RR – Page 132 – OncoPrescribe

FDA Approves OPDIVO® for Relapsed Classical Hodgkin Lymphoma

May 27, 2016April 7, 2017 RR

SUMMARY: The FDA on May 17, 2016, granted accelerated approval to OPDIVO® (Nivolumab) for the treatment of patients with Classical Hodgkin Lymphoma (cHL) that has relapsed or progressed after autologous Hematopoietic Stem Cell Transplantation (HSCT) and post-transplantation ADCETRIS® (Brentuximab vedotin). The American Cancer Society estimates that in the United States for 2016, about 8500 new cases of Hodgkin lymphoma will be diagnosed and over 1100 patients will die of the disease. Hodgkin lymphoma is classified into two main groups-Classical Hodgkin lymphomas and Nodular Lymphocyte Predominant type, by the World Health Organization. The Classical Hodgkin lymphomas include Nodular sclerosing, Mixed cellularity, Lymphocyte rich, Lymphocyte depleted subtypes and accounts for approximately 10% of all malignant lymphomas. Nodular sclerosis Hodgkin lymphoma histology, accounts for approximately 80% of Hodgkin lymphoma cases in older children and adolescents in the United States. Classical Hodgkin Lymphoma is a malignancy of primarily B lymphocytes and is characterized by the presence of large mononucleated Hodgkin and giant multinucleated Reed-Sternberg (RS) cells collectively known as Hodgkin and Reed-Sternberg cells (HRS). The HRS cells in turn recruit an abundance of ineffective inflammatory cells and infiltrates of immune cells. Preclinical studies suggest that HRS cells evade immune detection by exploiting the pathways associated with immune checkpoint, Programmed Death-1 (PD-1) and its ligands PD-L. Classical Hodgkin Lymphoma is an excellent example of how the tumor microenvironment influences cancer cells to proliferate and survive.

The most common genetic abnormality in Nodular sclerosis subtype of Hodgkin lymphoma is the selective amplification of genes on the short arm of chromosome 9 (9p24.1) which includes JAK-2 with resulting increased expression of PD-1 ligands such as PDL1 and PDL2 on HRS cells, as well as increased JAK-STAT activity, essential for the proliferation and survival of Hodgkin Reed-Sternberg (HRS) cells. Infection with Epstein–Barr virus (EBV) similarly can increase the expression of PDL1 and PDL2 in EBV-positive Hodgkin's lymphomas. It would therefore seem logical to block or inhibit immune check point PD-1 rather than both its ligands, PDL1 and PDL2.

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. Under normal circumstances, Immune checkpoints or gate keepers inhibit intense immune responses by switching off the T cells of the immune system. 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), etc. By doing so, one would expect to unleash the T cells, 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 demonstrated significant responses in a phase 1b trial involving patients with relapsed/refractory cHL (Ansell SM et al. NEJM 2015;372:311–319).

This accelerated approval of OPDIVO® was based on two single-arm, open label, multicenter trials (CheckMate-205 and -039) of OPDIVO®, in adults with relapsed or refractory cHL. These trials enrolled patients regardless of PD-L1 expression status on Reed-Sternberg cells. The median age was 37 years and patients had a median of 5 prior therapies. The primary endpoint was Objective Response Rate (ORR) and additional outcome measures included Duration of Response (DOR). Patients received OPDIVO® (Nivolumab) at a dose of 3 mg/kg every 2 weeks and treatment was continued until patients had a complete response, tumor progression or severe toxicities.

The efficacy of OPDIVO® was evaluated in 95 patients with cHL from the two single-arm trials, previously treated with autologous Hematopoietic Stem Cell Transplantation (aHSCT) and post-transplantation ADCETRIS® (Brentuximab vedotin). Patients had received a median of 17 doses of OPDIVO®. The ORR with OPDIVO® was 65% with 58% Partial Remission and 7% Complete Remission. The median time to response was 2.1 months and the estimated median DOR was 8.7 months. The most common adverse reactions (20% or more) of any grade were fatigue, upper respiratory tract infection, cough, pyrexia, and diarrhea.

