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PRIORITY PRESS - ECCO-17 - 38th ESMO Multidisciplinary Congress

Amsterdam, The Netherlands / September 27-October 1, 2013

Amsterdam - Gastrointestinal stromal tumors (GIST) are a rare but treatable soft tissue sarcoma. Unlike other gastrointestinal cancers, more than 85% of GISTs express the KIT oncogene. Treatments that target the tyrosine kinase activity of KIT can often stabilize disease for several years but over time, resistance develops and patients rapidly progress. Now a multi-kinase inhibitor has been shown to extend progression-free survival compared with placebo in metastatic GIST. The same multi-kinase inhibitor was also associated associated with improved overall and progression-free survival in metastatic colorectal cancer (mCRC) when given as monotherapy. Other targeted approaches in mCRC are currently being explored with some success as well. 

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

In the world of molecular medicine, gastrointestinal stromal tumors (GIST) are a highly targetable tumor. Indeed, uncontrollably activated mutant kinases are the oncogenic drivers in over 85% of GISTs—making them a fitting tumor for treatments that target KIT and PDGFRA mutations. KIT is a growth factor receptor associated with tyrosine kinase activity and when mutated, may result in GIST. In KIT-negative GISTs, the most likely mutation occurs in the PDGFRA gene. Historically, patients with metastatic GIST could not expect to live more than a year.

This prognosis changed with the introduction of imatinib. Imatinib targets the tyrosine kinase function of activated KIT and PDGFRA mutations, and is now a standard-of-care for non-resectable GIST. Following disease stabilization with a tyrosine kinase inhibitor (TKI), long-term tumor control is often possible. Nevertheless, as Siehl et al. point out (Recent Results Cancer Res. 2007;176:145-51), resistance to imatinib occurs at a median of 18 to 26 months.

Once patients fail imatinib, guidelines indicate that the dose of imatinib should be doubled from 400 mg/day to 800 mg/day; patients who fail to respond to dose escalation should then be treated with sunitinib, another TKI. Response to sunitinib tends to be less robust, with most GIST patients progressing within a year. Until recently, patients with advanced GIST who were resistant to both imatinib and sunitinib had no other treatment option and rapidly progressed. Regorafenib is a multi-kinase-targeted therapy that inhibits a number of signaling pathways in addition to KIT and PDGFR.

These pathways include not only those which drive tumor growth but also those that facilitate tumor proliferation and metastatic spread, leading to the progression of GIST.

GRID Study

The potency of using a multi-kinase inhibitor was demonstrated in the GRID study—GIST – Regorafenib in Progressive Disease. Recently published in the Lancet (2013;381:295-302), GRID enrolled 199 patients with metastatic or unresectable GIST who had progressed after treatment with imatinib and sunitinib,  with more than 43% of GRID patients having received more than 2 prior lines of therapy. Patients received either oral regorafenib, 160 mg/day or placebo, for the first 3 weeks of each 4-week cycle.

As Demetri et al. reported, median progression free survival (PFS) for patients in the multi-kinase inhibitor arm was 4.8 months compared with 0.9 months for placebo controls—a 73% relative risk reduction in PFS in favor of active therapy (P<0.0001). “The vast majority of GISTs are affected by KIT or PDGFRA and all of the drugs that work in GIST hit these 2 targets, this one included,” Dr, Jean-Yves Blay, Professor of Medical Oncology, Claude Bernard University, Lyon, France, said in an interview.  In GRID, the most common adverse events (AEs) of any grade in the active treatment arm were hypertension (49%), hand-foot skin reactions (56%), fatigue (39%) and diarrhea (41%).

Looking more closely at the time course to AEs, (Abstract 3827) “we saw that the incidence of the most common AEs in the regorafenib group peaked early during treatment so that lower levels of AEs occurred in later treatment cycles, with no evidence of cumulative toxicity,” Dr. Blay noted. Hand-foot skin reactions tend to be the most problematic of the AEs associated with this particular targeted approach.

As Dr. Blay noted, the best way to manage hand-foot skin reactions is to reduce the dose. “The key message here is that we need to be flexible,” Dr. Blay emphasized. “The idea is not to say: treatment is 160 mg/day and we’ll never move from that—we have to adapt, see patients frequently and make sure patients are comfortable enough on the dose we give them so that they can continue with the drug.”

