CYRAMZA® Improves Overall Survival in Advanced Gastric Cancer

In a multinational double-blind phase III trial, targeting VEGFR-2 signaling with CYRAMZA® , improved overall survival in patients with previously treated advanced or metastatic gastric or gastroesophageal junction adenocarcinoma. CYRAMZA® is the first biological treatment that has demonstrated survival benefit when given as a single agent in this patient population. This study was published in the Lancet, 2014.

Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD) an international, randomised, multicentre, placebo-controlled, phase 3 trial

SUMMARY: It is estimated that there were approximately 21,600 new cases and 10,990 deaths from gastric cancer in the United States in 2013. The biology of gastric cancer appears to be different in different parts of the globe. Following progression after first line treatment for metastatic disease, the median survival is approximately 3 months. Ramucirumab (CYRAMZA®) is a recombinant human IgG1 monoclonal antibody that binds to Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) and blocks binding of the VEGFR ligands VEGF-A, VEGF-C, and VEGF-D and thus inhibits ligand-induced proliferation and migration of endothelial cells. This is unlike AVASTIN® (Bevacizumab) which inhibits VEGF-A. REGARD is a multinational double-blind phase III trial, in which 355 patients with previously treated advanced or metastatic gastric or gastroesophageal junction adenocarcinoma were randomly assigned in a 2:1 ratio to receive CYRAMZA® at 8 mg/kg, IV (N=238) or Placebo (N=117) every 2 weeks. Both groups also received best supportive care. The median age was 60 years and the ECOG performance of the patient population was 0 or 1. Patients received a median of four doses of CYRAMZA® or a median of three doses of Placebo. The primary endpoint was Overall Survival. The median Overall Survival in the CYRAMZA® group was 5.2 months vs 3.8 months in the Placebo group (HR = 0.78, P=0.047). The median Progression-Free Survival was also prolonged in the CYRAMZA® group (2.1 vs 1.3 months, HR = 0.48, P <0 .001). The most common adverse events of any grade in the CYRAMZA® group were hypertension, diarrhea, headache and hyponatremia. The authors concluded that VEGFR-2 signaling is an important therapeutic target in advanced gastric cancer and CYRAMZA® is the first biological treatment that has demonstrated survival benefit when given as a single agent in patients with advanced gastric or gastroesophageal junction adenocarcinoma, progressing after first-line chemotherapy. Fuchs CS, Tomasek J, Yong CJ, et al. Lancet. 2014;383:31-39

Treatment of Advanced Non–Small-Cell Lung Cancer with Epidermal Growth Factor Receptor (EGFR) Mutation or ALK Gene Rearrangement Results of an International Expert Panel Meeting of the Italian Association of Thoracic Oncology

SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 27% of all cancer deaths. It is the leading cause of cancer death among both men and women. The American Cancer Society’s estimates that over 224,000 new cases of lung cancer will be diagnosed in the United States in 2014 and over 159,000 will die of the disease. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, adenocarcinoma now is the most frequent histologic subtype of lung cancer. In the mid 1990’s, following a meta-analysis of 52 randomized clinical trials, platinum based doublet chemotherapy became the accepted standard, for patients with Stage IV Non Small Cell Lung Cancer (NSCLC), after this combination demonstrated a 27% reduction in the risk of death compared to supportive care. Since then, significant advances have been made and it is now established that Platinum/Pemetrexed (ALIMTA®) combination results in superior survival in those with non squamous histology tumors whereas Platinum/ Gemcitabine (GEMZAR®) combination is superior in patients with squamous cell histology. In 2004, the discovery of Epidermal Growth Factor Receptor (EGFR) mutations in some advanced NSCLC cases with adenocarcinoma histology and the favorable responses with EGFR Tyrosine Kinase Inhibitors (TKIs) such as TARCEVA® (Erlotinib) and IRESSA® (Gefitinib), changed the treatment paradigm in favor of targeted therapy for this patient subset. Subsequently, the discovery of rearrangements of the Anaplastic Lymphoma Kinase (ALK) gene in some patients with advanced NSCLC and adenocarcinoma histology, led to the development of agents such as XALKORI® (Crizotinib) and ZYKADIA® (Ceritinib), with promising results. It has become clear that appropriate, molecularly targeted therapy for tumors with a molecular abnormality, results in the best outcomes. This new paradigm lead to the development of evidence based recommendations by a panel of experts in thoracic oncology taking the “driver oncogenes and driver mutations” into consideration. According to the US Lung Cancer Mutation Consortium (LCMC), two thirds of patients with advanced adenocarcinoma of the lung, have a molecular driver abnormality. The most common oncogenic drivers in patients with advanced adenocarcinoma of the lung are, KRAS in 25%, EGFR in 21% and ALK in 8% as well as other mutations in BRAF, HER2, AKT1 and fusions involving RET and ROS oncogenes. These mutations are mutually exclusive and the presence of two simultaneous mutations, are rare. The following guidelines have been put together, to better manage patients with advanced adenocarcinoma of the lung.                                   

