Highlights from: Annual Meeting of the American Society of Clinical Oncology Chicago, Illinois; June 1–5, 2007

Meeting

Highlights Highlights from: Annual Meeting of the American Society of Clinical Oncology Chicago, Illinois; June 1-5, 2007

Six-Year Follow-up Results of the MOSAIC Trial of Adjuvant Chemotherapy MOSAIC was a landmark randomized phase III trial that investigated the role of oxaliplatin-containing chemotherapeutic regimen as adjuvant therapy for patients with stage II/III colon cancer.1 In this study, patients were randomized to receive infusional LV5FU2 (leucovorin/5-fluorouracil) or FOLFOX4 (5-FU/LV/oxaliplatin) and were treated every 2 weeks for a total of 12 cycles. The primary endpoint of the study was disease-free survival (DFS). Secondary endpoints included safety and overall survival (OS). The updated results of this study were presented at the American Society of Clinical Oncology (ASCO) annual meeting, held June 1-5, 2007, in Chicago, IL.2 Patients treated with FOLFOX4 showed a statistically significant improvement in 5-year DFS compared with patients on the LV5FU2 arm (73.3% vs. 67.4 %; P = 0.003). The improvement in 5-year DFS was highly significant for patients with stage III disease who were treated with FOLFOX4 compared with LV5FU2 (66.4% vs. 58.9%, respectively; P = 0.005). For patients with stage II disease, the difference in 5-year DFS between the 2 treatment arms did not reach statistical significance (83.7% vs. 79.9%; P = 0.258), although there was a trend favoring patients treated with FOLFOX4. However, when the group of stage II patients was stratified by high-risk and low-risk disease, patients Prepared by: Carlos Becerra, MD; Yull Arriaga, MD Reviewed by: Edward Chu, MD

with high-risk stage II disease who were treated with FOLFOX4 experienced a significant improvement in their 5-year DFS (82.1% vs. 74.9%; hazard ratio [HR], 0.76). In contrast, patients deemed to have low-risk stage II disease derived absolutely no benefit in terms of DFS. Of note, patients with high-risk stage II disease derived the same level of benefit in 5-year DFS as those with stage II disease (approximately 7%). At a median follow-up of 73.5 months, the difference in OS was statistically significant for patients with stage III disease treated with FOLFOX4 (73% vs. 68.6%, respectively; P = 0.029), but was not significant in patients with stage II disease (86.9% vs. 86.8%, respectively; P = 0.996). With respect to safety profile, patients who received FOLFOX4 experienced a higher incidence of grade 4 neutropenia (12.2% vs. 0) and grade 3 neuropathy (12.4% vs. 0). However, with continued follow-up of patients, the incidence of peripheral sensory neuropathy has continued to resolve in the majority of patients, with only 0.7% still experiencing grade 3 neuropathy compared with 12.4% at completion of adjuvant therapy. Moreover, no increase in the incidence of secondary cancers was observed in either arm of the study. The importance of oxaliplatin-based chemotherapy in the adjuvant setting has also been confirmed by the NSABP (National Surgical Adjuvant Breast and Bowel Project) C07 study.3 In this study, patients with resected stage II/III colon cancer were randomized to receive weekly 5-FU/LV (Roswell Park regimen) or weekly 5-FU/LV in combination with oxaliplatin every 2 weeks. With a median

follow-up of 34 months, the difference in DFS and the HR between the experimental and control arm were remarkably similar to the results of the MOSAIC trial. In general, the toxicities were also similar except for a lower incidence of chronic cumulative neuropathy in the NSABP C07 study (because of less cumulative dose of oxaliplatin) and a higher incidence of gastrointestinal toxicity, mainly in the form of diarrhea and dehydration.4

Clinical Relevance The updated analysis of the MOSAIC trial confirms the clinical benefit and safety of FOLFOX4 chemotherapy in the adjuvant therapy of stage III and highrisk stage II disease. However, this analysis also showed that patients with low-risk stage II disease do not derive any benefit in terms of DFS or OS when treated with FOLFOX4. Although this study might not have been sufficiently powered to show a significant difference in this particular subset, these findings suggest that treatment with oxaliplatin-based chemotherapy cannot be recommended for patients with low-risk stage II disease.