Metastatic CRC

In the Phase III CORRECT (Abstract 2156) patients with metastatic colorectal cancer (mCRC) were treated with regorafenib monotherapy or placebo. As reviewed here by Dr. Salvatore Siena, Ospedale Niguarda Ca Granda, Milan, Italy, there was a 22% relative risk reduction in overall survival (OS)  and an approximately 50% improvement in PFS in patients on the active therapy compared with placebo (P=0.005 and P<0.001, respectively). Rates of AEs were predictably higher in the multi-kinase inhibitor group.

However, higher AEs rates in the active treatment arm of CORRECT did not appear to adversely affect quality of life (QoL). Using the EORTC QoL questionnaire, investigators observed only a -1.9 difference in global health status between those on active treatment compared with controls. A difference on the EORTC questionnaire of 10 or more is considered clinically meaningful. There were also no differences over time in several domains of the EQ-5D score, another index of health, between the 2 treatment groups.

Thus, despite higher AE rates in the multi-kinase inhibitor arm, “in general, there was no apparent difference in QoL over time," he concluded.

In a late-breaking abstract (LBA17), Dr. Volker Heinemann, Professor of Medical Oncology, University of Munich, Germany, presented new data in which the effect of various mutations within the KRAS wild-type population of mCRC FIRE-3 patients was analyzed. Of 592 patients evaluated, Dr. Heinemann and colleagues reported that patients with KRAS wild-type mCRC are more likely to benefit from the addition of cetuximab to the standard FOLFIRI regimen (5-fluorouracil, leucovorin, irinotecan) compared with FOLFIRI plus bevacizumab, both given as first-line therapy. In patients with KRAS wild-type mCRC, OS was extended by about 7.5 months to a median OS of 33.1 months in the arm containing cetuximab compared with a median OS of 25.6 months in the FOLFIRI plus bevacizumab arm.

In contrast, no additional OS benefit was seen among patients with KRAS-mutant tumors who were treated with the same cetuximab-containing regimen relative to that containing bevacizumab at a medium OS of 19.1 months vs 20.6 months, respectively.

Additional improvements in both OS and PFS were also reported in the aflibercept plus FOLFIRI arm in the VELOUR intent-to-treat (ITT) population after excluding rapid adjuvant progressors (Abstract 2260). Improvements were also observed regardless of whether patients had been exposed to prior bevacizumab. As Van Cutsem et al. observed, rapid adjuvant progressors are usually refractory to any subsequent therapy and have an extremely poor prognosis. In the current post-hoc analysis, all rapid adjuvant progressors were excluded. As expected, when rapid adjuvant progressors were excluded from the overall ITT population, aflibercept was associated with a 1.9 month incremental benefit over placebo, for a 22.1% relative risk reduction in death.

“These findings reinforce the benefit of aflibercept treatment in clinically relevant populations of mCRC patients, including those with prior bevacizumab use,” the authors concluded. As reported by Dr. Timothy Price, Queen Elizabeth Hospital, Adelaide, Australia, several other monoclonal antibodies that target the epidermal growth factor receptor (EGFR) have been shown to be effective for the treatment of wild-type KRAS mCRC as well.

In the Phase III ASPECT study (LBA#18), panitumumab was directly compared to cetuximab in a total of 999 patients with chemotherapy-refactory KRAS wild-type mCRC. Patients had previously been treated with irinotecan, oxaliplatin and fluorouracil for metastatic disease and approximately one-quarter had received prior bevacizumab. Patients received either panitumumab (6 mg/kg every 2 weeks) or cetuximab, 400 mg/m² followed by 250 mg/m² weekly.

At a median follow-up of approximately 9 months, the median OS in the panitumumab arm was 10.4 months vs 10.0 months, thus meeting the primary end point of this non-inferiority trial. Median PFS was also similar between the 2 arms at 4.1 months and 4.4 months for panitumumab and cetuximab, respectively.

Serious AEs were also observed in roughly one-third of patients in both treatment arms.

Summary

Regardless of the mutation giving rise to the original tumor, malignancies evolve in response to treatment. Over time, even highly effective therapies fail as treatment-resistant mutations emerge. Multi-targeted therapies interrupt numerous signaling pathways simultaneously, blocking proliferation and metastatic spread more effectively than agents with a narrower spectrum. Broader spectrum blockade has now been shown to extend PFS in GIST, as well as OS in mCRC, thereby extending life and preserving quality of life at the same time. Other combinations of targeted agents plus chemotherapy continue to be explored in mCRC as well.