EGFR Mutations and EGFR TKIs

• All patients with advanced NSCLC with the exclusion of pure squamous cell carcinoma should be tested for EGFR mutations before first line treatment decision is made. Because EGFR mutations and ALK rearrangement are mutually exclusive, routine testing of the other is not required for those patients with one known genomic abnormality.

• Patients should be tested for the most common sensitizing mutations such as deletions in exon 19 and L858R point mutations in exon 21, as these patients clearly benefit from first line EGFR TKIs. EGFR expression by IHC (ImmunoHistoChemical) staining, EGFR gene copy by FISH (Fluorescence In Situ Hybridization) and blood based proteonomic testing by VERISTRAT® is currently not recommended for the selection of first line EGFR TKIs.

• Any one of the three available agents, TARCEVA® (Erlotinib), GILOTRIF® (Afatinib) or IRESSA® (Gefitinib) are recommended for first line treatment, as per the regulatory label, because of the absence of data on direct comparisons.

• Platinum based chemotherapy should be considered after EGFR TKI failure in eligible patients and there is no evidence to recommend a preferred chemotherapy regimen in EGFR mutation positive patients.

• If EGFR mutation positive results become available after commencement of first line chemotherapy, early interruption of chemotherapy is discouraged. However maintenance therapy with EGFR TKI should be considered after completion of first line chemotherapy.

• In patients with unknown EGFR mutational status, first line platinum based chemotherapy is the standard of care.

• Continuing EGFR TKI beyond disease progression after its use as first line treatment is not recommended.

ALK Rearrangements and Treatment Selection

• Currently, ALK status is determined by FISH technique although ALK testing by IHC analysis is gaining momentum.

• All patients with advanced NSCLC with the exclusion of pure squamous cell carcinoma should be tested for ALK rearrangement before decision about first line treatment is made. Because EGFR mutations and ALK rearrangements are mutually exclusive, routine testing of the other is not required for those patients with one known genomic abnormality.

• In the US, XALKORI® (Crizotinib) is approved for use in any line of treatment.

• Chemotherapy is allowed in any line of treatment although it is preferable to use it following treatment failure with XALKORI®.

• ZYKADIA® (Ceritinib) is approved in the US for treatment of patients with disease progression on or who are intolerant to XALKORI® (Crizotinib).

• If ALK positive results become available after commencement of first line chemotherapy, early interruption of chemotherapy is discouraged. In these patients, XALKORI® should be used as second line treatment following disease progression on chemotherapy. Maintenance therapy with XALKORI® is not recommended.

• In clinical practice, a repeat biopsy is not recommended at disease progression after treatment with EGFR TKIs or ALK inhibitors.
Gridelli C, de Marinis F, Cappuzzo F, et al. Clinical Lung Cancer 2014;15:173-181

CALGB/SWOG 80405 Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC)

