Dual Inhibition Improves Outcomes for Patients with BRAF-Mutated Colorectal Tumors

February 24th, 2017

SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 135,430 new cases of ColoRectal Cancer will be diagnosed in the United States in 2017 and over 50,260 patients are expected to die of the disease. The DNA MisMatchRepair (MMR) system is responsible for molecular surveillance and works as an editing tool that identifies errors within the microsatellite regions of DNA and removes them. Defective MMR system leads to MSI (Micro Satellite Instability) and hypermutation, triggering an enhanced antitumor immune response. MSI (Micro Satellite Instability) is therefore a hallmark of defective/deficient DNA MisMatchRepair (MMR) system and occurs in 15% of all colorectal cancers. Defective MisMatchRepair can be a sporadic or heritable event. Approximately 65% of the MSI tumors are sporadic and MSI-High tumors tend to have better outcomes. Patients with stage IV colorectal cancer are now routinely analyzed for extended RAS and BRAF mutations. KRAS mutations are predictive of resistance to Epidermal Growth Factor Receptor (EGFR) targeted therapy. Approximately 5-10% of all metastatic CRC tumors present with BRAF V600 mutations and BRAF V600 is recognized as a marker of poor prognosis in this patient group. These patients tend to have aggressive disease with a higher rate of peritoneal metastasis and do not respond well to standard treatment intervention. Approximately 25% of the BRAF-mutated population in the metastatic setting has MSI-High tumors, but MSI-High status does not confer protection to this patient group.

The Mitogen-Activated Protein Kinase pathway (MAPK pathway) is an important signaling pathway which enables the cell to respond to external stimuli. This pathway plays a dual role, regulating cytokine production and participating in cytokine dependent signaling cascade. The MAPK pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAF family of kinases includes ARAF, BRAF and CRAF signaling molecules. BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. The BRAF V600 mutations results in constitutive activation of the MAP kinase pathway. Inhibiting BRAF can transiently reduce MAP kinase signaling. However, this can result in feedback upregulation of EGFR signaling pathway, which can then reactivate the MAP kinase pathway. This aberrant signaling can be blocked by dual inhibition of both BRAF and EGFR.

ZELBORAF® (Vemurafenib), is a selective oral inhibitor of mutated BRAF whereas ERBITUX® (Cetuximab) is a monoclonal antibody targeting Epidermal Growth Factor Receptor (EGFR). Preclinical studies have shown that adding CAMPTOSAR® (Irinotecan) to ZELBORAF® and ERBITUX®, in patients with refractory BRAF V600E metastatic CRC, led to a durable responses and this combination was safe and tolerable. However, both single agent ZELBORAF® and ERBITUX® were shown to have limited activity in this patient group.

Based on this scientific rationale, a phase II trial was conducted (SWOG 1406), in which 106 metastatic ColoRectal Cancer patients, with mutations in BRAF V600 and extended RAS wild-type, were enrolled. Patients were randomized to receive CAMPTOSAR® 180 mg/m2 IV every 14 days and ERBITUX® 500 mg/m2 IV every 14 days, with or without ZELBORAF® 960 mg orally twice daily. The median age was 62 years and about 50% of patients had received 1 prior regimen for metastatic or locally advanced unresectable metastatic CRC, and 39% had received prior treatment with CAMPTOSAR® . Prior therapy with anti-EGFR agent or RAF or MEK inhibitors was not allowed. Crossover from the control arm to the experimental group was allowed, after documented disease progression. The primary endpoint was Progression Free Survival.

The median Progression Free Survival was 4.4 months with the triplet, versus 2.0 months with CAMPTOSAR® plus ERBITUX® (HR=0.42; P =0.0002). The response rate was 16% versus 4%, and the Disease Control Rate was 67% versus 22% (P =0.001), with a higher Duration of Response with the addition of ZELBORAF® to CAMPTOSAR® and ERBITUX® (Triplet). Approximately 50% of the patients in the control group crossed over to the experimental group at the time of disease progression. Overall Survival data and efficacy at cross-over, data, remain immature. Patients in the experimental group (Triplet group) experienced more grade 3/4 toxicities such as neutropenia, anemia and nausea, and this increase was attributed to increased duration of exposure to therapy.