The authors concluded that patients with Classical Hodgkin Lymphoma treated with OPDIVO® after autologous Hematopoietic Stem Cell Transplantation (aHSCT) and post-transplantation ADCETRIS®, have very high response rates and long Duration of Responses with acceptable toxicities. OPDIVO® is the first PD-1 inhibitor, approved for a hematologic malignancy. Checkmate 205: Nivolumab (nivo) in classical Hodgkin lymphoma (cHL) after autologous stem cell transplant (ASCT) and brentuximab vedotin (BV)—A phase 2 study. Younes A, Santoro A, Zinzani PL, et al. J Clin Oncol 34, 2016 (suppl; abstr 7535)

FDA Approves Combination of LENVIMA® and AFINITOR® for Advanced Renal Cell Carcinoma

May 20, 2016March 31, 2017 RR

SUMMARY: The FDA on May 13, 2016 approved LENVIMA® (Lenvatinib) in combination with AFINITOR® (Everolimus), for the treatment of advanced Renal Cell Carcinoma, following one prior anti-angiogenic therapy. LENVIMA® was first approved in 2015 for the treatment of locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer. The American Cancer Society estimates that about 62,700 new cases of kidney cancer will be diagnosed in the United States in 2016 and over 14,000 patients will die from this disease.

LENVIMA® is an oral multitargeted TKI (Tyrosine Kinase Inhibitor), which targets Vascular Endothelial Growth Factor Receptor (VEGFR)1-3, Fibroblast Growth Factor Receptor (FGFR)1-4, REarranged during Transfection tyrosine kinase receptor (RET), c-KIT, and Platelet Derived Growth Factor Receptor (PDGFR). LENVIMA® differs from other TKIs with anti-angiogenesis properties by its ability to inhibit FGFR-1, thereby blocking the mechanisms of resistance to VEGF/VEGFR inhibitors. In addition, it controls tumor cell growth by inhibiting RET, c-KIT, and PDGFR beta and influences tumor microenvironment by inhibiting by FGFR and PDGFR beta. AFINITOR® (Everolimus) does not inhibit tyrosine kinases, but is a specific inhibitor of mTOR (Mammalian Target of Rapamycin), which is a serine/threonine kinase, normally activated further downstream in the signaling cascade. With the inhibition of mTOR, protein synthesis is inhibited resulting in decreased angiogenesis, cell proliferation and survival as well as decreased levels of HIF-1 alpha.

Metastatic Renal Cell Carcinoma is currently treated with sequential therapy using single agent VEGF or mTOR inhibitors. The current FDA approval was based on a multicenter open-label phase II study in which 153 patients were randomized in a 1:1:1 ratio to receive LENVIMA® plus AFINITOR® (N=51), LENVIMA® monotherapy (N=52), or AFINITOR® monotherapy (N=50). Enrolled patients had advanced or metastatic Renal Cell Carcinoma and had previously received anti-angiogenic therapy. Patients in the combination group received LENVIMA® 18 mg QD along with AFINITOR® 5 mg QD, orally, whereas patients in the single agent groups received either LENVIMA® 24 mg QD or AFINITOR® 10 mg QD. Patients were not allowed to crossover in this study. Using the MSKCC (Memorial Sloan Kettering Cancer Center) risk classification, patients were well balanced between the treatment groups. The primary endpoint was Progression Free Survival. Secondary endpoints included Objective Response Rate (ORR) and Overall Survival (OS).

It was noted that the median PFS in the combination group was 14.6 months compared with 5.5 months in the AFINITOR® alone group (HR=0.37; P=0.0005). This meant a 63% reduction in the risk of disease progression. The median OS with the combination treatment was 25.5 months compared to 15.4 months with AFINTOR® alone (HR=0.67) and this meant a 33% reduction in the risk of death. The ORR with the LENVIMA® and AFINITOR® combination was 37% compared with 6% in the AFINITOR® alone group. The PFS at one year was 31% with the combination treatment versus 14% with single agent AFINITOR® and at 2 years 51% of patients remained alive in the combination treatment group compared with 26% in the single-agent AFINITOR® group. The most common grade 3-4 toxicities in the combination group included diarrhea, fatigue, arthralgia, hypertension and anemia.

The authors concluded that a combination of LENVIMA® and AFINITOR® significantly improves Progression Free Survival, in patients with metastatic Renal Cell Carcinoma, who had progressed on previous VEGF targeted therapy and this combination therapy may change the treatment paradigm for this patient population. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Motzer RJ, Hutson TE, Glen H, et al. Lancet Oncol. 2015;16:1473-1482.