SUMMARY: The American Cancer Society estimates that approximately 137,000 new cases of colorectal cancer will be diagnosed in the United States in 2014 and over 50,000 are expected to die of the disease. Even though colon cancer localized to the bowel is potentially curable with surgery and adjuvant chemotherapy, advanced colon cancer is often incurable. Standard chemotherapy when combined with anti EGFR (Epidermal Growth Factor Receptor) targeted monoclonal antibodies such as VECTIBIX® (Panitumumab) and ERBITUX® (Cetuximab) as well as anti VEGF agent AVASTIN® (Bevacizumab), have demonstrated improvement in Progression Free Survival and Overall Survival. The benefit with anti EGFR agents however is only demonstrable in patients with metastatic colon cancer, whose tumors do not harbor KRAS mutations in codons 12 and 13 of exon 2 (KRAS Wild Type). It is now becoming clear that even amongst the KRAS Wild Type patient groups, about 15% to 20% have other rare mutations such as NRAS and BRAF mutations, which confer resistance to anti EGFR agents. Therefore, pan RAS (expanded RAS) testing may become relevant. To determine the optimal combination treatment regimen, this phase III intergroup trial evaluated the addition of ERBITUX® or AVASTIN® to physician’s choice of standard first line chemotherapy such as FOLFIRI or mFOLFOX6. Even though the original study included unselected metastatic colorectal cancer patients and randomization to a third arm (combination of ERBITUX® and AVASTIN®), this study was amended to include only pts with KRAS Wild Type tumors and the combination ERBITUX® and AVASTIN® arm was deleted. Patients were randomized to either ERBITUX® 400 mg/m2 week one and then 250 mg/m2, weekly or AVASTIN® 5 mg/kg every 2 weeks given along with FOLFIRI or mFOLFOX6 chemotherapy (physicians choice at the time of enrollment). The median age was 59 years and treatment groups were Chemo plus AVASTIN® (N=559) and Chemo plus ERBITUX® (N=578). Approximately 27% of the patients received FOLFIRI chemotherapy regimen and 76% received mFOLFOX6 chemotherapy regimen. Treatment was given until disease progression and median follow up was 24 months. The primary endpoint was Overall Survival. The median Overall Survival was similar in the ERBITUX® combination and the AVASTIN® combination groups (about 29 months) and so was the Progression Free Survival in both groups (about 10.5 months). The chemotherapy used with either of the antibodies had no influence on the outcomes. The toxicity profiles were different as expected, with increased incidence of Grade 3-4 rash (7% versus 0%) and diarrhea (11% versus 8%), in the ERBITUX® group and increased incidence of Grade 3-4 hypertension (7% versus 1%) and gastrointestinal events (2% versus 0.5%), in the AVASTIN® group. The authors concluded that either ERBITUX® or AVASTIN® in combination with chemotherapy have equivalent overall survival benefit, when given as first line therapy, for patients with metastatic colorectal cancer, whose tumors are KRAS Wild Type. It remains to be seen however, if pan RAS (expanded RAS) testing and other molecular studies will identify subsets of patients who will benefit from specific antibody chemotherapy combination regimens. Venook AP, Niedzwiecki D, Lenz H, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr LBA3)

Randomized comparison of adjuvant aromatase inhibitor (AI) exemestane (E) plus ovarian function suppression (OFS) vs tamoxifen (T) plus OFS in premenopausal women with hormone receptor-positive (HR+) early breast cancer (BC) Joint analysis of IBCSG TEXT and SOFT trials

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately, 233,000 new cases of invasive breast cancer will be diagnosed in 2014 and 40,000 women will die of the disease. Approximately 75% of patients with breast cancer are hormone receptor positive (Estrogen Receptor/Progesterone Receptor positive) and this is a predictor of response to endocrine therapy. In premenopausal woman, the ovary is the main source of estrogen production, whereas in postmenopausal women, the primary source of estrogen is the Aromatase enzyme mediated conversion of androstenedione and testosterone to estrone and estradiol in extragonadal/peripheral tissues. Presently available therapies include Tamoxifen and other Selective ER Modulators, which modulate ER alpha activity, Aromatase Inhibitors and Ovarian ablation that decrease estrogen production and FASLODEX® (Fulvestrant) that down regulates Estrogen Receptor. Aromatase Inhibitors (AI’s) are often prescribed, due to their superiority over Tamoxifen, for postmenopausal women with Hormone Receptor positive breast tumors, in adjuvant as well as metastatic settings. AI’s however, are not effective in premenopausal women, as these individuals derive their estrogen mainly from ovaries and not extragonadal tissues. The 2000 Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) overview, as well as subsequent studies comparing adjuvant ovarian ablation/suppression with adjuvant chemotherapy in premenopausal women with hormone positive breast tumors, have demonstrated similar magnitude of benefit. The TEXT (Tamoxifen and Exemestane Trial) and SOFT (Suppression of Ovarian Function Trial) are two phase III randomized trials, conducted at the same time and included premenopausal women (average age was 43 years) with hormone receptor positive early breast cancer. In the joint analysis of these two trials in which 5738 women were enrolled, the authors set out to answer 2 important questions – whether adjuvant AI improves outcomes in this patient group when their Ovarian Function is suppressed and whether there is any benefit with Ovarian Function suppression in premenopausal women suitable for adjuvant Tamoxifen. TEXT randomized patients (N=2672) within 3 months of surgery to 5 years of AROMASIN® (Exemestane) plus Ovarian Function Suppression (OFS) or 5 years of Tamoxifen plus OFS. The SOFT study randomized patients (N=3066) to 5 years of AROMASIN® plus OFS or 5 years of Tamoxifen plus OFS or 5 years of Tamoxifen alone. OFS choices included oophorectomy, ovarian irradiation or 5 years of TRELSTAR® (Triptorelin), a GnRH (Gonadotropin Releasing Hormone) agonist. The primary endpoint of these two studies was Disease Free Survival (DFS). In this joint analysis the outcomes for 4690 women randomized to receive AROMASIN® plus OFS or Tamoxifen plus OFS for 5 years, were analyzed. The 5 year Disease Free Survival was 91.1% in the AROMASIN® plus OFS group and 87.3% in the Tamoxifen plus OFS group (HR=0.72, P<0.0002). Compared to patients receiving Tamoxifen plus OFS, AROMASIN® plus OFS reduced the relative risk of premenopausal women developing a subsequent invasive breast cancer by 28% and the relative risk of breast cancer recurrence by 34%. The authors concluded that this largest joint analysis, evaluating adjuvant AI therapy with OFS in premenopausal women with Hormone receptor positive breast cancer, has demonstrated that 5 years of highly effective adjuvant endocrine therapy without chemotherapy can result in excellent outcomes. Further, AROMASIN® may be better than tamoxifen, when given with Ovarian Function Suppression. Pagani O, Regan MM, Walley B, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr LBA1)

