Updated Results from T-DM1 and Regorafenib Trials, plus Other Highlights from ESMO 2012

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Regorafenib represents a new potential standard of care for patients with chemorefractory metastatic disease … as long as the patients are in good condition.

—Eric Van Cutsem, MD

The 35th European Society for Medical Oncology (ESMO) Congress in Vienna broke all records for attendance, with about 16,000 attendees from all over the world. Some sessions were standing room only, including the Presidential Symposia, the ESMO-ASCO Joint Symposium on genomics in breast cancer, and the Special Session on melanoma. To complement our more comprehensive news coverage of key ESMO presentations, additional studies of interest are summarized below.

New Data from EMILIA

The novel drug-antibody conjugate T-DM1 extended survival compared with chemotherapy in women with advanced HER2-positive breast cancer in an updated analysis of the phase III EMILIA trial presented by lead author, Sunil Verma, MD, Sunnybrook Odette Cancer Center, Toronto, Canada.1 Women randomly assigned to T-DM1 were 32% less likely to die, compared with the group randomly assigned to lapatinib (Tykerb) plus capecitabine (Xeloda), the reference arm.

Median overall survival was 30.9 months in the T-DM1 arm vs 25.1 months in the lapatinib/capecitabine arm. The absolute 6-month difference in survival between the two arms was highly statistically significant (P < .0001).

“These are some of the best survival data reported to date in metastatic breast cancer,” Dr. Verma stated. “These findings suggest that T-DM1 should be an important therapeutic option in the treatment of HER2-positive breast cancer.”

The results he presented were based on the second interim overall survival analysis of EMILIA, now with a median follow-up of about 19 months, and these updated results were also published in The New England Journal of Medicine2 on the day of the presentation (see page 10). Final overall survival findings will be presented in 2014. However, these will be descriptive only, as patients in the reference arm are now allowed to cross over to receive T-DM1.  Secondary endpoints in the trial were all significantly improved with T-DM1 vs lapatinib/capecitabine, he said.

The overall rate of grade 3 or more severe adverse events was higher in the lapatinib/capecitabine arm (57%) compared with T-DM1 (41%). T-DM1 was associated with higher rates of thrombocytopenia and elevated serum aminotransferase levels, whereas the lapatinib/capecitabine regimen was associated with higher rates of diarrhea, nausea, vomiting, and hand-foot syndrome. The rate of cardiac toxicity, a concern with trastuzumab (Herceptin), was low in both treatment arms.

EMILIA enrolled 991 patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. Baseline demographic and disease characteristics were well balanced. About 61% had prior anthracycline treatment.

CORRECT Trial Update

Regorafenib (Stivarga) produced a sustained survival benefit in patients with heavily pretreated metastatic colorectal cancer, according to an update of the phase III CORRECT trial.3 The benefit of regorafenib was seen across all prespecified subgroups. With longer follow-up, no new safety concerns were identified.

During the ESMO meeting, regorafenib was approved by FDA for treatment of metastatic colorectal cancer in the salvage setting (see page 22). The final updated analysis of overall survival presented at ESMO by Eric Van Cutsem, MD, University Hospitals Gasthuisberg/Leuven, Belgium, followed on the heels of the first preplanned interim overall survival analysis presented at the 2012 ASCO Annual Meeting, demonstrating a significant survival benefit (P < .0052).

The updated analysis showed that median overall survival was 6.4 months for regorafenib vs 5 months for placebo (P = .0038), representing a 21% reduced risk of death for the multikinase inhibitor. At 6 months, 52.2% of those who received regorafenib were alive vs 43% of the placebo group. At 1 year, 24% and 17%, respectively, were alive.

Dr. Van Cutsem noted that patients included in CORRECT all had good performance status despite the failure of standard treatments. “Results show that the benefit of treatment is sustained over time, with manageable side effects. Regorafenib represents a new potential standard of care for patients with chemorefractory metastatic disease … as long as the patients are in good condition.”

In the CORRECT trial, 760 patients from 14 countries whose disease had progressed on several lines of standard treatment were randomly assigned to oral regorafenib or placebo for 2 weeks on and 1 week off. Randomization was carried out in a 2:1 ratio. Both groups also received best supportive care.

Adverse events associated with regorafenib included hand-foot syndrome (46%), fatigue (47.6%), hypertension (27.8%), diarrhea (38%), and rash or skin desquamation (26%).

Translational studies are planned to identify a biomarker for response to regorafenib based on serum and tissue samples from patients enrolled in CORRECT.

Maintenance Bevacizumab

More support for the continuation of bevacizumab (Avastin) beyond disease progression in metastatic colorectal cancer came from the phase III BEBYP trial by the Gruppo Oncologico Nord Ovest.4 The study randomized patients who had received bevacizumab plus first-line chemotherapy with a fluoropyrimidine monotherapy, or FOLFIRI (leucovorin, fluorouracil [5-FU], irinotecan), FOLFOX (leucovorin, 5-FU, oxaliplatin), or FOLFOXIRI (leucovorin, 5-FU, oxaliplatin, irinotecan) to receive a second line of chemotherapy using either FOLFOX or FOLFIRI alone or with bevacizumab.

Among 184 patients followed for 18 months, median progression-free survival was 4.97 months without bevacizumab and 6.77 months with maintenance bevacizumab, representing a 35% reduction in risk (P = .0062), reported Gianluca Masi, MD, of the University Hospital of Pisa. Overall survival data are immature, but 52 deaths have occurred among controls and 46 among bevacizumab recipients.