FDA Approves IMBRUVICA® as Initial Therapy for Patients with Chronic Lymphocytic Leukemia

May 20, 2016March 31, 2017 RR

SUMMARY: The FDA on March 4, 2016 approved the expanded use of IMBRUVICA® (Ibrutinib) as first line treatment for patients with Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma. IMBRUVICA® received approval in February 2014 for the treatment of Chronic Lymphocytic Leukemia (CLL) in patients who received at least one prior therapy and in July 2014 for the treatment of CLL with 17p deletion. The American Cancer Society estimates that approximately 18,960 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in 2016 and approximately 4660 patients will die from the disease. CLL is a disease of the elderly and the average age at the time of diagnosis is 72 years. There are two main types of lymphocytes, B and T lymphocytes/cells. B-cell CLL is the most common type of leukemia in adults. Normal B-cell activation and proliferation is dependent on B-cell receptor (BCR) signaling. This signaling is also important for initiation and progression of B-cell lymphoproliferative disorders. Bruton's Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. Following binding of antigen to the B-Cell Receptor, kinases such as Syk (Spleen Tyrosine Kinase), Lyn (member of the Src family of protein tyrosine kinases) and BTK (Bruton's Tyrosine Kinase) are activated, with subsequent propagation through PI3K/Akt, MAPK, and NF-κB pathways. This results in B-cell activation and proliferation. IMBRUVICA® (Ibrutinib) is an oral, irreversible inhibitor of BTK and inhibits cell proliferation and promotes programmed cell death (Apoptosis) by blocking B-cell activation and signaling. In elderly CLL patients with comorbid conditions, Chlorambucil is often considered as a standard first-line therapy because of the higher rate of toxicities associated with FLUDARA® (Fludarabine) and TREANDA® (Bendamustine).

RESONATE-2 is a international, open-label, randomized, phase III trial, in which the efficacy of two oral agents , IMBRUVICA® and Chlorambucil, were compared, in previously untreated elderly patients with CLL or Small Lymphocytic Lymphoma. In this study, 269 treatment naïve patients with CLL or Small Lymphocytic Lymphoma, who were 65 years of age or older, were randomly assigned in a 1:1 ratio, to receive IMBRUVICA® 420 mg PO once daily (N=136) or Chlorambucil at a dose of 0.5 mg/kg on days 1 and 15 of each 28 day cycle, increased to a maximum of 0.8 mg/kg, if tolerated (N=133). Patients with chromosome del (17p) were excluded. The median age was 73 years and 70% of patients were over age 70. The primary end point was Progression Free Survival (PFS) and secondary end points included, Overall Response Rate (ORR), Overall Survival (OS), and sustained hematologic improvement.

With a median follow-up of 28.1 months, patients in the IMBRUVICA® group had a significantly longer Progression Free Survival (PFS) compared to the Chlorambucil group (median not reached versus 18.9 months), with a risk of progression or death 84% lower with IMBRUVICA®, compared to Chlorambucil (HR=0.16; P<0.001). IMBRUVICA® significantly prolonged Overall Survival, in spite of 41% of the patients crossing over from the Chlorambucil group to IMBRUVICA®. The 2 year Overall Survival rate was 94.7% in the IMBRUVICA® group and 84.3% in the Chlorambucil group (HR=0.44). Further, IMBRUVICA® significantly improved Overall Response Rate, compared with Chlorambucil (82% vs 35%; P< 0.0001) and also significantly improved hemoglobin and platelets levels from baseline values, compared with Chlorambucil. The most common adverse events associated with IMBRUVICA® were diarrhea, fatigue, cough and nausea and were mostly Grade 1 toxicities.

The authors concluded that IMBRUVICA® significantly improves Progression Free Survival, Overall Survival and Overall Response Rate, compared to Chlorambucil, in previously untreated patients with CLL or Small Lymphocytic Lymphoma, and should therefore be considered for all elderly patients who are not candidates for aggressive systemic therapy. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. Burger JA, Tedeschi A, Barr PM, et al. N Engl J Med 2015; 373:2425-2437

