What s New in Colon Cancer? Therapy over the last decade

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1 What s New in Colon Cancer? 9/19/2014 Michael McNamara, MD Therapy over the last decade Cytotoxic chemotherapy - 5FU ( Mayo, Roswell, Infusional) - Xeloda (01 ) - Oxaliplatin (02 ) - Irinotecan (96 ) Anti- EGFR monoclonal antibodies - Cetuximab (04) - Panitumumab (06) Anti- VEGF monoclonal antibody - Bevacizumab (04 )

2 Incremental yet significant improvements in survival BSC: Med OS 4-6 mo 5FU: Med OS 8-10 mo Irinotecan & oxaliplatin: - Med OS mo VEGF/EGFR: - Med OS mo - In some current trials, Med OS is 30 months Redefining the role of surgery in metastatic disease With limited treatment options, surgery was employed for patients with limited metastatic disease (lung /liver) % 5 and 10 year survival With effective chemotherapy regimens, the definition of resectable disease has evolved Expanded the number of patients who may potentially receive curative intent metastatectomy

3 So, What s new? Points to discuss New Drugs Biologic agents in the first line of therapy KRAS and extended RAS testing Maintenance therapy Evolution of thought on approaching liver metastasis

4 New Drugs Regorafenib - Oral drug - Broad spectrum TKI (VEGFR, KIT, PDGFR, BRAF, etc) - FDA approved 2012 salvage Aflibercept - Intravenous - Targets VEGF-A and VEGF-B - FDA approved 2012 in combination with FOLFIRI after oxaliplatin failure Bevacizumab Aflibercept VEGF A B Regorafenib VEGFR Endothelial and smooth muscle proliferation, migration. Vascular permeability, remodeling of the ECM, hemostasis

5 Regorafenib Grothey et al.: lancet CORRECT trial patients who had failed all conventional therapy - Randomized to placebo or Regorafenib Regorafenib Median OS v 5.0 months (HR 0.77, Sig) Median PFS v 1.7 months Response rates - 1% Disease control - 41% v 15%

6 Regorafenib However, toxicity was not insignificant This may in part be due to the study population Common toxicity - HFS* - HTN* - Fatigue* - Fever - Rash - Anorexia - Diarrhea* - Hepatitis! Aflibercept Fusion protein composed of binding domain fragments of VEGFR1 and VEGFR2 combined with a human Fc IgG Functions as a decoy receptor - Binding VEGF-A, VEGF-B, and others

7 Aflibercept Van Cutsem et al.: J Clin Oncol VELOUR trial patients who failed prior oxaliplatin based therapy with or without prior bevacizumab - Randomized to FOLFIRI or FOLFIRI with Aflibercept Aflibercept Median OS v 12.1 months Median PFS v 4.7 months Response rates 19.8% v 11.1% It did not appear that prior bevacizumab use influenced outcomes Toxicity was consistent with VEGF axis based therapy

8 Aflibercept However, impact of this trial was complicated by another study which specifically looked at continuation of bevacizumab after progression on first line therapy Bev containing regimens. Bennouna et al. Lancet Oncol TML study Second line aflibercept or bevacizumab? In the TML study, patients who had progressed on a first line Bevacizumab containing regimen were randomized to second line therapy with or without bevacizumab Median OS v 9.8 months (HR 0.81, Sig)

9 First Line anti-vegf or anti- Bevacizumab has predominately been studied as a first line agent in combination with chemotherapy, and appears to provide a modest survival benefit Anti-EGFR MoAbs cetuximab and panitumumab initially were tested in the salvage setting - The first trials of anti- in treatment naïve patients demonstrated increased RR and PFS, but unclear survival impact First Line anti-vegf or anti- Not too long ago, therefore, VEGF targeted therapy was employed in treatment naïve metastatic CRC and anti-egfr MoAb were administered to patients after initial chemotherapy failure

10 First Line anti-vegf or anti- However, initial studies used expression of EGFR to select patients for anti- It became clear that EGFR expression was not the appropriate biomarker to predict response of these agents Other biomarkers were examined First Line anti-vegf or anti- KRAS mutations (exon 2) are present in about 40% of CRC and were found to predict a lack of benefit for anti-egfr Tx KRAS is downstream of the EGFR, and facilitates EGFR signal transduction through the MAPK pathway. Mutations result in constitutive activity

11 First Line anti-vegf or anti- When only KRAS Wildtype patients are examined, the benefit of anti-egfr therapy becomes more pronounced, and a survival benefit becomes more apparent in the first line setting KRAS mutations are then used to exclude patients from First Line anti-vegf or anti- Additional mutations in KRAS exons 3 and 4 and NRAS exons 2,3 & 4 are found in about 15-20% of patients It appears that these mutations also impair resistance to anti-egfr MoAbs When all-ras testing is used to examine patients, survival benefits in treatment naïve patients appear to be quite substantial

