Category: Hem/Onc Updates

Use of Molecular Biomarkers to Inform Adjuvant Therapy for Colon Cancer

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SUMMARY: The role of adjuvant chemotherapy in patients with stage III ColoRectalCancer (CRC) has been well established, with improvement in Disease Free Survival (DFS) and Overall Survival (OS). The same however, cannot be stated for patients with Stage II CRC. Several Prognostic (outcome regardless of specific treatment) and Predictive (benefit from a specific therapy) molecular biomarkers have been developed to help make treatment decisions which include MSI (MicroSatellite Instability), LOH 18q (Loss of heterozygosity on the long arm of chromosome 18), P53, TS (Thymidylate Synthase), KRAS, BRAF, ERCC1 (Excision Repair Cross-Complementation group 1), Oncotype DX and Coloprint. Even though LOH 18q, P53, TS, KRAS, BRAF and ERCC1 are of prognostic value, they presently do not provide clinical utility in the management of early stage CRC. The biomarkers of interest are MSI, Oncotype DX Colon Cancer Assay and ColoPrint. MMR and MSI: MSI is the hallmark of defective/deficient DNA MisMatchRepair (MMR) system and develops following a germline mutation in one of the MMR genes. The MMR gene system consists of several proteins which are responsible for surveillance and correction of DNA errors. These genes include MLH1, MSH2, MSH6, PMS2 and EPCAM. MSI-high (MSI-H, MMR deficient) is actually a good prognostic marker in early stage CRC, with less likelihood of lymph node involvement, systemic metastases and with improved survival. These patients do not benefit from DNA inhibiting anti-metabolites such as 5-FluoroUracil (5-FU). In fact, treatment with 5-FU could be detrimental, whereas they may be more responsive to Irinotecan. This is in contrast to early stage CRC patients with tumors that are MicroSatelliteStable (MSS) or MSI-low (MSI-L) and MMR proficient, who benefit from 5-FU based adjuvant chemotherapy with significantly improved DFS. It should be noted that the prognosis for patients with early stage CRC, whose tumors harbor V600E BRAF mutation and are MSI-H, is similar to CRC patients with MSS tumors. MSI is a genetic marker of Lynch Syndrome (Hereditary Nonpolyposis Colorectal Carcinoma – HNPCC) and approximately 15% of sporadic CRC share the genetics of Lynch Syndrome and are MSI-H and MMR-deficient. By evaluating the MMR/MSI status of a CRC patient, a clinician may be able to assess a patient’s prognosis, predict response to therapy and detect Lynch’s Syndrome, which constitutes about 3-5% of CRC cases. MSI is a functional assay and can be detected by PCR whereas ImmunoHistoChemistry (IHC) can confirm the presence or absence of MMR proteins.

ONCOTYPE DX COLON CANCER ASSAY: Oncotype DX Colon Cancer assay is a multigene expression assay and evaluates genes in the patient’s tumor, using paraffin slides. It consists of 7 potential recurrence genes and 5 internal reference genes and has been clinically validated from three prospective trials, to assess risk of recurrence, in patients with Stage II and III CRC. The Oncotype DX colon cancer assay is able to prognosticate the risk of recurrence of a particular CRC tumor but unlike the Oncotype DX assay for Breast Cancer, is unable to predict clinical benefit from adjuvant chemotherapy.

COLOPRINT: This assay uses an18 gene expression profile and requires fresh tissue. This assay is also able to assess the risk of recurrence in Stage II CRC but is unable to predict the benefit from adjuvant chemotherapy.

In summary, testing for MSI should be performed in all patients with Stage II CRC. Genetic signatures derived from Oncotype Dx Colon Cancer assay and ColoPrint may have limited clinical value for patients with early stage CRC. NCCN guidelines recommend adjuvant chemotherapy for high risk Stage II CRC. High risk for recurrence is defined as tumors that are poorly differentiated (except those tumors that are MSI-H), lymphovascular invasion, perineural invasion, bowel obstruction, localized perforation, close, indeterminate or positive margins and examination of less than 12 lymph nodes. Mettu NB, Hurwitz H and Hsu DS. Oncology 2013;27:746-754

PERJETA® combination Improves Response Rates

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The FDA on September 30, 2013 approved PERJETA® for use in combination with HERCEPTIN® (Trastuzumab) and TAXOTERE® (Docetaxel) for the neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer. The accelerated approval by the FDA was based solely on the improved pCR rate with the three drug combination with no demonstrable improvement in event-free survival or overall survival. A confirmatory phase III trial is underway, with results expected in 2016. One would hope that the complete response rates would translate into improved survival. Stay tuned.

Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere) a randomised multicentre, open-label, phase 2 trial

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SUMMARY: PERJETA® (Pertuzumab) is a recombinant, humanized, monoclonal antibody that binds to the HER2 dimerization domain and prevents the dimerization of HER2 with other HER receptors, ie. HER3, HER1 and HER4. HERCEPTIN® (Trastuzumab) is a monoclonal antibody that specifically targets the HER2 receptor and blocks the downstream signalling pathways. The accelerated approval of PERJETA® for the neoadjuvant treatment of breast cancer was based on a randomized, multicenter, open-label, phase II trial, in which 417 patients with HER2-positive, operable, locally advanced or inflammatory breast cancer (T2-4d), were randomly assigned to receive preoperative therapy with either HERCEPTIN® plus TAXOTERE® (Docetaxel), PERJETA® plus HERCEPTIN® and TAXOTERE®, PERJETA® plus HERCEPTIN® or PERJETA® plus TAXOTERE®. Patients in the three drug group received preoperative therapy with PERJETA®, HERCEPTIN® and TAXOTERE® every 3 weeks for a total of 4 cycles and following surgery, all patients received 3 cycles of Fluorouracil, ELLENCE® (Epirubicin), and CYTOXAN® (Cyclophosphamide) – (FEC) IV every 3 weeks and HERCEPTIN® was continued every 3 weeks for a total of one year of therapy. The primary endpoint was pathological Complete Response (pCR) rate defined as the absence of invasive cancer in the breast. The FDA definition of pCR is the absence of invasive cancer in the breast and lymph nodes. All treatment groups were well balanced. Seven percent of patients had inflammatory breast cancer, 32% had locally advanced cancer and 70% had clinically node-positive breast cancer. Forty-seven percent of the patients had hormone receptor-positive disease. The FDA defined pCR rates were 39.3% in the PERJETA® plus HERCEPTIN® and TAXOTERE® group and 21.5% in the HERCEPTIN® plus TAXOTERE® group P=0.0063). Of Interest, the pCR rates in the three drug group were lower in patients with hormone receptor positive tumors compared to patients with hormone receptor negative tumors. The most common adverse events in the three drug group were alopecia, diarrhea, nausea and neutropenia. The accelerated approval by the FDA was based solely on the improved pCR rate with the three drug combination with no demonstrable improvement in event-free survival or overall survival. A confirmatory phase III trial is underway, with results expected in 2016. Gianni L, Pienkowski T, Im YH, et al. Lancet Oncol. 2012;13:25-32

ABRAXANE® TO THE RESCUE

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The recent approval by the FDA of ABRAXANE® in combination with GEMZAR® (Gemcitabine) for the first line treatment of patients with metastatic Adenocarcinoma of the Pancreas gives the Oncology Health Care Providers a much needed option to treat this group of patients. With a significant improvement in the Overall Survival, Progression Free Survival and Response Rates, ABRAXANE® combination will very likely replace the more toxic FOLFIRI regimen by virtue of its efficacy and tolerability.

Oral Apixaban for the Treatment of Acute Venous Thromboembolism

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SUMMARY: Apixaban (ELIQUIS®) is an oral, direct coagulation factor Xa inhibitor, similar to XARELTO® (Rivaroxaban). In this double blind study, ELIQUIS® was compared with conventional therapy, which included subcutaneous Enoxaparin (LOVENOX®) followed by Warfarin. Five thousand three hundred ninety five (5395) patients with acute deep vein thrombosis, pulmonary embolism or both, were randomly assigned to receive either ELIQUIS® 10 mg BID for one week followed by 5 mg BID for 6 months (n=2691) or conventional therapy with LOVENOX® followed by Warfarin (n=2704). The primary efficacy outcome was recurrent symptomatic venous thromboembolism or death, related to venous thromboembolism. ELIQUIS® was non inferior to conventional therapy (P<0.001). The risk of major bleeding was slightly lower in the ELIQUIS® group. This efficacy and safety of ELIQUIS® was demonstrable in all patient subgroups. ELIQUIS®, similar to XARELTO®, will very likely be approved for the treatment of Venous ThromboEmbolism. Unlike Vitamin K antagonists (Warfarin), the newer oral anticoagulants do not require coagulation monitoring as they have a rapid onset of action, relatively stable pharmacokinetics and are not associated with significant drug interactions. It is important to realize however, that there are no agents presently available to reverse bleeding associated with these new oral anticoagulants. Development of antidotes that bind to factor Xa inhibitors, in order to reverse bleeding complications, are underway. Agnelli G, Buller HR, Cohen A, et al. N Engl J Med 2013; 369:799-808

Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment of KRAS wild-type metastatic colorectal cancer German AIO study KRK-0306 (FIRE-3)

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SUMMARY: It is common practice to combine anti-EGFR agent ERBITUX® (Cetuximab) or anti-VEGF agent AVASTIN® (Bevacizumab) with chemotherapy, in the initial management of patients with metastatic colorectal cancer. There is however a higher likelihood for patients with tumors expressing wild type KRAS (non-mutated KRAS), to respond to ERBITUX®. In this randomized multicenter study, a CAMPTOSAR® (Irinotecan) based backbone, FOLFIRI (folinic acid, fluorouracil and Irinotecan) given along with ERBITUX® (Group A) was compared with FOLFIRI plus AVASTIN® (Group B), in treatment naïve patients with metastatic ColoRectal Cancer (mCRC). Of the 592 patients with wild type KRAS mCRC, 297 patients were randomized to Group A and 295 patients to Group B. The median age was 64 years. The median duration of treatment was 4.7 months and 5.3 months in Group A and Group B respectively. The primary endpoint was Objective Response Rate (ORR). Even though the ORR was comparable in Groups A and B (62% vs 57%), there was a significant improvement in the overall survival (OS) favoring Group A (28.8 vs 25.0 months, HR= 0.77, P=0.0164). The comparable response rates and surprising improvement in OS in the ERBITUX® group suggests that either ERBITUX® or AVASTIN® can be added to FOLFIRI, in the first-line treatment of wild type KRAS mCRC patients. It is however clear that in wild type KRAS mCRC patients, it may be harmful to combine ERBITUX® with FOLFOX chemotherapy regimen, as was seen in the EPOCH trial and based on MRC COIN trial, NORDIC-VII trial and N0147 trial, ERBITUX® should not be combined with FOLFOX chemotherapy regimen as there is no added benefit. It is now well established that mCRC that harbors KRAS mutations in exon 2 (about 40% of the patients) do not benefit from anti-EGFR therapies. The PRIME study has given us aditional insight and it appears that other activating RAS mutations may also predict lack of response to anti-EGFR therapies. With regards to BRAF mutations, they portend a poor prognosis, regardless of treatment. Heinemann V, Weikersthal LF, Decker T, et al. J Clin Oncol 31, 2013 (suppl; abstr LBA3506)

Obinutuzumab (GA101) plus chlorambucil (Clb) or rituximab (R) plus Clb versus Clb alone in patients with chronic lymphocytic leukemia (CLL) and preexisting medical conditions (comorbidities) Final stage 1 results of the CLL11 (BO21004) phase III trial

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SUMMARY: Obinutuzumab or GAZYVA® (GA101) is glycoengineered, fully humanized, third generation, type II anti-CD20 antibody (IgG1 monoclonal antibody) that selectivity binds to the extracellular domain of the CD20 antigen on malignant human B cells. It has enhanced antibody-dependent cellular cytotoxicity (ADCC) and strong apoptosis-inducing activity. In contrast, RITUXAN® (Rituximab) is a first generation chimeric anti-CD20 targeted monoclonal antibody. In this phase III trial, LEUKERAN® (Chlorambucil – Clb)) was compared with a combination of GAZYVA® plus LEUKERAN® (GClb) and a combination of RITUXAN® plus LEUKERAN® (RClb). Five Hundred and eighty nine (589) treatment naïve CLL patients over 70 years of age with comorbidities were enrolled of whom 118 patients received Clb, 238 received GClb and 233 received RClb. The primary endpoint was Progression-Free Survival (PFS). Chemoimmunotherapy with both GClb and RClb significantly prolonged PFS compared to Clb alone. The median PFS was 10.8 months with Clb alone compared to 23 months for GClb (HR=0.14, P<0.0001) and 15.7 months for RClb (HR=0.32, P<0.0001). There were no Complete Responses (CR) with Clb alone whereas the CR rates with GClb and RClb were 22% and 8% respectively. This study gives new life to LEUKERAN® when given in combination with CD20 targeted monoclonal antibodies and may be of value when treating elderly patients with comorbid conditions. Goede V, Fischer K, Humphrey K, et al. J Clin Oncol 31, 2013 (suppl; abstr 7004)