FDA Approves GILOTRIF® for Squamous Cell Carcinoma of the Lung

May 13, 2016March 24, 2017 RR

SUMMARY: The FDA on April 15, 2016 approved GILOTRIF® (Afatinib) tablets for the treatment of patients with advanced Squamous Cell Carcinoma of the lung, whose disease has progressed after treatment with Platinum-based chemotherapy. Lung cancer is the second most common cancer in both men and women and the American Cancer Society estimates that for 2016, about 224,390 new cases of lung cancer will be diagnosed and over 158,000 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of Non Small Cell Lung Cancer (NSCLC), 25% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large cell carcinomas. Non Small Cell Lung Cancer patients with Squamous Cell histology have been a traditionally hard- to-treat, patient group, with less than 5% of patients with advanced SCC, surviving for five years or longer. Some of the advanced NSCLC tumors are dependent on the Epidermal Growth Factor Receptor (EGFR) for cell proliferation and survival, regardless of EGFR mutation status. TARCEVA® (Erlotinib) is a reversible EGFR Tyrosine Kinase Inhibitor and is presently approved by the FDA for the treatment of locally advanced or metastatic NSCLC, after failure of at least one prior chemotherapy regimen. GILOTRIF® (Afatinib) is an oral, irreversible blocker of the ErbB family which includes EGFR (ErbB1), HER2 (ErbB2), ErbB3 and ErbB4. GILOTRIF® was approved by the FDA in July 2013, for the first line treatment of patients with metastatic NSCLC, whose tumors have Epidermal Growth Factor Receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations.

This additional indication approved by the FDA was based on the LUX-Lung 8 study, which is a phase III trial in which 795 patients with Stage IIIB/IV Squamous Cell Carcinoma of the lung who had progressed on first line platinum based doublet therapy, were randomized 1:1 to receive GILOTRIF® 40 mg PO daily (N=398) or TARCEVA® 150 mg PO daily (N=397). Treatment was given until disease progression. The median age was 65 years. Majority of the patients were male, caucasian and ex-smokers. The Primary endpoint was Progression Free Survival (PFS) and Secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR), Disease Control Rate (DCR), patient reported outcomes and safety. The Primary endpoint of Progression Free Survival (PFS) was met and reported in 2014 and favored GILOTRIF® over TARCEVA®. The authors in this analysis reported the Overall Survival data, as well as updated data on Progression Free Survival and other Secondary endpoints. The median Overall Survival was 7.9 months with GILOTRIF® and 6.8 months with TARCEVA® (HR=0.81; P=0.007). This meant a 19% reduction in the risk of death with GILOTRIF® when compared to TARCEVA® and this survival advantage was consistent across all time points. The updated median Progression Free Survival for GILOTRIF® was 2.4 months versus 1.9 months for TARCEVA® (HR=0.82; P=0.04) which meant an 18% reduction in the disease progression. The Disease Control Rate was 51% for GILOTRIF® and 40% with TARCEVA® (P=0.002). Based on patient reported outcomes, symptoms including cough and dyspnea were better with GILOTRIF® compared to TARCEVA®. Incidence of severe adverse events was similar with both therapies, with patients on GILOTRIF® experiencing more grade 3 diarrhea and stomatitis and patients receiving TARCEVA® experiencing more grade 3 rash.

The authors concluded that GILOTRIF® should be the TKI of choice for the second line treatment of patients with Squamous Cell Carcinoma of the lung, as it significantly improves Overall Survival, Progression Free Survival, Disease Control Rate and controls symptoms with manageable toxicities, when compared to TARCEVA®. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Soria J, Felip E, Cobo M, et al. The Lancet Oncology 2015;16:897-907

Five Year Follow up Data without Adjuvant Chemotherapy, Utilizing Oncotype DX 21-gene Recurrence Score Assay

May 13, 2016March 24, 2017 RR

The West German Study Group (WSG) PlanB phase III trial, used Recurrence Score assay prospectively, to define a low risk subset of patients with node negative disease with high risk traditional parameters and patients with node positive disease (HR+, HER2 negative), who could be treated with adjuvant endocrine therapy alone, sparing chemotherapy. In this study, patients with a Recurrence Score of 11 or less were defined as having low risk for recurrence, even in those considered to have tumor with high risk features such as large tumor size, high tumor grade and lymph node involvement. Patients were considered to be at intermediate or high risk if they had a Recurrence Score of 12 or more and 25 or more, respectively. Gluz and colleagues had previously reported 3-year follow up results of a planned interim analysis of this study, and were able to show significant difference between tumor grade, Ki-67 and Oncotype DX Recurrence Score.

In this current analysis, the authors reported the 5-year Disease Free Survival (DFS) outcomes of this large prospective trial. This analysis included data from 3,198 patients with early stage hormone receptor positive or HER2 negative breast cancer. The median age was 56 years and 32.5% of the patients had grade 3 tumors and 41% of the patients had node positive disease. Patients with a Recurrence Score of 11 or less received hormonal therapy and adjuvant chemotherapy was omitted. The intermediate and high risk patients were randomized to receive six cycles of TAXOTERE® (Docetaxel)/CYTOXAN® (Cyclophosphamide) or four cycles of ELLENCE® (Epirubicin)/CYTOXAN® followed by four cycles of TAXOTERE®. The primary endpoint was Disease Free Survival (DFS) defined as invasive or noninvasive relapse.