The authors concluded that the addition of ZELBORAF® to the combination of CAMPTOSAR® and ERBITUX® resulted in a 58% reduction in the risk of disease progression and a higher Disease Control Rate, suggesting that simultaneous EGFR and BRAF inhibition (Dual Inhibition) is effective in BRAF V600 mutated ColoRectal Cancer. Subgroup analysis will examine the role of CAMPTOSAR® pre-treatment and the outcomes of patients based on tumor MicroSatellite Instability. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG 1406). Kopetz S, McDonough SL, Morris VK, et al. J Clin Oncol 35, 2017 (suppl 4S; abstract 520)


IBM Artificial Intelligence Platform Highly Concordant with Physician Recommendations

February 24th, 2017

SUMMARY: Watson for Oncology, is an Artificial Intelligence (AI) computer developed by IBM in collaboration with Memorial Sloan Kettering Cancer Center. This revolutionary tool has the advanced ability to analyze the meaning and context of structured and unstructured data in the patients chart and is able to assimilate key patient information and then deliver evidence based treatment recommendations, through analytical approaches. The authors conducted this study to assess concordance between the Artificial Intelligence platform, Watson for Oncology (WFO) and their own multidisciplinary tumor board, which comprised of a group of 12 to 15 oncologists, who met weekly to review cases from their hospital system. The goal of the study was to understand how Watson for Oncology would impact oncologists day-to-day practice, and how Watson’s recommendations compared to the decisions of their team of experts.

The researchers studied 638 patients with breast cancer treated at Manipal Comprehensive Cancer Center in Bengaluru, India. Patient data was entered into the Watson for Oncology (WFO) computer system and the degree of concordance between WFO’s recommendations and those of the tumor board were analyzed, in addition to the time it took for each group to come up with their recommendations. In this study, WFO analyzed more than 100 patient attributes for breast cancer and provided treatment options ranked as follows – Recommended Standard Treatment (REC), For Consideration (FC) and Not Recommended (NREC). These recommendations provided by WFO were evidence based and the computer system allowed the treating physicians to learn more about the recommendations and the rationale behind those recommendations.

It was noted that 90% of WFO’s Recommendations for Standard Treatment (REC) and For Consideration (FC) were concordant with the recommendations of the tumor board. WFO recommendations were concordant nearly 80% of the time in non-metastatic breast cancer, but only 45% of the time in metastatic disease. In patients with triple-negative breast cancer, WFO agreed with the physicians 68% of the time, but in HER-2 negative cases, WFO’s recommendations matched the physician’s recommendations only 35% of the time. The authors attributed the difference in concordance to fewer treatment options for triple-negative breast cancer, compared to HER-2 negative breast cancer. Further, including HER-2 patients made more treatment options available and this would increase the demands on human thinking capacity. Additionally, more complicated cases lead to more divergent opinions on the recommended treatment.

This study also compared the amount of time it took to provide recommendations, after the data was captured and analyzed. It took an average of 20 minutes when done manually, but after gaining more familiarity with the cases, the time decreased to about 12 minutes. Watson for Oncology by comparison, took a median time of 40 seconds to capture and analyze data and give a treatment recommendation.

It was concluded that while Artificial Intelligence is a step towards personalized medicine, it should not be viewed as a replacement for a physician, but rather as a complement. In the end, the best treatment option for the patient should be determined together by the treating physician and the patient. Double blinded validation study to assess performance of IBM artificial intelligence platform Watson for oncology in comparison with Manipal multidisciplinary tumor board—first study of 638 breast cancer cases. Somashekhar SP, Kumar R, Rauthan A, et al. Presented at: San Antonio Breast Cancer Symposium, Friday, Dec. 9, 2016; San Antonio, TX. Abstract S6-07


White Wine May Increase Melanoma Risk in UV-spared sites

February 17th, 2017

SUMMARY: It is estimated that in the US, about 87,110 new cases of melanoma will be diagnosed in 2017 and about 9,730 patients will die of the disease. The incidence of melanoma has been on the rise for the past three decades. Alcohol related cancers account for 5.8% of all cancer deaths worldwide and there is compelling epidemiological evidence supporting that alcohol causes cancer of the oropharynx, larynx, oesophagus, liver, colon, rectum and breast (seven sites).

