions on metastatic colo­ rectal cancer and hepatocellular carcinoma, including two focused on treatment of the elderly, a group usually excluded from clinical trials.

First-Line Treatment With Modified FOLFOX6 (mFOLFOX6) + Panitumumab or Bevacizumab in Patients With RAS/BRAF Wild-Type Metastatic Colorectal Carcinoma (mCRC)

• Fernando Rivera, MD, Hospital Universitario Marques de Valdecilla, Santander, Spain Adding first-line panitumumab to modified FOLFOX6 (mFOLFOX6) compared with adding first-line bevacizumab in patients with RAS/BRAF wild-type metastatic colorectal carcinoma (mCRC) led to similar response rates, but the responses were faster, deeper, and longer lasting, according to Dr. Rivera. Presenting results of the randomized phase 2 PEAK study (NCT00819780), Dr. Rivera noted that panitumumab is a monoclonal antibody targeting epidermal growth factor receptor (EGFR) and bevacizumab is a monoclonal antibody targeting vascular endothelial growth factor (VEGF). Patients in PEAK had previously untreated KRAS exon 2 wild-type mCRC. They received mFOLFOX6 plus panitumumab (6 mg/kg every two weeks) or bevacizumab (5 mg/kg every two weeks). Earlier analysis among PEAK subjects had shown the panitumumab-containing arm to be associated with a longer median overall survival (OS) of 41.3 versus 28.9 months (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.39–1.02; P = 0.058). RECIST (Response Evaluation Criteria in Solid Tumors) overall response rates were similar between treatments (P = 0.80). Dr. Rivera pointed out, however, that RECIST does not fully take into account such factors as timing, depth, and duration of response, which may influence long-term outcomes in mCRC. Benefits in the panitumumab arm included a shorter time to treatment response (a median 2.1 months versus 3.8 months; HR, 0.86; P = 0.44). Also, the median duration of response was longer with panitumumab plus mFOLFOX6 than for bevacizumab plus mFOLFOX6 (13.0 versus 8.4 months; HR, 0.49; P = 0.0052). Furthermore, the median depth of response (the percentage of tumor reduction) was greater in the panitumumab The author is a freelance medical writer living in New York City.

arm (74% versus 49%; P = 0.0009). Adding panitumumab to FOLFOX6 also benefited the endpoint of achieving early tumor shrinkage of 30% or more by week 8, at a rate of 65% compared with 45% for bevacizumab plus mFOLFOX6. A tumor resection analysis revealed similar resection numbers and successful complete resection levels between groups. “Early, deep, and sustained tumor responses may offer clinical benefit to patients with metastatic colorectal cancer. The long-term impact of such responses warrants further investigation,” Dr. Rivera concluded. Commenting on the PEAK findings in an interview, Richard Goldberg, MD, of the James Cancer Hospital at Ohio State University in Columbus, Ohio, said, “This study supports that either strategy is reasonable.” The faster and deeper responses with panitumumab would be more clinically significant had they enabled more tumor resections with better surgical outcomes, he added. Dr. Goldberg noted that patients need to be told of the differing panitumumab and bevacizumab side-effect profiles. Bevacizumab’s main adverse effects include hypertension, which is manageable, and rare vascular events such as thromboses or perforations. “Acneiform rash, panitumumab’s main adverse event, is a real concern for many patients and can be a source of some discomfort,” Dr. Goldberg said. While it is more visible than bevacizumab’s adverse events (AEs), it may be prevented with moisturizing cream, sunblock, and antibiotics such as minocycline.

Results From the Large, Open-Label Phase 3b CONSIGN Study of Regorafenib in Patients With Previously Treated Metastatic Colorectal Cancer

• Eric Van Cutsem, MD, PhD, University Hospitals and Katholieke Universiteit Leuven, Belgium, and co-chairman, ESMO 17th World Congress on Gastrointestinal Cancer The need for dose reductions or interruptions in the CONSIGN trial testing regorafenib in a setting resembling daily practice among patients with previously treated colorectal cancer points to the importance of patient selection, according to Dr. Van Cutsem. In prior regorafenib reporting from the pivotal phase 3b open-label CORRECT trial among 760 patients, treatment-emergent drug-related AEs occurred in 93% of regorafenib patients and in 61% of those assigned to placebo, with hand and foot skin reactions, fatigue, diarrhea, hypertension, and rash or desquamation as the most common grade 3 or higher treatment-emergent AEs. In that trial, regorafenib, an oral multikinase inhibitor targeting angiogenesis, oncogenesis, and the tumor microenvironment, improved OS compared with placebo (6.4 months versus 5.0 months; HR, 0.77; P = 0.0052). The study was launched, Dr. Van Cutsem noted, to allow regorafenib access pre-authorization for patients who had progressed on standard treatments for mCRC, to characterize