Phase III CAIRO Study Comparing Sequential Versus Combination Chemotherapy with Capecitabine, Irinotecan, and Oxaliplatin In 2007, there are 3 chemotherapy agents (5-FU, oxaliplatin, and irinotecan) and 3 biologic agents (bevacizumab, cetuximab, and panitumumab) that are Food and Drug Administration approved for the treatment of patients with metastatic colorectal cancer (CRC; mCRC). Presently, significant focus has

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been placed on combining these different agents into various regimens in the first-, second-, and third-line settings to determine any potential clinical benefit. However, it has been suggested that the sequencing of treatment options, instead of combining them upfront, might be able to decrease toxicity without compromising overall clinical efficacy and survival. This particular issue was addressed by investigators in the CAIRO study and its results presented at the 2007 ASCO meeting by Punt et al on behalf of the Dutch Colorectal Cancer Group.5 A total of 820 patients with previously untreated unresectable CRC were randomized to the combination treatment arm or the sequential treatment arm. Patients in the combination treatment arm received CAPOX (oxaliplatin 130 mg/m2 on day 1 and capecitabine 1000 mg/m2 orally twice a day on days 1-14 every 3 weeks) followed by CAPIRI (capecitabine/irinotecan) upon disease progression (irinotecan 250 mg/m2 on day 1 and capecitabine 1000 mg/m2 orally twice a day on days 1-14 every 3 weeks). Patients on the sequential treatment arm received capecitabine (1250 mg/m2 twice a day on days 1-14 every 3 weeks) as initial therapy followed by irinotecan alone (350 mg/m2 every 3 weeks) upon disease progression. At the time of tumor progression on irinotecan, the treatment was switched to XELOX (capecitabine/oxaliplatin) as third-line therapy. The primary endpoint of the study was OS, and secondary endpoints included response rate (RR), progression-free survival (PFS), safety, and quality of life (QOL). The combination approach yielded significantly improved RR (41% vs. 20%; P < 0.0001) and PFS (7.8 months vs. 5.8 months; P = 0.0002) compared with the sequential strategy. However, median OS, which was the primary endpoint of this trial, was similar between the sequential versus combination arms of the study (16.3 months vs. 17.4 months; P = 0.33). One-year survival was also virtually identical (64% vs. 67%). With respect to the safety profile, the adverse events reported for both treatment arms were similar except for a higher incidence of

palmar-plantar erythrodysesthesia (13% vs. 7%; P = 0.004) in the sequential treatment arm. This finding can be explained, at least in part, by a higher initial dose of capecitabine used in the sequential versus combination arm.

Clinical Relevance This trial demonstrated that median OS is equivalent between sequential and combination strategies. A similar result was observed in the FOCUS trial, in which the issue of sequential versus combination chemotherapy was addressed.6 Taken together, these studies highlight the important role of effective salvage therapies that are now available for patients with mCRC and suggest that sequential therapy might be a reasonable treatment option for patients who are considered to have "good" tumor biology and for those who do not manifest tumor-related symptoms. Finally, the potential integration of biologic agents in this sequential approach deserves further investigation, because they might enhance overall clinical efficacy and maintain safety profile.

Preliminary Results from the Phase III CRYSTAL Trial of Irinotecan and 5-Fluorouracil/ FA with and Without Cetuximab in the First-Line Treatment of Metastatic Colorectal Cancer A current standard treatment approach for patients with metastatic colon cancer includes initial therapy with a cytotoxic regimen of FOLFOX or FOLFIRI in combination with the anti-vascular endothelial growth factor (VEGF) bevacizumab.7,8 Cetuximab is a chimeric monoclonal antibody (MoAb) that targets the extracellular domains of the epidermal growth factor receptor (EGFR). The role of cetuximab in CRC has been studied in patients with disease that has progressed on irinotecan-based regimens, demonstrating significant clinical activity in this refractory disease setting.9 One important question that remains to be answered is whether cetuximab could improve the clinical benefit in patients with previously untreated metastatic colon cancer. Several phase II stud-