The mechanism of alcohol related carcinogenesis is not well understood and may vary from each target organ. Alcohol is predominantly metabolized in the liver to acetaldehyde, which is a carcinogen. Acetaldehyde is then converted into acetic acid radicals also known as acetyl radicals. There is strong evidence to suggest that acetaldehyde damages DNA. This mechanism of alcohol related carcinogenesis has been implicated in cancer of the oropharynx, larynx, esophagus and liver. With regards to breast cancer, breast tissue may be more susceptible to alcohol than other sites. Even moderate alcohol intake has been associated with increased levels of circulating sex hormones which in turn can activate cellular proliferation.

Even though the association between alcohol consumption and increased risk of numerous cancers is well known, there has been little or no evidence to associate alcohol consumption to melanoma. The authors in this study investigated whether alcohol intake was associated with risk of melanoma, by using data from three large prospective cohort studies, which included 210,252 participants. These individuals were followed for a mean of 18.3 years. The participants responded to questionnaires approximately every 4 years from 1984 to 2007 and provided information on their alcohol intake. A standard drink was defined at 12.8 grams of alcohol (one drink is considered to be 12 ounces of beer, 5 ounces of wine, or 1.5 ounces of hard liquor).

In this pooled analysis, a total of 1,374 cases of invasive melanoma were documented during the follow up period. Higher alcohol intake was associated with an increased incidence of invasive melanoma (HR=1.14; P=0.04). When analyzed by the type of alcoholic beverages and after adjusting for other alcoholic beverages, white wine consumption was associated with an increased risk of melanoma (HR 1.13; P<0.01). It was also noted that alcohol consumption-related melanoma risk, was higher in the UV-spared sites such as the torso which receives less sun exposure, compared with UV-exposed sites such as head, neck, or extremities. Individuals who consumed 20 grams or more of alcohol a day were 73% more likely to be diagnosed with melanomas of the trunk compared to nondrinkers (HR=1.3;P=0.02), whereas only 2% of the individuals were more likely to be diagnosed with melanoma of the head, neck and extremities compared with non drinkers (HR=1.02; P=0.25).

The researchers noted that there was no evidence that age, smoking history, caffeine intake, physical activity, hair color, mole count or BMI, modified the association between alcohol intake and melanoma, when these results were stratified by those variables. It was hypothesized that white wine may have higher levels of pre-existing acetaldehyde (which gives the pleasant fruity aroma), than beer or hard liquors and the antioxidants in the red wine may offset the carcinogenic risks associated with acetaldehyde.

The authors concluded that these findings support the American Cancer Society Guidelines for Cancer Prevention, to limit alcohol intake, and alcohol consumption was associated with a modest increase in the risk of melanoma, particularly on parts of the body that are less sun exposed. Alcohol Intake and Risk of Incident Melanoma: A Pooled Analysis of Three Prospective Studies in the United States. Rivera A, Nan H, Li T, et al. Cancer Epidemiol Biomarkers Prev. 2016;25:1550-1558


