Review efficacy results from tumor-location subgroup post hoc analyses of 3 phase III trials in RAS wild-type mCRC

The CRYSTAL Study

CRYSTAL primary tumor location post hoc analysis: Efficacy in patients with left- and right-sided RAS wild-type mCRC⁵

RAS wild-type subpopulation by primary tumor location (n=364): CRYSTAL regimen (n=175); FOLFIRI alone (n=189)

OR=odds ratio.

CRYSTAL study safety profile¹

No new relevant safety findings were identified in the RAS subpopulation analysis³

• The CRYSTAL study used a cetuximab product. ERBITUX provides approximately 22% higher exposure compared to this product; however, the safety data provided from CRYSTAL is consistent in incidence and severity of adverse reactions with those seen for ERBITUX in this indication¹

¶Adverse reactions occurring in ≥10% of patients in the cetuximab combination arm and at a higher incidence (≥5%) compared to the FOLFIRI-alone arm.

#Adverse reactions were graded using the National Cancer Institute Common Toxicity Criteria (NCI CTC), version 2.0.

**Infusion reaction defined as any event meeting the medical concepts of allergy/anaphylaxis at any time during the clinical study or any event occurring on the first day of dosing and meeting the medical concepts of dyspnea and fever or by the following events: “acute myocardial infarction,” “angina pectoris,” “angioedema,” “autonomic seizure,” “blood pressure abnormal,” “blood pressure decreased,” “blood pressure increased,” “cardiac failure,” “cardiopulmonary failure,” “cardiovascular insufficiency,” “clonus,” “convulsion,” “coronary no-reflow phenomenon,” “epilepsy,” “hypertension,” “hypertensive crisis,” “hypertensive emergency,” “hypotension,” “infusion related reaction,” “loss of consciousness,” “myocardial infarction,” “myocardial ischemia,” “prinzmetal angina,” “shock,” “ sudden death,” “syncope,” or “systolic hypertension.”

‡‡Acne-like rash defined by the following events: “acne,” “acne pustular,” “butterfly rash,” “dermatitis acneiform,” “drug rash with eosinophilia and systemic symptoms,” “dry skin,” “erythema,” “exfoliative rash,” “folliculitis,” “genital rash,” “mucocutaneous rash,” “pruritus,” “rash,” “rash erythematous,” “rash follicular,” “rash generalized,” “rash macular,” “rash maculopapular,” “rash maculovesicular,” “rash morbilliform,” “rash papular,” “rash papulosquamous,” “rash pruritic,” “rash pustular,” “rash rubelliform,” “rash scarlatiniform,” “rash vesicular,” “skin exfoliation,” “skin hyperpigmentation,” “skin plaque,” “telangiectasia,” or “xerosis.”

FIRE-3 study and post hoc analysis: Efficacy results in patients with mCRC^6,7

The FIRE-3 study may not be adequately powered, nor error-controlled, for subgroup analyses. Treatment differences observed in the RAS wild-type subpopulation cannot be regarded as statistically significant. The analyses described here were exploratory.

FIRE-3 data should not be interpreted as suggesting that cetuximab + FOLFIRI is more effective than bevacizumab + FOLFIRI, irrespective of RAS status or primary tumor origin (left or right colon).

Limitations of the RAS post hoc analysis data: 96% of patients in the intention-to-treat (ITT) population were evaluable for RAS status. RAS wild-type subpopulation data presented may not be representative of the label population.

• The primary endpoint in the ITT population was ORR in patients with KRAS wild-type mCRC and the result was not statistically significant^6,7

• Limitations of Use: ERBITUX is not indicated for treatment of RAS-mutant colorectal cancer or when the results of the RAS mutation tests are unknown

‡‡Objective response (complete response + partial response) was investigator-assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.0.^6,7

FIRE-3 study design and post hoc analyses^5-7

FIRE-3 study design

FIRE-3 was an open-label, randomized, multicenter, phase III trial comparing cetuximab + FOLFIRI^ǁǁ vs bevacizumab + FOLFIRI in first-line treatment of patients with KRAS exon 2 wild-type mCRC.⁶

