gi cancer symposium 2012 report presentation

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Report from GI Cancer Symposium 2012

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Fight Colorectal CancerCheat sheet

AE ~ Adverse EventBSC ~ Best Supportive CareCAPOX ~ (also called XELOX) Capecitabine and OxaliplatinDCR ~ Disease Control RateFOLFOX ~ 5FU/Leucovorin, OxaliplatinKRAS WT ~ Kristen Rat Sarcoma/Wild TypemCRC ~ Metastatic Colorectal CancerMSI ~ Microsatellite InstabilityOS ~ Overall SurvivalORR ~ Overall Response RatePET ~ Positron Emission TomographyPt/Pts ~ Patient/PatientsPFS ~ Progression Free SurvivalQOL ~ Quality of LifeSD ~ Stable Disease


Dr. Daniel Sargent, PhDMayo Clinic Cancer Center

Biostatistician for the gastrointestinal research program at the Mayo Clinic Cancer Center and is involved in multiple ongoing clinical trials of both cancer treatment and cancer

screening.


Where have we been and where are we going?

2007 to 2012

What’s happened in the last 5 years?


GI ASCO 2007Family members of people with crc have a high risk of having polyps with the potential to become cancer

• Increasing the dose of cetuximab (Erbitux®) until a rash• appeared increased tumor response rates

PET scanning before surgery helps make better decisions on which pts should have surgery& improves survival

Patient communications & expectations data were shared showing more than 1/3 of pts would choose chemotherapy even if it only improved their chances against a recurrence by 1%


GI ASCO 2012

• Biomarkers (Predictive and Prognostic)

• Elderly patients responses to certain therapies

• Erbitux and Brivanib in combination for refractory metastatic disease

• Quality of life assessment data presented

• New data for metastatic refractory colorectal cancer patients

Biomarkers

Background ~ 20% of stage II CRC patients will experience a relapse of their disease, and may benefit from adjuvant chemotherapy

Question ~ How do we determine who those patients are?

The “ColoPrint index” was determined on 320 patients, using gene expression, fresh tissue, MSI-status, and patient follow-up

Conclusions ~ ColoPrint: • Available as a diagnostic test with high precision and reproducibility • Improves the prognostic accuracy of pathological factors and MSI• Helps to identify low risk patients, who may be safely managed without chemotherapy

Caveats ~ Requires fresh tissue, still a modest size trial

Biomarkers

Background ~ Identifying a prognostic marker would aid in the management of patients with node negative colon cancer

Question ~ What is the prognostic value of guanylyl cyclase for disease recurrence in untreated stage II colon cancer?

GCC mRNA was quantified from 310 stage II patients, enrolled in 2 studies between 1991-2006. Patients classified according to their GCC lymph node ratio.

Clinical outcomes included time to recurrence, overall survival, and disease free survival

Conclusion ~ Patients with GCC lymph node ratio high risk have significantly poorer outcomes compared to patients with low risk status.

Caveats ~ Modest size study, limited institutions, validation study ongoing

Elderly Patient PopulationBackground ~ Cross trial comparison of age, comparing 3 trials in patients with stage III disease

Question ~ What affect does age have on the effectiveness of Oxaliplatin based adjuvant therapy?

Conclusion ~ The benefits of adding Oxaliplatin to 5-FU are less in patients greater than 70 years of age

NSABP C-07 MOSAIC NO16968 FLOX FOLFOX XELOX

Age, years <70 >70 <70 >70 <70 >70DFS

Hazard Ratio 0.76 1.03 ~0.75 0.91 0.8 0.86OS

Hazard Ratio 0.8 1.18 ~0.77 1.1 0.82 0.91

Elderly Patient PopulationBackground ~ While colon cancer is predominantly a disease of the elderly, older patients are underrepresented in clinical trials.

Question ~ Do treatment patterns and benefits realized by trial participants pertain to older patients?

Retrospective analysis of 3390 stage II and stage III patients >66 years old who received 5FU/LV, FOLFOX, CAP or CAPOX within 3 months after surgery.

Conclusion ~ Treatment outcomes for elderly pts were comparable between CAP based and 5FU/LV-based regimens and consistent with results reported in randomized clinical trials.

Risk of death

HR 95% CI p-value5FU/LV 1 FOLFOX 0.7 0.55 - 0.90 0.005CAP 1.17 0.88 - 1.56 0.293CAPOX 0.44 0.20 - 0.98 0.044

Cetuximab + Brivanib

Background ~ Cetuximab has improved overall survival in pts with metastatic, refractory, KRAS wild type CRC

Question ~ Will the addition of Brivanib, a tyrosine kinase inhibitor targeting vascular endothelial and fibroblast growth receptors, improve overall survival in a phase III trial?

Phase III trial, of pts with mCRC, previously treated w/combination therapy, randomized:

• CET 400mg/m2 loading dose, followed by weekly 250mg/m2 + 800 mg oral BRIV daily or placebo

Conclusion ~ Despite positive effects of PFS, the combination of CET and BRIV did not significantly improve overall survival

Brivanib Arm Placebo Arm Hazard Ratio

Median OS 8.8 months 8.1 months 0.88

Median PFS 5.0 months 3.4 months 0.72

Partial Response 13.60% 7.20%

Stable Disease 50% 44%

Cetuximab + Brivanib QOL DataBackground ~ Although the primary endpoint (overall survival) was not improved, PFS favored the CET + BRIV arm

Question ~ When looking at quality of life as a secondary endpoint, what effect did the CET + BRIV arm have on QOL?

750 randomized patients were assessable for QOL

Receiving CET 400mg/m2 loading dose, followed by weekly 250mg/m2 + 800 mg PO BRIV daily or placebo

Median time to QOL DET (deterioration)1.6 months vs 1.1 monthsMedian time to QOL PF (physical function) 5.6 months vs 1.7 months

Conclusion ~ Despite a PFS benefit, the combination of CET + BRIV worsened time to QOL DET and PF, in pts with refractory KRAS WT mCRC

RegorafenibBackground ~ Regorafenib (small molecule), an oral multikinase inhibitor of a broad range of angiogenic, oncogenic, and stromal kinases, was study in a Phase 1 trial, and showed results in disease control of 74% in pts with mCRC who had progressed after all approved therapies

Question ~ In a larger phase III CORRECT trial, what is the efficacy and safety of regorafenib in this difficult to treat patient population?

Phase III, 760 patients randomized 2:1 to receive regorafenib 160mg orally, 3 wks on, 1 wk off, + BSC or placebo

Regorafenib Placebo HRMedian OS 6.4 months 5.0 months 0.77Median PFS 1.9 months 1.7 months 0.49

ORR 1.60% 0.40% SD 43.80% 14.90%

DCR 44.80% 15.30%

Regorafenib (con’t)

Regorafenib (con’t)

Affect did not differ by KRAS status

Most frequent grade 3 adverse events in the regorafenib arm:Hand foot reaction 16%Fatigue 9%Diarrhea 7%Hypertension 7%

Conclusion ~ Statistically significant benefit in OS and PFS was observed for regorafenib over placebo in patients with mCRC who have failed all approved standard therapies. No new or unexpected safety signals were found.

Conclusions

• Biomarkers will be key to treating stage II (and perhaps stage III) patients, as we know many patients do not need treatment

• Less intensive therapy an appropriate option for elderly patients

• Benefit in PFS may not be sufficient to truly benefit the patient

• Regorafenib provides modest benefit in last line setting, but clearly worthy of further study in earlier lines of therapy


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gi cancer symposium 2012 report presentation

Health & Medicine

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low risk patients