GAZYVA® Superior to RITUXAN® in Follicular Lymphoma

February 17th, 2017

SUMMARY: The American Cancer Society estimates that in 2017, about 72,240 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,140 individuals will die of this disease. Indolent Non Hodgkin Lymphomas are mature B cell lymphoproliferative disorders and include Follicular Lymphoma, Nodal Marginal Zone Lymphoma (NMZL), Extranodal Marginal Zone Lymphoma (ENMZL) of Mucosa-Associated Lymphoid Tissue (MALT), Splenic Marginal Zone Lymphoma (SMZL), LymphoPlasmacytic Lymphoma (LPL) and Small Lymphocytic Lymphoma (SLL). Follicular Lymphoma is the most indolent form and second most common form of all NHLs and they are a heterogeneous group of lymphoproliferative malignancies. Approximately 20% of all NHLs are Follicular Lymphomas. Advanced stage indolent NHL is not curable and as such, prolonging Progression Free Survival (PFS) and Overall Survival (OS), while maintaining Quality of Life, have been the goals of treatment intervention. Asymptomatic patients with indolent NHL are generally considered candidates for “watch and wait” approach. Patients with advanced stage symptomatic Follicular Lymphoma are often treated with induction chemoimmunotherapy followed by maintenance RITUXAN® (Rituximab). This can result in a median Progression Free Survival (PFS) of 6-8 yrs and a median Overall Survival of 12-15 yrs. However, approximately 30% of the patients will relapse in 3 years.

GAZYVA® (Obinutuzumab) 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. By virtue of binding affinity of the glycoengineered Fc portion of GAZYVA® to Fcγ receptor III on innate immune effector cells (natural killer cells, macrophages and neutrophils), Antibody-Dependent Cell-mediated Cytotoxicity (ADCC) and Antibody-Dependent Cellular phagocytosis are significantly enhanced, but induces very little Complement-Dependent Cytotoxicity. This is in contrast to RITUXAN® which is a first generation type I, chimeric, anti-CD20 targeted monoclonal antibody that kills lymphoma cells primarily by Complement-Dependent Cytotoxicity and also ADCC.

GAZYVA® along with Bendamustine in the phase III GADOLIN study, prolonged PFS, compared with Bendamustine alone, in patients with relapsed/refractory indolent Non Hodgkin lymphoma. Based on this promising data, the GALLIUM phase III trial was conducted in treatment naïve patients with Follicular Lymphoma. This study included 1,202 patients with newly diagnosed Follicular Lymphoma, who had Grade I-IIIa tumors and had an ECOG PS of 2 or less. Patients were randomized to receive either GAZYVA® plus chemotherapy, followed by GAZYVA® maintenance (N=601), or RITUXAN® plus chemotherapy, followed by RITUXAN® maintenance (N=601). The chemotherapy regimens used were CHOP, CVP or Bendamustine, based on the discretion of the treating physician. Patients received either RITUXAN® 375mg/m2 IV on day 1 of each cycle or GAZYVA® 1000 mg IV on days 1, 8, and 15 of cycle 1 and day 1 of subsequent cycles, for either eight 21-day cycles (CHOP and CVP) or six 28-day cycles (Bendamustine). Patients who achieved a complete response (CR) or partial response (PR) at the end of induction therapy, received maintenance therapy with RITUXAN® or GAZYVA® every 2 months for 2 years or until disease progression. The median age was 59 years and 57.1% of patients received Bendamustine, 33.1% received CHOP, and 9.8% received CVP. The primary endpoint was PFS and secondary endpoints included Response Rate, Overall Survival (OS), Disease Free Survival and safety. Upon recommendations from the Independent Monitoring Committee, the study was unblinded after a preplanned interim efficacy analysis.

After a median follow-up of 34.5 months, patients in the GAZYVA® group had a 34% reduction in the risk of progression or death compared with those in the RITUXAN® group (HR=0.66; P=0.001). There was however no difference between the two treatment groups in the 3-year Overall Survival (OS) rate (P=0.21). Response rates were similar in both GAZYVA® and RITUXAN® treatment groups. Patients treated with GAZYVA® had more serious adverse events, 46.1% versus 39.9% in the RITUXAN® group, but the discontinuation rate was similar in both treatment groups.

The authors concluded that for treatment naïve Follicular Lymphoma patients, combining GAZYVA® with chemotherapy resulted in a clinically meaningful improvement in PFS compared with RITUXAN® plus chemotherapy and should therefore be the new standard of care for this patient population. Obinutuzumab-Based Induction and Maintenance Prolongs Progression-Free Survival (PFS) in Patients with Previously Untreated Follicular Lymphoma: Primary Results of the Randomized Phase 3 GALLIUM Study. Marcus RE, Davies AJ, Ando K, et al. Presented at the 58th American Society of Hematology (ASH) Annual Meeting. December 3-6, 2016; San Diego, CA. Abstract 6.