ies using cetuximab/FOLFIRI or cetuximab/FOLFOX have suggested that the addition of cetuximab is able to improve clinical benefit associated with cytotoxic chemotherapy.10,11 At this year’s ASCO meeting, the results of the phase III CRYSTAL study were presented.12 In this study, patients with untreated, unresectable colon cancer were randomized to receive FOLFIRI or FOLFIRI plus cetuximab. Only patients whose tumors expressed EGFR by immunohistochemistry were allowed to enter on the study. Additional inclusion criteria included histologically confirmed unresectable CRC, measurable disease, an Eastern Cooperative Oncology Group (ECOG) PS of 0-2, and adequate organ function. The primary endpoint was PFS, and secondary endpoints included ORR, OS, safety, and QOL measures. A total of 1217 patients were enrolled onto the study. The combination of cetuximab/FOLFIRI resulted in a significantly improved median PFS of 8.9 months versus 8 months with FOLFIRI treatment alone (HR, 0.85; log-rank P value = 0.0479), and the 1-year PFS rate was in favor of the combination arm (34% vs. 23%). Higher grades of skin toxicities were associated with longer PFS (5.4 months vs. 9.4 months vs. 11.3 months for grades 0/1, 2, and 3 skin toxicities, respectively) in the cetuximab/FOLFIRI arm. Patients in the cetuximab/FOLFIRI arm had an ORR of 46.9% versus 38.7% for those in the FOLFIRI-alone arm (P = 0.0038). Of note, the R0 resection rate was also significantly higher for patients in the cetuximab/FOLFIRI arm (4.3% vs. 1.5%; P = 0.0034) and was also higher in patients with liver-limited metastatic disease (9.8% vs. 4.5%). With respect to safety profile, adverse events in both treatment arms were similar except for a higher incidence of diarrhea (15.2% vs. 10.5%), skin toxicity (18.7% vs. 0.2%), and infusion reactions (2.3 % vs. 0) in patients treated on the cetuximab/ FOLFIRI compared with those on the FOLFIRI arm.

Clinical Relevance The CRYSTAL study is the first large phase III randomized study to report on Clinical Colorectal Cancer July 2007 • 557

MEETING HIGHLIGHTS the clinical benefit of cetuximab in chemotherapy-naive patients with mCRC. The study is important because it shows that cetuximab can be safely and effectively combined with chemotherapy in the first-line setting. Moreover, its integration with FOLFIRI chemotherapy results in a significant increase in the R0 surgical resection rate for patients who present with initially unresectable disease. Thus, cetuximab should be considered as an appropriate first-line and neoadjuvant therapy, especially in patients with liver-limited disease.

Interim Analysis of the Phase III PACCE Trial: Panitumumab with Chemotherapy plus Bevacizumab for Metastastic Colorectal Cancer Panitumumab is a fully human monoclonal immunoglobulin G2 antibody that specifically binds to the extracellular domain of the EGFR, a transmembrane glycoprotein member of the Erb family of receptors.13 Binding of panitumumab to the EGFR inhibits EGFR dimerization, tyrosine kinase autophosphorylation, and activation of downstream signaling pathways, which in turn results in inhibition of cancer cell growth, proliferation, and induction of apoptosis.14,15 Earlier phase II studies have demonstrated the activity and efficacy of panitumumab in chemotherapyrefractory mCRC.16-18 An open label, randomized, multiinstitutional, phase III trial demonstrated the superiority of panitumumab plus best supportive care (BSC) compared with BSC alone in patients with chemotherapy-refractory, EGFR-expressing mCRC.19 Of note, BSC patients who experienced progression could receive panitumumab in a crossover study. In this study, the median PFS time in the panitumumab arm was 8 weeks (95% confidence interval [CI], 7.9-8.4 weeks) compared with 7.3 weeks (95% CI, 7.1-7.7 weeks) in the BSC-alone arm (HR, 0.54; 95% CI, 0.44-0.66; P < 0.0001). Overall survival was similar in both groups, although this result was confounded by the fact that patients randomized to BSC were able to receive panitumumab at the time of disease progression. In terms of