Safety and Tumor Responses with Lambrolizumab (Anti–PD-1) in Melanoma

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SUMMARY:Lambrolizumab (MK-3475) is a humanized anti–PD-1 monoclonal antibody. The programmed death 1 (PD-1) receptor is an inhibitory receptor expressed on activated T-cells in the tumor micro environment. The anti–PD-1 antibody by blocking the PD-1 receptor essentially unleashes the immune system to fight off cancer cells. One hundred and thirty five patients with advanced melanoma regardless of their prior therapy with YERVOY® (Ipilimumab) received IV Lambrolizumab every 2-3 weeks. There was no difference in the response rates between patients who had prior therapy with YERVOY® and those who did not (38%). Majority of these patients had a rapid and durable response. The median progression-free survival was more than 7 months. The most common adverse events, mostly low grade were, fatigue, rash, pruritus, and diarrhea. The authors concluded that Lambrolizumab can significantly benefit patients with advanced Malignant Melanoma, regardless of their prior therapy with anti-CTLA 4 antibody, YERVOY® and with minimal toxicity. Hamid O, Robert C, Daud A, et al. N Engl J Med 2013; 369:134-144

Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT)

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SUMMARY: The FDA recently approved ABRAXANE® ((Paclitaxel albumin-bound particles) for use in combination with GEMZAR® (Gemcitabine) for the first line treatment of patients with metastatic adenocarcinoma of the pancreas. This approval was based on the demonstration of improved overall survival (OS) in a multi-center, international, open-label, randomized trial. Eight hundred and sixty one (861) patients with metastatic pancreatic cancer were randomized to receive either the combination of ABRAXANE® and GEMZAR® (n=431) or GEMZAR® alone (n=430). Patients were stratified based on geographic region, performance status, and presence of liver metastasis. The median age was 63 years. The primary end point was OS and secondary endpoints included progression-free survival (PFS) and overall response rate (ORR. There was a statistically significant prolongation of OS for patients in the combination group with a 28% reduction in the risk of death [HR= 0.72; P < 0.0001]. The median OS was 8.5 months in the combination group and 6.7 months in the single agent GEMZAR® group. There was in addition a significant improvement in the PFS in the combination arm vs the single agent arm (5.5 months vs 3.7 months, respectively.HR= 0.69; P < 0.0001). Objective response rates were 23% in the combination group and 7% in the single agent GEMZAR® group (P<0.0001). Serious adverse reactions in patients receiving combination therapy included fever, vomiting, dehydration and pneumonia. This is clearly a major development in the management of advanced pancreatic cancer patients. Von Hoff DD, Ervin TJ, Arena FP, et al. J Clin Oncol 30: 2012 (suppl 34; abstr LBA148)

Long-Term Survival of Participants in the Prostate Cancer Prevention Trial

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SUMMARY: In the landmark Prostate Cancer Prevention Trial (PCPT), Finasteride (PROSCAR®) reduced the risk of Prostate Cancer development and therefore the symptoms associated with it by 33%, compared to Placebo. However, in those who did develop Prostate Cancer while on PROSCAR®, there was an increased risk of high grade tumors. After 18 years of follow up of these patients, it appears that in spite of this set back, there was no difference in the overall survival between the PROSCAR® group and the placebo group. The U.S. Preventive Services Task Force (USPSTF) has been against Prostate Cancer screening, as the consensus is that majority of the Prostate Cancers detected by screening would never become apparent in an individual’s lifetime, if this individual was not screened and therefore would never cause a problem. This long term data begs a very important question – Is it worthwhile taking PROSCAR® for Prostate Cancer prevention? Thompson IM, Goodman PJ, Tangen CM, et al. N Engl J Med 2013;369:603-610