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Meeting Highlights: European Society of Medical Oncology regorafenib safety in a large cohort of patients, and to assess progression-free survival (PFS). CONSIGN was a prospective, single-arm trial conducted at 188 sites in 25 countries among 2,872 patients who received oral regorafenib (160 mg once daily [three weeks on, one week off]) until progressive disease. The median duration of treatment was 2.5 months (0–30), with a median daily dose of 160 mg. Treatment modifications were necessary in 87% of patients (interruptions/ delays in 84% and dose reductions in 49%). Treatment-related grade 3 or higher AEs were reported in 57% of patients, with serious events in 9% and grade 5 events in less than 1%. One nonfatal case of drug-induced liver injury was identified. In the pivotal CORRECT trial, median PFS was 1.9 months (95% CI, 1.9–2.1). In CONSIGN it was 2.7 months (95% CI, 2.6–2.7). KRAS mutation status did not affect PFS. Dr. Van Cutsem concluded, “The rate of dose reductions and treatment interruptions highlights the importance of optimal patient selection, management, and dose modification.”

SIRFLOX: Randomized Trial Comparing First-Line mFOLFOX6 ± Bevacizumab Versus mFOLFOX6 + Selective Internal Radiation Therapy (SIRT) ± Bevacizumab in Patients With Metastatic Colorectal Cancer (mCRC)—Analysis by Presence Or Absence of Extra-Hepatic Metastases and Bevacizumab Treatment

• Guy van Hazel, Professor, University of Western Australia, Perth, Australia; and Theo Ruers, MD, Professor, the Netherlands Cancer Institute, Antoni Van Leeuwenhoek Ziekenhuis, Amsterdam, the Netherlands

Radiofrequency Ablation Combined With Chemotherapy for Unresectable Colorectal Liver Metastases: Long-Term Survival Results of a Randomized Phase II Study of the EORTC-NCRI CCSG-ALM Intergroup 40004

• Theo Ruers, MD, the Netherlands Cancer Institute, Antoni Van Leeuwenhoek Ziekenhuis, Amsterdam, the Netherlands

Phase 1 Study of PV-10 for Chemoablation of Hepatocellular Cancer and Cancer Metastatic To The Liver

• Paul Goldfarb, MD, Sharp Clinical Oncology Research, San Diego, California With the liver being the predominant site of disease in hepatocellular carcinoma (HCC) and metastatic colon cancer, and with results from trials of three locoregional strategies across various phases of testing demonstrating promising results at this meeting, interest in these therapies is intensifying. In recent prior reporting of the phase 3 SIRFLOX trial of selective internal radiation therapy (SIRT) in mCRC patients with liver-dominant metastases, SIRT with FOLFOX-based chemotherapy reduced disease progression in the liver by 31% compared with FOLFOX alone. The primary endpoint of PFS, however, was not achieved. SIRT is delivered in the

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form of yttrium-90 microspheres via a hepatic artery injection (SIR-Spheres). Dr. van Hazel presented updated and extended SIRFLOX findings from the subgroup of 318 patients who had metastases only in the liver (FOLFOX plus bevacizumab, 159; FOLFOX plus bevacizumab plus SIRT, 159). Among them, PFS with SIRT was extended by 8.7 months (FOLFOX plus bevacizumab, 12.4 months; FOLFOX plus bevacizumab plus SIRT, 21.1 months; HR, 0.64; 95% CI, 0.48–0.86, P = 0.003). Among patients who had liver and extrahepatic metastases, however, the improvement in PFS with SIRT (16.7 versus 12.6 months; P = 0.147) was not significant. Dr. van Hazel also noted that the cumulative incidence of liver progression was superior for SIRT regardless of whether patients received bevacizumab (P = 0.018 and P = 0.028, respectively). Commenting on the SIRFLOX results, Professor Chris Verslype, MD, a specialist in oncology and hepatology at University Hospital in Leuven, Belgium, said, “First-line radioembolization in combination with bevacizumab and chemotherapy is able to retard progression in the liver. It does seem to be safe.” He added that SIRFLOX use at his institution is now restricted to patients with very limited extrahepatic disease. “Here we can probably make a difference in the long run for our patients.” Offering phase 2 trial results of standard systemic treatment (FOLFOX in about three-fourths of cases, bevacizumab in 17%) for unresectable colorectal liver metastases with or without radiofrequency ablation, Dr. Ruers reported long-term OS (median follow-up, 9.7 years). In an earlier report, the primary endpoint of OS greater than 38% at 30 months had been met in both groups, with 61.7% OS in the group receiving systemic treatment plus radiofrequency ablation and 57.6% OS among those receiving only systemic treatment. Eight-year PFS was 2.0% for those receiving systemic therapy and 22.3% for systemic therapy plus radiofrequency ablation (HR, 0.57; 95% CI, 12.7–33.7, P = 0.005). Eight-year OS was 8.8% for systemic therapy alone and 35.9% for radiofrequency ablation (HR, 0.58; 95% CI, 0.38–0.88; P = 0.010). Progressive disease was the main cause of death (56.7% for systemic plus radiofrequency ablation and 81.4% for systemic only). “The findings encourage the use of ablative techniques as a treatment modality in patients with unresectable colorectal liver metastases,” Dr. Ruers said. In metastatic melanoma, a phase 2 study of locoregional chemoablation with PV-10 (10% rose bengal solution) has demonstrated high complete response rates and durable local control; phase 3 testing is under way. The first results of phase 1 evaluation of PV-10 in patients with liver tumors (nonresectable HCC or liver metastases) 1 cm or larger were presented in a poster by Dr. Goldfarb. PV-10 is injected directly into lesions, and has been shown to have effects on noninjected and distant lesions. In the phase 1 trial, subjects having at least one liver tumor 1 cm or larger were administered a single percutaneous intralesional injection of PV-10 to one target lesion at a dose of 0.25 mL or 0.50 mL per cm3 lesion volume. Reporting preliminary findings in the first six patients, Dr. Goldfarb noted that the only AEs were injectionsite and photosensitivity reactions, with no sequelae. Stable disease was demonstrated in all tumors, with partial responses in two of four evaluable patients. In a larger cohort including the