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safety profile, rash, hypomagnesemia, and diarrhea were the most common toxicities associated with panitumumab. Based on these results, the US Food and Drug Administration approved panitumumab for the treatment of EGFRexpressing chemotherapy-refractory mCRC on September 27, 2006. Currently, the standard first-line therapy for patients with untreated mCRC in the United States is oxaliplatin- or irinotecan-based chemotherapy plus bevacizumab, a humanized MoAb that targets the VEGF-A.20,21 Preclinical and preliminary clinical studies have suggested that combining antibodies that target EGFR and VEGF with cytotoxic chemotherapy might improve treatment efficacy in mCRC.22,23 The PACCE trial was a randomized, controlled, openlabel, community-based, phase 3b study that evaluated the role of panitumumab added to standard cytotoxic chemotherapy plus bevacizumab as first-line treatment for mCRC.24 The interim analysis of this study was presented by Hecht et al at the 9th World Congress on Gastrointestinal Cancer, held June 30, 2007, in Barcelona, Spain. The goal of the PACCE trial was to evaluate the efficacy and safety of panitumumab added to standard chemotherapy plus bevacizumab as first-line treatment for mCRC. Eligible patients included those with an ECOG PS of 0/1 and no previous chemotherapy or biologic therapy for mCRC. Previous adjuvant chemotherapy was allowed if it was received > 6 months before enrollment in the study. No EGFR testing was required. Eight hundred patients were assigned in a 1:1 randomization to an oxaliplatin-based chemotherapy (Ox-CT) plus bevacizumab stratum with or without panitumumab. Additionally, 200 patients were assigned in a 1:1 randomization to an irinotecan-based chemotherapy (Ir-CT) plus bevacizumab stratum with or without panitumumab. Treatment in each group was continued until disease progression or toxicity occurred. The primary endpoint of the study was to detect a 30% improvement in PFS with the addition of panitumumab to Ox-CT plus bevacizumab. Secondary endpoints included ORR, time to treatment failure, OS, and

safety profile. Baseline demographics and clinical characteristics were similar among the 4 treatment groups. In terms of clinical efficacy, median PFS for panitumumab/Ox-CT plus bevacizumab was 9 months (95% CI, 8.5-10.4 months) compared with 10.5 months (95% CI, 9.7-11.6 months) for patients treated with Ox-CT plus bevacizumab. Median OS for panitumumab/Ox-CT plus bevacizumab was 18.6 months (95% CI, 16.4-20.6 months) and had not yet been reached for Ox-CT plus bevacizumab. The ORR by central review was similar in panitumumab/Ox-CT plus bevacizumab and the Ox-CT plus bevacizumab (39% and 41%, respectively). The incidence of serious adverse events (SAEs) was higher in patients who received panitumumab/Ox-CT plus bevacizumab and when compared with patients treated with Ox-CT plus bevacizumab (56% vs. 37%). Of note, the rate of grade 4 adverse events was 28% in panitumumab/Ox-CT plus bevacizumab and 18% in Ox-CT plus bevacizumab. In particular, there was an increased incidence of grade 3 dehydration, diarrhea, and infections in patients who received panitumumab therapy.

Clinical Relevance The early interim analysis of the PACCE trial demonstrated an unfavorable risk-benefit profile for first-line therapy of mCRC with panitumumab added to standard Ox-CT plus bevacizumab, such that panitumumab has a negative impact on clinical efficacy as well as safety profile. This study raises relevant issues regarding the safety and efficacy of using multiple targeted agents with standard chemotherapy as first-line treatment for mCRC, especially as it relates to panitumumab. Clinical studies conducted to date suggest that no such safety signals exist when the anti-EGFR antibody cetuximab us combined with bevacizumab and cytotoxic chemotherapy. Based on the results of this study, it is clear that panitumumab can not be simply substituted for cetuximab in combination regimens that include cytotoxic chemotherapy and bevacizumab.