• Patients were randomized (1:1) to receive either FOLFIRI + cetuximab^ǁǁ (n=297) or FOLFIRI + bevacizumab^ǁǁ (n=295) as first-line treatment
• The primary endpoint in the ITT population was objective response (complete or partial response) using RECIST 1.0, investigator-assessed. Secondary endpoints included median PFS and median OS

RAS post hoc analysis

In a post hoc analysis of the FIRE-3 study, 475 patient tumor samples were retested for other RAS mutations (exons 2-4 of both KRAS and NRAS).⁷

• 400 were found to be wild-type (final RAS wild-type population) and 75 were found to have mutations to one or more of the RAS genes tested

Primary tumor location RAS post hoc analysis

In this post hoc analysis of the FIRE-3 study, patients with RAS wild-type mCRC were evaluated based on primary tumor location.^5,7

• Among patients with RAS wild-type tumors (n=400), 98% (n=394) were evaluable for primary tumor location; of those, 77% (n=306) had left-sided tumors and 22% (n=88) had right-sided tumors. Patients with transverse colon tumors were included in the right-sided analysis
• A post hoc analysis of efficacy data was performed on patient subgroups defined by treatment arm, followed by primary tumor location:
  • Left-sided tumor subpopulation: cetuximab + FOLFIRI, n=157; bevacizumab + FOLFIRI, n=149
  • Right-sided tumor subpopulation: cetuximab + FOLFIRI, n=38; bevacizumab + FOLFIRI, n=50

ǁǁOn day 1 of each 14-day treatment cycle, patients treated with cetuximab + FOLFIRI received an initial IV infusion of cetuximab 400 mg/m² over 120 minutes followed by weekly infusions of 250 mg/m² over 60 minutes. Patients treated with bevacizumab + FOLFIRI received an initial IV infusion of bevacizumab 5 mg/kg over 90 minutes, followed 2 weeks later over 60 minutes, and over 30 minutes every 2 weeks thereafter with the first dose administered after chemotherapy and all subsequent doses administered either before or after chemotherapy. For all patients, the FOLFIRI regimen included 14-day cycles of irinotecan (180 mg/m² IV on day 1 over 60-90 minutes), folinic acid (400 mg/m² [racemic] on day 1 over 120 minutes), and fluorouracil (400 mg/m² bolus on day 1 followed by 2400 mg/m² as a 46-hour continuous infusion). Treatment was continued until disease progression, unacceptable toxicity, or a complete response was achieved.⁶

CALGB/SWOG 80405 study and post hoc analysis: Efficacy in patients with KRAS wild-type mCRC⁸

The CALGB/SWOG 80405 study may not be adequately powered, nor error-controlled, for subgroup analyses. Treatment differences observed in the RAS wild-type subpopulation cannot be regarded as statistically significant. The analyses described here were exploratory. CALGB/SWOG 80405 data should not be interpreted as suggesting that cetuximab + FOLFIRI or FOLFOX is more effective than bevacizumab + FOLFIRI or FOLFOX, irrespective of RAS status or primary tumor origin (left or right colon).

Limitations of the RAS post hoc analysis data: Only 59% of patients in the ITT population were evaluable for RAS status. RAS wild-type subpopulation data presented may not be representative of the label population.

• The primary endpoint in the ITT population was OS in patients with KRAS wild-type mCRC and the result was not statistically significant

mFOLFOX6=leucovorin, fluorouracil, and oxaliplatin

The results for OS (HR=0.88; 95% CI: 0.72-1.08) and PFS (HR=1.03; 95% CI: 0.86-1.24) in the expanded RAS wild-type cohort were similar to those in the full cohort.

• Limitations of Use: ERBITUX is not indicated for treatment of RAS-mutant colorectal cancer or when the results of the RAS mutation tests are unknown

¶¶ERBITUX is only approved in combination with FOLFIRI when treating mCRC. In CALGB/SWOG 80405, choice of FOLFIRI/mFOLFOX6 was at the discretion of the physician.

##Objective response (complete response + partial response) was investigator-assessed according to RECIST 1.0.

