Liver-Directed Therapies Increase Survival in mCRC

At this year's ASCO annual meeting, it was clear that excellent work has been made toward the eradication of cancer, and the world of gastrointestinal (GI) malignancies was no exception. A theme of novel approaches to therapies encompassed the studies presented in the management of GI cancers. It was galvanizing to hear how investigators thought "outside of the box" to find better, more effective, more tolerable ways to treat these diseases.

Liver-Directed Therapy in mCRC Conveys Survival Benefit

One of the most exciting reports on the management of GI cancers was a pair of oral abstracts that addressed the value and timing of liver-directed therapies in the management of unresectable hepatic metastases in patients with colorectal cancers. Options for local therapies are not new, but their true value previously has remained unclear. The indication for such treatment has been focused on disease palliation rather than survival benefit.

To better define the role of liver-directed therapy, Dr Theo Ruers^[1] presented a study in which patients with hepatic metastatic disease from colorectal cancer were prospectively and randomly assigned to receive treatment with either chemotherapy alone or chemotherapy augmented by radiofrequency ablation (RFA) to the liver lesions. A statistically significant improvement in overall survival (OS) resulted, with average OS of 45.6 months when the RFA was incorporated into treatment, vs 40.5 months when chemotherapy was used alone; progression-free survival (PFS) was significantly improved in the RFA arm as well.

Separately, Dr Peter Gibbs^[2] presented the results of a study in which patients with colorectal cancer that had metastasized to the liver were randomly assigned to receive first-line treatment of chemotherapy alone or chemotherapy along with selective internal radiation therapy (SIRT) to the liver lesions. SIRT consisted of yttrium-90 (Y-90) resin microspheres. Although overall PFS was not statistically improved with the addition of SIRT, median PFS in the liver was significantly and impressively extended in the SIRT arm: PFS was 20.5 months in the SIRT arm vs 12.6 months in the control arm. The OS data are still maturing, but it would be surprising if this robust 8-month improvement in PFS did not to translate into an OS benefit.

In both studies, additional toxicities were limited and reasonable. These studies support the incorporation of liver-directed therapy in the management of hepatic metastatic colorectal cancers and broaden the range of therapies available to patients with these incurable cancers.

Mutational Status Continues to Sharpen CRC Therapy

Two very interesting studies evaluated the potential for aspirin^[3] or vitamin D^[4] in the management of colorectal cancers. Both studies suggested a benefit to these approaches, noting limitations in the manner in which the studies were conducted and thus emphasizing a need for prospective, randomized investigations. These studies join a mounting body of evidence for the use of these relatively simple interventions as therapies for colon cancer.

A number of studies reported on the continual development of the genomic and proteomic heterogeneity of colorectal cancers. In a story that never seems to be complete, the role of the mutational status of KRAS and BRAF mutations as prognostic factors in colorectal cancers was discussed Dr Julien Taieb,^[5] who presented interesting data on these targets in the adjuvant setting. Finding that BRAF or KRAS mutations correlated to a significantly shorter time to relapse and overall survival, Dr Taieb's presentation suggested that these mutations could be considered as future adjuvant stratifiers.

Using a cousin target to EGFR, Dr Salvatore Siena^[6] reported on the HERACLES trial, where the HER2 status of colorectal tumors was evaluated as a therapeutic option. Although HER2 overexpression occurred in a rare 5% of tumors evaluated, management of HER2 overexpressing tumors with dual anti-HER2 therapies, using trastuzumab (Herceptin®) and lapatinib (Tykerb®), was found to be an effective option, giving further validation to the "right tumor/right drug" mantra in colorectal cancer management.

These and other studies presented during ASCO 2015 underscored that a one-size-fits-all model will not be effective for colorectal cancers going forward. Further personalization of therapies addressing specific mutations and target expression probably will be the next step in successful systemic therapy.