12 First Line anti-vegf or anti- So, for KRAS mutant patients, biologic therapy for CRC targets the VEGF pathway What about for patients with no RAS mutations. Are they better served with front line anti-egfr or anti-vegf therapy? First Line anti-vegf or anti- Heinmann et al. ASCO 2013 abst - FIRE-3 trial patients - Randomized to FOLFIRI + bevacizumab or cetuximab - Amended in 08 to include only KRAS exon 2 WT

13 First Line anti-vegf or anti- In the KRAS WT population - RR 58% v 62% (the same) - Med PFS 10.3 v 10 months (the same) - Med OS 28.8 v 25 months (HR 0.77, Sig) in favor of FOLFIRI / cetuximab Extended RAS (later analysis) - Med OS improvement was even more pronounced First Line anti-vegf or anti- Schwartzberg et al. J Clin Oncol : PEAK randomized phase 2 study - FOLFOX / Bevacizumab (v) FOLFOX / Panitumumab - Med OS by KRAS exon 2 testing 34 v 24 months in favor of panitumumab Again, potentially more pronounced when analyzed by all RAS Wt

14 First Line anti-vegf or anti- Hard to explain why a regimen that does not improve RR or PFS would increase the median OS Suggests that anti- may be appropriate as a component of front line therapy in patients without KRAS/NRAS mutations Further evaluation is required to be more definitive. Maintenance therapy There is no defined length of treatment, and many patients stay on therapy until progression or treatment related toxicity develops FOLFOX is more commonly employed in the first line setting than FOLFIRI A common problem with oxaliplatin is peripheral sensory neuropathy This often leads to oxaliplatin cessation before treatment failure

15 Maintenance therapy Therefore, several trials have investigated maintenance therapy with 5FU or complete treatment holidays A recent study, reported at ASCO 2014, is relatively informative. Maintenance therapy Koopman et al. J Clin Oncol 2014, suppl 3 LBA The CAIRO3 trial - Patients received 6 cycles of XELOX / bevacizumab. - Patients with SD/PR were randomized to either observation or maintenance xeloda / bevacizumab - At progression, patients were to go back on XELOX / Bev

16 Maintenance therapy Randomization First progression Second progression Xeloda / Bev Xelox / Bev Xelox / Bev x 6 R Observation Xelox / Bev PFS-1 PFS-2 Maintenance therapy Randomization Xeloda / Bev PFS 1 = 8.5 mo Xelox / Bev PFS 2 = 11.7 mo Xelox / Bev x 6 PFS 1 = 4.1 mo PFS 2 = 8.5 mo Observation Xelox / Bev Median OS = 21.7 v 18.2 months (NS)

17 Maintenance therapy The general theme in maintenance trials - Maintenance = continued full dose therapy - Maintenance > complete stop - Overall, staying on some therapy is preferred In practice, decisions are more nuanced - I discuss treatment breaks and maintenance - Patient preference, volume of disease, toxicity, tumor response Surgical resection of liver metastasis It is fairly clear that resection of metastatic lesions can result in long term disease free survival (>10 years) Most of the data pertains to liver metastasis, but lung lesions are also approached with curative intent Who benefits? How do we select patients?

18 Surgical resection of liver metastasis Historically, clinical features were used to determine the feasibility of hepatic resection Preferred 1-3 lesions, <3-5cm in size, uni-lobar, long disease free intervals from initial CR surgery to liver recurrence, low CEA, node negative primary cancers, wide margins achievable Surgical resection of liver metastasis This has evolved, largely based on retrospective reports from single high volume centers, to be defined not clinically, but by anatomic and physiologic factors

19 Surgical resection of liver metastasis Patients with synchronous lesions, bilobar distribution, multiple lesions (>3), larger tumors, close margings, are all potentially resectable Provided: Sufficient liver remnant (physiologic) and resectable (no major vascular invasion) Surgical resection of liver metastasis This has resulted in a literature referred to as conversion therapy - Requires highly active regimens - Reducing tumor volume to allow physiologic / anatomic resection Procedures like portal vein embolization - The hepatic lobe to be resected is embolized in advance. - This induces hypertophy of the anticipated remnant lobe

20 Surgical resection of liver metastasis The argument in favor of this aggressive approach is that outcomes are better than can be achieved with chemotherapy alone The argument against this approach is that it simply reflects selection bias No RCT of surgery and chemo v chemo alone for stage 4 disease exist. Other methods to treat liver metastasis Several techniques are also employed - RFA - Embolization (bland, radioactive, chemotherapy) - HIA chemotherapy - SBRT

21 Questions?