Regorafenib in Refractory GIST

The multi–tyrosine kinase inhibitor regorafenib significantly delayed disease progression in all subgroups of patients with gastrointestinal stromal tumor (GIST) refractory to both imatinib (Gleevec) and sunitinib (Sutent), and appeared to confer benefits when continued after progression, according to subgroup and postprogression analyses of the phase III GRID trial.5

Upon progression, the study was unblinded and placebo recipients could cross over to receive regorafenib, while those whose disease progressed on regorafenib could continue the drug, if desired. Previous analyses of the 199-patient trial found a 4-month improvement in progression-free survival with regorafenib (hazard ratio [HR] = 0.27; P < .0001).

The drug conferred benefits regardless of the number of prior systemic therapies, geographic region, age, baseline ECOG performance score, duration of prior treatment with imatinib, or presence of KIT/PDGFRA mutations, reported Peter Reichardt, MD, PhD, of HELIOS Klinikum in Bad Saarow, Germany.

When continued after progression (n = 41), regorafenib was associated with an additional 4.5 months of remission; when given upon crossover (n = 56), it delayed progression for an additional 5.0 months. “This suggests that continuous kinase inhibition after progression may benefit patients by slowing tumor progression,” Dr. Reichardt suggested.

Neuroendocrine Data

Since pancreatic neuroendocrine tumors are highly vascular, and since the mTOR inhibitor everolimus (Afinitor) has antiangiogenic activity, RADIANT-3 investigators evaluated potential tumor markers in the vascular endothelial growth factor (VEGF) pathway. The results were presented by James C. Yao, MD, of The University of Texas MD Anderson Cancer Center in Houston.6

Pretreatment plasma samples were assessed for levels of the angiogenic cytokines VEGF-A, soluble receptors sVEGFR1 and sVEGFR2, and placental growth factor (PlGF). The multivariate analysis showed that sVEGFR1 and PlGF were significant prognostic markers, with lower baseline levels associated with longer progression-free survival. This means that patients with high sVEGFR1 and high PlGF are likely to have a worse prognosis. None of the markers, however, proved predictive of a benefit with everolimus, Dr. Yao reported.

In a separate presentation, an updated overall survival analysis of the phase III sunitinib trial was reported by Sandrine Faivre, MD, PhD, of Assistance Publique–Hôpitaux de Paris, Université Paris Diderot, Hôpital Beaujon, Clichy, France.6,7 The trial closed early and 69% of patients on the placebo arm eventually crossed over to sunitinib, potentially confounding the overall survival analysis.

Dr. Faivre presented overall survival data 2 years after study closure and after adjusting for crossover using four different statistical methods. The intent-to-treat analysis without adjustment for crossover showed median survival to be 33 months with sunitinib and 26.7 months with placebo (HR = 0.71). Adjusted for crossover, median survival with sunitinib ranged from 16.4 months (HR = 0.43) to 26.7 months (HR = 0.49), depending on the model employed. This yielded an overall survival benefit of 6.3 to 16.7 months, Dr. Faivre reported. ■

Disclosure: Dr. Verna has received honoraria from Roche/Genentech and GlaxoSmithKline, and research grants from Roche and Sanofi-Aventis. Dr. Reichardt is on the advisory board of Bayer. Dr. Masi reported no potential conflicts of interest. Dr. Van Cutsem has received research funding (via his institution) from Bayer. Dr. Faivre has received honoraria from Pfizer and Novartis. Dr. Yao has been a paid consultant for and has received research support (via his institution) from Novartis.


1. Verma S, Miles D, Gianni L, et al: Updated overall survival results from EMILIA, a phase 3 study of trastuzumab emtansine (T-DM1) vs capecitabine (X) and lapatinib (L) in HER2-positive locally advanced or metastatic breast cancer (MBC). 2012 ESMO Congress. Abstract LBA12. Presented October 1, 2012.

2. Verma S, Miles D, Gianni L, et al: Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. Oct 1, 2012 (early release online).

3. Van Cutsem EJD, Grothey A, Sobrero A, et al: Phase 3 CORRECT trial of regorafenib in metastatic colorectal cancer (mCRC): Overall survival updated. 2012 ESMO Congress. Abstract LBA18. Presented October 1, 2012.

4. Masi G, Loupakis F, Salvatore L, et al: A randomized phase III study evaluating the continuation of bevacizumab beyond progression in metastatic colorectal cancer patients who received bevacizumab as part of first-line treatment: Results of the BEBYP trial by the Gruppo Oncologico Nord Ovest. 2012 ESMO Congress. Abstract LBA17. Presented October 1, 2012.

5. Reichardt P, Casali PG, Kang Y-K, et al: Clinical benefit with regorafenib across subgroups and post-progression in patients with advanced gastrointestinal stromal tumor after progression on imatinib and sunitinib: Phase 3 GRID trial update. 2012 ESMO Congress. Abstract 14780. Presented September 30, 2012.

6. Yao JC, Shah M, Panneerselvam A, et al: The VEGF pathway in patients with pancreatic neuroendocrine tumors: Efficacy of everolimus by baseline marker level, and prognostic and predictive effect analyses from RADIANT-3. 2012 ESMO Congress. Abstract 11540. Presented September 29, 2012.

7. Faivre S, Niccoli P, Raoul JL, et al: Updated overall survival analysis from a phase III study of sunitinib vs placebo in patients with advanced, unresectable pancreatic neuroendocrine tumor. 2012 ESMO Congress. Abstract 11550. Presented September 29, 2012.