Novel Medical Therapies for Upper GI Metastatic Disease

The gastroesophageal sessions featured several great studies. What was perhaps most exciting about these presentations were the investigations of novel, nonchemotherapeutic medical therapies in the management of metastatic disease. In the phase 2 INTEGRATE study, regorafenib (Stivarga®), which has an established role in the management of metastatic colorectal cancers, was explored in metastatic gastroesophageal cancers.^[7] The study demonstrated a prolongation of PFS, and although OS was not significantly improved, it trended towards improvement. Toxicities of grade 3 or greater were relatively low, with the most common grade 1-2 toxicities being fatigue and anorexia. On the basis of these results, a phase 3 study is certainly warranted.

Immunotherapies are an area of intense investigation, and it was exciting to continue to learn of this treatment's potential application in GI cancers. To that end, Dr Yung-Jue Bang^[8] presented results of KEYNOTE-012, which looked at the use of the anti-PD-1 immunotherapy pembrolizumab (Keytruda®) in the management of patients with gastric cancer who have tumors expressing the PD-1 target. The results suggested a manageable toxicity and a promising antitumor activity, although further investigations are still warranted before this can become a standard in the management of these cancers.

New Options for Neuroendocrine, Pancreatic Tumors

Two studies confronted the need for additional options in the management of neuroendocrine tumors. Dr James Yao^[9] discussed the SWOG S0518 phase 3 trial, which compared the combination of octreotide (Sandostatin®) with interferon vs octreotide with bevacizumab for the management of advanced, poorly differentiated carcinoid tumors. Although the arm including bevacizumab (Avastin®) treatment demonstrated greater radiographic responses, PFS was not statistically different between the two treatment arms. The investigators suggest that the two agents have similar antitumor activity in these cancers. Moreover, because interferon is not typically incorporated into the treatment of these patients along with the octreotide, it is not clear that either second agent (interferon or bevacizumab) is needed. In the treatment of advanced pancreatic neuroendocrine tumors, Dr Matthew Kulke^[10] presented on the CALGB 80701 study regarding the addition of bevacizumab to everolimus (Zortress®, Afinitor®). Patients were randomly assigned in a 1:1 manner to receive either everolimus monotherapy vs everolimus in combination with bevacizumab. An improvement in PFS, the primary endpoint, did result with the combination therapy but at a price of higher toxicity. Further investigations of this combination are certainly warranted, noting that a high number of patients may ultimately require dose alterations of the everolimus.

Coming to ASCO 2015, I was particularly eager to learn the results of the phase 2 PEGPH20 study in pancreatic cancer. High tumor levels of hyaluronan are associated with increased tumor interstitial pressures and thus limitations of tumor stroma perfusion. This limited perfusion could lead to decreased delivery of cytotoxic chemotherapy to the tumor. PEGPH20 depletes tumor hyaluronan, thus perhaps allowing for increased chemotherapy perfusion into the tumors. Dr Sunil Hingorani^[11] presented results of a phase 2 study where PEGPH20 was added to conventional gemcitabine (Gemzar®)/nab-paclitaxel (Abraxane®) doublet chemotherapy. This treatment was found to be well tolerated. When tumors were stratified by expression of hyaluronan, those with higher expression of the hyaluronan had improved PFS. There was a trend toward improved OS, which did not achieve statistical significance, but with these results, a phase 3 global study is to begin in 2016.

Finally, in the ongoing efforts to improve the numbers of patients who can successfully undergo curative surgery for pancreatic cancers, a report of the Alliance A021101 neoadjuvant study by Dr Matthew Katz was encouraging.^[12] Patients who had pancreatic tumors considered to be borderline resectable were treated, in the neoadjuvant setting, with modified FOLFIRINOX followed by radiation with concurrent capecitabine. Subsequent resection of tumors was not affected, and efficacy was suggested by a high rate of an R0 resection and a pathologic response.

In the management of gastrointestinal cancers, this proved to be a highly successful ASCO meeting. A number of new treatment types, delivery systems, and modalities for agent selection were presented. In most cases, these results were encouraging and promise an upcoming expansion of our options for management across the spectrum of gastrointestinal cancers.

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