The ASH Choosing Wisely® campaign five hematologic tests and treatments to question

SUMMARY: CHOOSING WISELY® is a quality improvement initiative led by the American Board of Internal Medicine Foundation in collaboration with leading medical societies in the United States such as the American Society of Hematology (ASH). This organization was established to improve quality of medical care, after it was noted that about 25% of the tests ordered at the time of hospital admission and 65% of the tests ordered on subsequent days were avoidable. Further, there is ample evidence to suggest that reducing unneeded investigations can decrease costs, increase patient satisfaction and quality of care. CHOOSING WISELY® has challenged medical societies to identify 5 tests, procedures or treatments, within each specialty's clinical domain, that are offered to patients, despite the lack of evidence demonstrating its benefit. The goal is to make positive changes in the actual delivery of patient care. The ASH identified 5 tests and treatments that practicing hematologists should give due consideration to, that in some situations are not evidence based and which in certain cases are associated with risks that outweigh the benefits and are not cost efficient.

Multitarget Stool DNA Testing for Colorectal-Cancer Screening

SUMMARY: The American Cancer Society estimates that approximately 137,000 new cases of colorectal cancer will be diagnosed in the United States in 2014 and over 50,000 are expected to die of the disease. It is the third leading cause of cancer death in the U.S. and the lifetime risk of developing colorectal cancer is 1 in 20. Implementation of screening programs in the U.S. has resulted in a 46% decrease in the rate of death from colorectal cancer, from its peak. The U.S. Preventive Services Task Force recommends annual screening with high sensitivity Fecal Occult Blood Testing (FOBT), sigmoidoscopy every 5 years with high-sensitivity FOBT every 3 years and screening colonoscopy every 10 years. Fecal Immunochemical testing (FIT) measures intact human globin protein as opposed to heme. Animal heme from meat will not trigger a false positive test with FIT and as such dietary restrictions are not necessary. Further, FIT is superior to FOBT in detecting advanced adenomas and only requires one stool specimen, as opposed to three specimens for FOBT. COLOGUARD® is highly sensitive, noninvasive, multitarget, stool based DNA test, for colorectal cancer screening ie.early detection of colorectal cancer and precancerous lesions. This test takes advantage of the genetic and epigenetic alterations that leads to the development of colorectal cancer and analyzes the altered DNA signatures of cancerous and precancerous cells that exfoliate into the colon. In addition, this test includes an immunochemical assay for human hemoglobin. The stool samples can be easily collected, mailed from home, and requires no bowel preparation, medication restrictions or dietary change. The purpose of this study was to determine the sensitivity of COLOGUARD® as compared with FIT, for the detection of screening-relevant colorectal cancer. The study was conducted at 90 medical centers throughout the United States and Canada and evaluable patients (N=9989) were asymptomatic individuals between ages 50 and 84 years who were required to provide a stool sample and undergo screening colonoscopy within 90 days. Enrollment was weighted toward those aged 65 years or older. The primary outcome was the ability of COLOGUARD® to detect colorectal cancer and secondary outcomes were the ability of COLOGUARD® to detect advanced precancerous lesions, polyps with high grade dysplasia and serrated sessile polyps measuring 1 cm or more, when compared to FIT. (Sensitivity is defined as the proportion of persons with disease who have a positive test and Specificity is defined as proportion of persons without disease who have a negative test.) The sensitivity for detecting colorectal cancer was 92% with COLOGUARD® and 74% with FIT (P=0.002). The sensitivity for detecting advanced precancerous lesions was 42.4% vs 23.8% (P<0.001), polyps with high-grade dysplasia was 69.2% vs 46.2% (P=0.004) and serrated sessile polyps measuring 1 cm or more were 42.4% vs 5.1%, (P<0.001) with COLOGUARD® and FIT respectively. Specificities with COLOGUARD® were lower compared to FIT (P<0.001). The authors concluded that COLOGUARD® can detect significantly more colorectal cancers and precancerous lesions than FIT. The high sensitivity of this non-invasive, stool DNA test, to detect curable stage of colorectal cancer, may increase the number of people, who will choose to be screened for colorectal cancer. Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. N Engl J Med 2014; 370:1287-1297