The FDA recommends against using screening tests for ovarian cancer screening FDA Safety Communication

February 10th, 2017

SUMMARY: The American Cancer Society estimates that about 22,440 women will be diagnosed with ovarian cancer in the United States for 2017 and about 14,080 will die of the disease. Ovarian cancer ranks fifth in cancer deaths among women, accounting for more deaths than any other cancer of the female reproductive system. Women who have reached menopause, women who have a family history of ovarian cancer, and women with the BRCA1 or BRCA2 genetic mutations have the highest risk for developing ovarian cancer. Over 75% of patients with ovarian cancer have advanced disease at the time of diagnosis. The FDA Safety Communication noted that despite extensive research and published studies there are currently no screening tests for ovarian cancer that are sensitive enough to reliably screen for ovarian cancer without a high number of inaccurate results.

The 2 tests used most often to screen for ovarian cancer are TransVaginal UltraSound (TVUS) and serum marker CA-125. TVUS is unable to differentiate benign from malignant ovarian mass. Serum marker CA-125 is usually associated with high-grade serous ovarian cancer, but is also expressed in normal tissues of the body such as the lungs and other reproductive organs. An increase in the serum marker CA-125 can be seen in non-malignant conditions such as endometriosis, peritonitis and in women with uterine fibroids. Even though serum marker CA-125 when elevated in patients, with an established diagnosis of ovarian cancer, is often used to follow the course of the disease, it has never been proven as an effective screening test for the early detection of ovarian cancer.

Nonetheless, numerous companies continue to claim that their commercially available diagnostic tests can effectively screen and detect ovarian cancer, with no data to support their claims. The FDA is concerned that women and their health care providers may rely on these inaccurate test results to make treatment decisions. Women with a false-positive result may undergo additional medical tests and/or unnecessary surgery, and may experience complications related to both. Conversely, women with a false-negative test may delay or not seek surgery or other treatment interventions for ovarian cancer. The later is particularly relevant for patients with BRCA mutations. Approximately 40% of BRCA1-mutation carriers and 18% of BRCA2-mutation carriers will develop ovarian cancer by age 70. It is recommended that patients who have BRCA1 mutations consider risk-reduction surgery (hysterectomy and bilateral bilateral salpingo-oophorectomy) by age 40 and those with BRCA2-mutations consider risk-reduction surgery no later than age 50.

Even though screenings for breast, colon and cervical cancers are successfully used for early detection and prevention of cancer-related deaths, a screening test for ovarian cancer with valid scientific data presently does not exist, and the FDA recommends against using currently offered tests to screen for ovarian cancer.

Recommendations:

For women, including those at increased risk of developing ovarian cancer

• Be aware that there is currently no safe and effective ovarian cancer screening test

• Do not rely on ovarian cancer screening test results to make health or treatment decisions

• Talk to your doctor about ways to reduce your risk of developing ovarian cancer, especially if you have a family history of ovarian cancer, or have the BRCA1 or BRCA2 genetic mutations

For physicians

• Do not recommend or use tests that claim to screen for ovarian cancer in the general population of women

• Be aware that testing higher risk asymptomatic patients for ovarian cancer has no proven benefit and is not a substitute for preventive actions that may reduce their risk

• Consider referring women at high risk of developing ovarian cancer, including those with BRCA mutations, to a genetic counselor or gynecologic oncologist, or other appropriate health care provider for more specialized care

U.S. Food and Drug Administration: The FDA recommends against using screening tests for ovarian cancer screening: FDA Safety Communication. Issued September 7, 2016. Available at http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm519413.htm