MEETING HIGHLIGHTS Further clinical studies are ongoing to determine the potential role of panitumumab with standard chemotherapy alone as first- and second-line therapy for mCRC.25,26

Preliminary Results of a Phase III Study of Cetuximab Added to Irinotecan for Patients with Oxaliplatin-Refractory Metastatic Colorectal Cancer: The EPIC trial Significant progress in the treatment of mCRC has been achieved in recent years with the addition of new cytotoxic drugs and targeted agents to fluoropyrimidine-based chemotherapy. Strategies to optimize the incorporation of targeted agents in the treatment of advanced mCRC continue to evolve and are the focus of ongoing clinical trials. Cetuximab is a chimeric immunoglobulin G1 MoAb that specifically binds to the extracellular domain of the EGFR, a transmembrane glycoprotein member of the ErbB family of receptors.27 The EGFR gene with overexpression of the EGFR protein is upregulated in up to 60%-80% of mCRC cases.28,29 In 2004, Cunningham and colleagues reported the results of phase II randomized phase II trial of cetuximab alone and cetuximab/irinotecan in patients with EGFR-expressing, irinotecan-refractory mCRC.27 A statistically significant improvement in objective RR (22.9% vs. 10.8%) and median time to progression (4.1 months vs. 1.5 months) was observed in the combination arm. Median OS was similar in both arms (8.6 months vs. 6.9 months). An acnelike rash occurred in 80% of patients in both arms. The rate of SAEs was similar in the combination and cetuximabalone arms. Based on this study along with clinical studies conducted in the United States, cetuximab became the first anti-EGFR inhibitor approved in the United States in combination with

irinotecan in patients with irinotecanrefractory mCRC or as monotherapy in patients who were deemed to be intolerant to irinotecan. The EPIC trial is a randomized phase III multi-institutional study that evaluated patients with oxaliplatinrefractory, EGFR-expressing mCRC and compared cetuximab/irinotecan with irinotecan alone; the preliminary results of this trial were presented at the 2007 Annual Meeting of the American Association of Cancer Research, and the QOL data were presented at the 2007 ASCO Annual Meeting.30,31 Patients with EGFR-expressing mCRC that had not responded to first-line oxaliplatin in combination with a fluoropyrimidine with an ECOG PS of b 2 were eligible for the study. Treatment arms consisted of the standard loading dose of cetuximab 400 mg/m2 followed by the weekly dose of 250 mg/m2 plus irinotecan 350 mg/m2 every 3 weeks (n = 640) or irinotecan 350 mg/m2 alone every 3 weeks (n = 650). Patients in the 2 treatment arms were well balanced for baseline demographics and clinical characteristics. The primary endpoint of this study was OS. The secondary endpoints included objective RR, PFS, and assessment of heath-related QOL through the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 questionnaire. Statistically significant improvements in PFS (HR, 0.69; P < 0.01) and objective RR (16.4% vs. 4.2%; P < 0.001) were observed in the combination arm compared with the irinotecan-alone arm. This improvement in clinical activity did not translate into a significant difference in median OS (10.7 months vs. 9.9 months; HR, 0.975) in patients treated with cetuximab/irinotecan. However, this result was most likely confounded by the fact that nearly 50% of patients who experienced progression on irinotecan alone

were able to receive irinotecan/cetuximab. In terms of safety profile, the most common treatment-related grade 3/4 adverse events included diarrhea (28.8% vs. 16.2%), vomiting (6.1% vs. 6.4%), and fatigue (9.2% vs. 4.9%) in the cetuximab/irinotecan versus irinotecan-alone arm, respectively. Other grade 3/4 toxicities included acneiform rash (8.2% vs. 0.5%), infusion reaction (1.4% vs. 0.8%), and hypomagnesemia (3.3% vs. 0.4%), respectively, which were all related to cetuximab therapy.30 Patients receiving cetuximab/irinotecan had better preservation of heath-related QOL on 10 of 15 evaluated scales, lower deterioration in symptom scores for pain, nausea, insomnia, and higher global health status scores.31