Deep Molecular Response Is Reached by the Majority of Patients Treated With Imatinib, Predicts Survival, and Is Achieved More Quickly by Optimized High-Dose Imatinib Results From the Randomized CML-Study IV

SUMMARY:Chronic Myeloid Leukemia (CML) constitutes approximately 10% of all new cases of leukemia. The American Cancer Society estimates that 5,980 new CML cases will be diagnosed in the United States in 2014 and 810 people will die of the disease. The hallmark of CML, the Philadelphia Chromosome (Chromosome 22), is a result of a reciprocal translocation between chromosomes 9 and 22, wherein the ABL gene from chromosome 9 fuses with the BCR gene on chromosome 22. As a result, the auto inhibitory function of the ABL gene is lost and the BCR-ABL fusion gene is activated resulting in cell proliferation and leukemic transformation of hematopoietic stem cells. The presently available Tyrosine Kinase Inhibitors (TKI’s) approved in the United States including GLEEVEC®, share the same therapeutic target, which is BCR-ABL kinase. Resistance to TKI’s occur as a result of mutations in the BCR-ABL kinase domain or amplification of the BCR-ABL gene. With the availability of newer therapies for CML, monitoring response to treatment is important. This is best accomplished by measuring the amount of residual disease using Reverse Transcription-Polymerase Chain Reaction (RT-PCR). This is expressed using the International Scale (IS) as BCR-ABL%, which is the ratio between BCR-ABL and a control gene. BCR-ABL kinase domain point mutations are detected, using the mutational analysis by Sanger sequencing. Majority of the patients receiving a TKI following diagnosis of CML achieve a Complete Cytogenetic Response (CCyR) within 12 months following commencement of therapy and these patients have a life expectancy similar to that of their healthy counterparts. However, some patients have deeper responses (MR3, MR4, and MR4.5) and it is presumed that this subgroup of patients with CML may stay in unmaintained remission even after treatment discontinuation. Moreover, it is not clear what proportion of patients with CML achieve deeper responses and deeper responses have not been shown to increase survival beyond that associated with CCyR. To address these questions, the authors in this report analyzed the data from the randomized CML – Study IV to characterize the frequency and impact of deep molecular response on survival with different treatment modalities. The study is a five arm trial in which the treatment groups included high dose Imatinib (GLEEVEC® 800 mg/day), GLEEVEC® 400 mg/day, GLEEVEC® 400 mg/day in combination with Interferon alfa (IFN), GLEEVEC® 400 mg/day in combination with Cytarabine, and GLEEVEC® 400 mg/day after IFN failure. The analysis included a total of 1538 patients and the principal objective of CML – Study IV was to determine the impact of MMR (Major Molecular Response) on survival, remission rates and survival probabilities. After a median follow up of 67.5 months, 5 year overall survival was 90%, 8 year overall survival was 86% and 5 year PFS was 87.5%. The cumulative rate of MR4.5, irrespective of treatment group (defined as 4.5 or more log reduction in BCR-ABL transcripts), was 66% at 8 years and 70% at 9 years and the median time to reaching MR4.5 was 4.9 years. High dose GLEEVEC® therapy and early Major Molecular Remission predicted deep molecular response (MR4.5). High dose GLEEVEC® resulted in a more rapid MR4.5 than with GLEEVEC® 400 mg/day (P = .016). Finally, this analysis showed that a confirmed MR4.5 at 4 years predicted significantly higher 8 year overall survival probability compared to CCyR (Complete Cytogenetic response: IS 1%) or MMR (major molecular response: IS 0.1%) – 92% versus 83%, P=0.047. The authors concluded that deep molecular response (MR4.5) is a new molecular predictor of long term survival in CML patients and is achieved in a majority of patients treated with GLEEVEC®, and is achieved more rapidly with optimized high-dose GLEEVEC®. The authors further pointed out that none of the patients with confirmed MR4.5 had disease progression and this may therefore provide a therapeutic rationale for discontinuing treatment in this subset of patients with CML. These findings may also justify the use of more effective second generation TKI’s to induce early and deep molecular responses. Hehlmann R, Müller MC, Lauseker M, et al. J Clin Oncol 2014;32:415-423