FDA Approves OPDIVO® for Bladder Cancer

February 10th, 2017

SUMMARY: The FDA on February 2, 2017 granted accelerated approval to OPDIVO® (Nivolumab), for the treatment of patients with locally advanced or metastatic urothelial carcinoma, who have disease progression during or following platinum containing chemotherapy, or have disease progression within 12 months of neoadjuvant or adjuvant treatment with a platinum-containing chemotherapy. Urothelial carcinoma accounts for 90 percent of all bladder cancers and can originate in the renal pelvis, ureter and urethra. The American Cancer Society’s estimates that in 2017, approximately 79,030 new cases of Bladder Cancer will be diagnosed and 16,870 patients will die of the disease. Treatment options for patients who progress after platinum based chemotherapy are limited, with poor outcomes. The response rates with standard chemotherapy in this patient population, is about 10%.

The treatment paradigm for solid tumors has been rapidly evolving, with a better understanding of the Immune checkpoints or gate keepers. Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies are being developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152), PD-1(Programmed cell Death 1), as well as Programmed cell Death Ligands (PD-L1) that are expressed by cells in the tumor micro environment. By inhibiting checkpoint proteins and their ligands, T cells are unleashed, resulting in T cell proliferation, activation and a therapeutic response.

OPDIVO® is an immune checkpoint PD-1 (Programmed cell Death 1) targeted, fully human, immunoglobulin G4 monoclonal antibody that has demonstrated antitumor efficacy in multiple tumor types. The FDA approval of OPDIVO® for patients with previously treated locally advanced or metastatic urothelial carcinoma, was based on CheckMate-275 trial which is an international, multicenter, phase II study, in which 270 patients with metastatic or surgically unresectable locally advanced urothelial carcinoma received OPDIVO® 3 mg/kg IV every 2 weeks until disease progression or unacceptable toxicity. All patients had prior platinum based therapy. The median age was 66 years. The primary endpoint was overall Objective Response Rate confirmed by blinded independent review committee, in all treated patients and by tumor PD-L1 expression (5% or more and 1% or more). The follow up for this study is still ongoing. The median follow up for overall survival was 7 months.

The Objective Response Rate across all treated patients was 19.6% and the responses were durable and the median duration of response has not been reached. There was a higher likelihood of response with increasing tumor PD-L1 expression. The Objective Response Rate was 28.4% in patients with PD-L1 expression of 5% or greater, 23.8% in patients with PD-L1 expression of 1% or greater and 16.1% in those with PD-L1 expression of less than 1%. The most common adverse events were fatigue, musculoskeletal pain, nausea, and decreased appetite.

The authors concluded that single agent therapy with OPDIVO® in previously treated patients with metastatic or surgically unresectable urothelial carcinoma, resulted in durable response rate, irrespective of PD-L1 expression and was associated with an acceptable safety profile. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Sharma P, Retz M, Siefker-Radtke A, et al. The Lancet Oncology. Published: 25 January 2017, DOI: http://dx.doi.org/10.1016/S1470-2045(17)30065-7


OPDIVO® (Nivolumab)

February 10th, 2017

The FDA on February 2, 2017 granted accelerated approval to OPDIVO® for treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with a platinum-containing chemotherapy. OPDIVO® is marketed by Bristol-Myers Squibb company.


RUBRACA® (Rucaparib)

February 10th, 2017

The FDA on November 19, 2016 granted accelerated approval to RUBRACA® for treatment of patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer, who have been treated with two or more chemotherapies. RUBRACA® is a product of Clovis Oncology, Inc.


DARZALEX® (Daratumumab)

February 10th, 2017

The FDA on November 21, 2016 approved DARZALEX® in combination with REVLIMID® (Lenalidomide) and Dexamethasone, or VELCADE® (Bortezomib) and Dexamethasone, for the treatment of patients with multiple myeloma, who have received at least one prior therapy. DARZALEX® is a product of Janssen Biotech, Inc.


OPDIVO® (Nivolumab)

February 10th, 2017

The FDA on November 10, 2016 approved OPDIVO® for the treatment of patients with recurrent or metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN), with disease progression on or after a platinum-based therapy. OPDIVO® is marketed by Bristol-Myers Squibb company.