Clinical Relevance The preliminary results of the EPIC trial demonstrate the superiority of cetuximab/irinotecan compared with irinotecan alone in the second-line therapy of patients with EGFR-expressing, oxaliplatin-refractory mCRC. This study provides the first clinical evidence of the efficacy, safety, and clinical benefit of cetuximab added to irinotecan in patients with oxaliplatin-refractory mCRC. Patients who received cetuximab/irinotecan had significant improvements in objective RR, PFS, QOL, and symptom control. Clinical benefit in the combination arm was demonstrated by higher scores in pain and nausea control, Global Health Status, and no exacerbation of irinotecan-associated SAEs. The lack of OS benefit in this trial was in part caused by subsequent cetuximab therapy in patients who received irinotecan alone after disease progression. Close to half of these patients received cetuximab, 89% of them in combination with irinotecan. In conclusion, this study supports the potential use of cetuximab/irinotecan as second-line therapy for patients with oxaliplatin-refractory mCRC.

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MEETING HIGHLIGHTS

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22. Shaheen RM, Ahmad SA, Liu W, et al. Inhibited growth of colon cancer carcinomatosis by antibodies to vascular endothelial and epidermal growth factor receptors. Br J Cancer 2001; 85:584-589. 23. Saltz LB, Lenz HJ, Hochster H, et al. Randomized phase II trial of cetuximab/bevacizumab/irinotecan (CBI) versus cetuximab/bevacizumab (CB) in irinotecan-refractory colorectal cancer J Clin Oncol 2005; 23(16 suppl):248s (Abstract #3508). 24. Hecht JR, Chidiac T, Mitchell E, et al. An interim analysis of efficacy and safety from a randomized controlled trial of panitumumab with chemotherapy plus bevacizumab for metastatic colorectal cancer. Paper presented at: 9th World Congress on Gastrointestinal Cancer; June 30, 2007; Barcelona, Spain. 25. STEPP: A phase 2, open-label, randomized clinical trial of skin toxicity treatment in subjects receiving second-line FOLFIRI or irinotecan only chemotherapy concomitantly with panitumumab. Available at: http://clinicaltrials.gov/ct/show/ NCT00332163?order=1. Accessed July 17, 2007. 26. A randomized, multicenter, phase 3 study to compare the efficacy of panitumumab in combination with oxaliplatin/ 5-fluorouracil/ leucovorin to the efficacy of oxaliplatin/ 5-fluorouracil/ leucovorin alone in patients with previously untreated metastatic colorectal cancer. Available at: http://clinicaltrials.gov/ct/show/NCT00364013?order=1. Accessed July 17, 2007. 27. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004; 351:337-345. 28. Porebska I, Harlozinska A, Bojarowski T. Expression of the tyrosine kinase activity growth factor receptors (EGFR, ERB B2, ERB B3) in colorectal adenocarcinomas and adenomas. Tumour Biol 2000; 21:105-115. 29. Messa C, Russo F, Caruso MG, et al. EGF, TGFalpha, and EGF-R in human colorectal adenocarcinoma. Acta Oncol 1998; 37:285-289. 30. Sobrero AF, Fehrenbacher L, Rivera F, et al. Randomized phase III trial of cetuximab plus irinotecan vs irinotecan alone for metastatic colorectal cancer (mCRC) after failing prior oxaliplatin-based therapy: the EPIC trial Presented at: Annual Meeting of the American Association of Cancer Research; April 12-16, 2007; San Diego, CA. 31. Eng C, Maurel J, Scheithauer W, et al. Impact on quality of life of adding cetuximab to irinotecan in patients who have failed prior oxaliplatin-based therapy: the EPIC trial. J Clin Oncol 2007; 25(18 suppl):164s (Abstract #4003).