CALGB/SWOG 80405 study design and post hoc analyses^8-10

CALGB/SWOG 80405 study design

CALGB/SWOG 80405 was a randomized phase III trial of cetuximab or bevacizumab with FOLFIRI or mFOLFOX6 for patients with KRAS wild-type untreated metastatic adenocarcinoma of the colon or rectum.⁸

• The choice of FOLFIRI or mFOLFOX6 was made by the patient and physician before trial enrollment and randomization
• Patients were randomized (1:1:1) to receive FOLFIRI/mFOLFOX6 + cetuximab^††† (n=902), FOLFIRI/mFOLFOX6 + bevacizumab^††† (n=899), or FOLFIRI/mFOLFOX6 + cetuximab + bevacizumab^††† (n=533) as first-line treatment. Of these, 1137 patients with confirmed KRAS wild-type tumors received bevacizumab (n=559) or cetuximab (n=578)^‡‡‡
• The primary endpoint in the ITT population was OS in patients with KRAS wild-type mCRC. Secondary endpoints included objective response (complete or partial response) using RECIST 1.0, investigator-assessed and median PFS

Primary tumor location RAS post hoc analysis

In this post hoc analysis of the CALGB/SWOG 80405 study, primary tumor location in patients with RAS wild-type mCRC was determined from patient case report forms.⁹

• Cetuximab or bevacizumab was administered with either FOLFIRI or mFOLFOX6, at the discretion of the physician
• Among the total 474 patients with RAS wild-type mCRC, 51% (n=244) were in the cetuximab group and 49% (n=230) were in the bevacizumab group. Patients with transverse colon tumors were excluded from analysis
  • Among patients in the cetuximab group (n=244), 71% (n=173) had left-sided tumors and 29% (n=71) had right-sided tumors
  • Among patients in the bevacizumab group (n=230), 66% (n=152) had left-sided tumors and 34% (n=78) had right-sided tumors¹⁰

†††On day 1 of each 14-day treatment cycle, patients treated with cetuximab + FOLFIRI/mFOLFOX6 received an initial IV infusion of cetuximab 400 mg/m² over 120 minutes followed by weekly infusions of 250 mg/m² over 60 minutes. Patients treated with bevacizumab + FOLFIRI/mFOLFOX6 received an initial IV infusion of bevacizumab 5 mg/kg over 90 minutes, followed by infusions over 30-60 minutes every other week thereafter. Cetuximab or bevacizumab was administered prior to chemotherapy. The FOLFIRI regimen included 14-day cycles of irinotecan (180 mg/m² IV on day 1 over 90 minutes), leucovorin (400 mg/m² on day 1 over 2 hours), and fluorouracil (400 mg/m² bolus on day 1 followed by 2400 mg/m² as a 46-48 hour continuous infusion). The mFOLFOX6 regimen included 14-day cycles of oxaliplatin (85 mg/m² IV on day 1 over 120 minutes), leucovorin (400 mg/m² IV on day 1 over 2 hours), and fluorouracil (400 mg/m² bolus on day 1 followed by 2400 mg/m² as a 46-48 hour continuous infusion).

‡‡‡A lack of efficacy of EGFR antibodies in KRAS exon 2 mutant tumors resulted in a pivotal amendment restricting eligibility to patients with confirmed KRAS wild-type tumors within 3 years of the start of the trial. The following year, the dual antibody treatment group was closed due to failure of the dual antibody with chemotherapy combination treatment. Patient enrollment and follow-up of a revised 2-group trial (cetuximab vs bevacizumab with chemotherapy regimens) was completed after 10 years and additional amendments. The final primary analysis cohort was comprised of 1137 patients with confirmed KRAS wild-type tumors and included 804 patients randomized after and 333 patients registered before the KRAS amendment was implemented.

REFERENCES

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11. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Colon Cancer V.3.2018. © National Comprehensive Cancer Network, Inc 2018. All rights reserved. Accessed August 17, 2018. To view the most recent and complete version of the guidelines, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.
12. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Rectal Cancer V.3.2018. © National Comprehensive Cancer Network, Inc 2018. All rights reserved. Accessed August 17, 2018. To view the most recent and complete version of the guidelines, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.