Meeting Highlights: European Society of Medical Oncology first 13 patients treated, 10 were alive at 54 months of follow-up. “Having liver cancer patients alive at up to 54 months of follow-up with no evidence of disease is remarkable,” said Eric A. Wachter, PhD, Chief Technology Officer at Provectus Biopharmaceuticals, the developer of PV-10. “This is even more extraordinary when you consider these patients received just one or two intralesional injections.” Dr. Verslype commented, “We may expect some immunological effects with this kind of treatment. Locoregional treatment doesn’t necessarily mean that the effect of the therapy remains limited to the tumor itself in the liver—there may be effects on distant tumor sites.” An expansion cohort includes 24 patients.

Hepatocellular Carcinoma in Elderly Patients: Final Results of the Italian Cohort of GIDEON Study • Teresa Zolfino, MD, Azienda Ospedaliera G. Brotzu, Cagliari, Italy While sorafenib was effective and well tolerated in both younger and elderly patients with HCC in the GIDEON study (Global Investigation of Therapeutic Decisions in HCC and of Its Treatment With Sorafenib), OS was longer among older patients, perhaps due to less severe disease at baseline. Dr.  Zolfino noted that elderly patients are often under­ represented in clinical trials. Her analysis of patients in GIDEON who had not received prior sorafenib showed that 141 of the 278 patients were at least 70 years of age. The standard sorafenib starting dose of 400 mg twice daily was administered in 89% of younger patients and in 85% of elderly patients. The median duration of treatment was similar in both subgroups: 4.2 months in younger patients and 3.5 months in the elderly subgroup. However, baseline characteristics associated with more advanced disease and worse outcomes in HCC (more advanced stage, macrovascular invasion, extrahepatic spread, lower performance status) were more frequent in the younger subgroup. That difference was also reflected in outcomes. Median OS was 10 months (8–18) in the younger subgroup and 20 months (12–23) in the older patients. Median PFS was longer in the elderly group (6.0 months versus 4.1 months), as was median time to progression (7.6 months versus 5.0 months, respectively, for elderly and younger patients). At the same time, complete responses were more frequent for older patients (1.4% versus 0.8%), and the incidence of patients with stable disease was higher in older patients than in younger patients (44.7% versus 37.6%), while progressive disease was lower among the older patients (31.9% versus 43.6%). For both younger and older subgroups, both serious and nonserious AEs were consistent with sorafenib’s known safety profile. The most common AEs were diarrhea, hand/foot skin reactions/rash, and fatigue. Permanent drug discontinuation rates attributed to AEs were also similar at 34.4% and 31.4% for younger and elderly patients, respectively. Outcome differences between the age groups, Dr. Zolfino cautioned, cannot be attributed to a differential in treatment effect because of the limitations and potential bias of non­ randomized observational studies. “In the Italian cohort of the GIDEON study, sorafenib was a

well-tolerated and effective treatment option in both younger and elderly patients. Elderly patients had longer overall survival than younger patients, possibly because of more advanced disease in the younger subgroup,” Dr. Zolfino concluded.

Recurrence-Free Survival According to Treatment Modality Among Elderly Stage III Colon Cancer Patients

• Felice van Erning, MD, Netherlands Comprehensive Cancer Organization, Eindhoven, the Netherlands A study examining the effect of toxicities on treatment intensity in elderly stage 3 colon cancer patients receiving adjuvant chemotherapy found that adding oxaliplatin to capecitabine may lead to toxicities that undercut the rationale for the extra drug. The 193 patients in Dr. van Erning’s study received adjuvant chemotherapy comprised of capecitabine and oxaliplatin (CAPOX) or capecitabine monotherapy (CapMono). They were all 70 years of age or older and had stage III (pT1-4N1-2M0) colon cancer. Investigating the effects of grade 3 and 4 toxicities on treatment characteristics, researchers found that among the 164 patients receiving capecitabine monotherapy, 51% had grade 3 and 4 toxicities compared with 80% of the 193 receiving capecitabine and oxaliplatin (P