It was noted that the 5-year DFS in the low risk group was 94%, 84% in the high risk group and 94% in the intermediate risk group (P<0.001). It should be noted that approximately 15% of the patients in the clinically determined intermediate or high risk group, with 0-3 lymph node involvement, fell in the low genomic risk group (Recurrence Score of 11 or less) and received hormonal therapy alone.

The authors concluded that West German Study Group (WSG) PlanB study is the first trial that has reported five year survival data using 21-gene Recurrence Score assay, which can identify patients with early breast cancer, who would benefit from hormonal therapy alone and could be spared chemotherapy. Based on these data, 21-gene Recurrence Score has stronger prognostic value compared to immunohistochemical studies such as Ki-67 and hormone-receptor expression and should therefore be routinely incorporated in clinical practice as a decision making tool for this patient population, in addition tumor size, grade and nodal status. Prospective WSG Phase III PlanB trial: Clinical outcome at 5 year follow up and impact of 21 Gene Recurrence Score result, central/local-pathological review of grade, ER, PR and Ki67 in HR+/HER2- high risk node-negative and –positive breast cancer. Gluz O, Nitz U, Christgen M, et al. Abstract 8LBA. Presented at: 10th European Breast Cancer Conference; March 9-11, 2016; Amsterdam.

OPDIVO® Granted Breakthrough Designation by FDA for Head and Neck cancer

May 6, 2016May 4, 2020 RR

SUMMARY: The FDA granted breakthrough therapy designation to Nivolumab (OPDIVO®), as a treatment for patients with recurrent or metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN), following a platinum based therapy. This designation was based on the findings from CheckMate-141 study, which demonstrated an improvement in Overall Survival (OS) with OPDIVO®, compared to investigator’s choice of therapy. The American Cancer Society estimates that 61,760 people will be diagnosed with Head and Neck cancer in 2016 and 13,190 patients will die of the disease. Patients with recurrent/metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN) have a poor prognosis with a median Overall Survival (OS) of about 13 months with first line therapy and about 6 months or less with later lines of therapy. 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. Survival of cancer cells in the human body may be to a significant extent related to their ability to escape immune surveillance by inhibiting T lymphocyte activation. The T cells of the immune system therefore play a very important role in modulating the immune system. Under normal circumstances, inhibition of an intense immune response and switching off the T cells of the immune system, is an evolutionary mechanism and is accomplished by Immune checkpoints or gate keepers. 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), etc. By doing so, one would expect to unleash the T cells, resulting in T cell proliferation, activation and a therapeutic response.

OPDIVO® is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response. CheckMate-141 is an open-label, phase III trial, in which 361 patients with recurrent or metastatic Squamous Cell Carcinoma of the oral cavity, pharynx, or larynx, were randomly assigned in a 2:1 ratio to receive either OPDIVO® (N= 240) or investigator’s choice of ERBITUX® (Cetuximab), TAXOTERE® (Docetaxel) or Methotrexate (N=121). OPDIVO® was administered intravenously at 3 mg/kg every 2 weeks. ERBITUX® dosing was 400 mg/m2 for the first dose followed by 250 mg/m2 weekly, TAXOTERE® dosing was 30 mg/m2 weekly and Methotrexate dosing was 40 mg/m2 weekly. The median age was 60 years, majority of patients were male, had received 2 or more prior systemic therapies and prior radiation therapy. Patients were stratified based on prior therapy with monoclonal antibody, ERBITUX® and HPV status was known for 50% of the participants. The primary endpoint was Overall Survival and secondary endpoints included Response Rates and Progression Free Survival (PFS).

This study was stopped earlier than scheduled after an independent monitoring panel determined that the primary endpoint for this study was met, with significant superiority of OPDIVO® over the investigator’s choice of therapy. The median Overall Survival with OPDIVO® was 7.5 months, compared to 5.1 months with investigator’s choice of therapy (HR=0.70; P=0.010). The 1-year Overall Survival with OPDIVO® was 36%, which was more than double, compared with investigator’s choice of therapy, which was 16.6%. Patients with PD-L1 expression of 1% or more benefited the most from treatment with OPDIVO®, with a median OS of 8.7 months, compared to 4.6 months in the control group (HR=0.55). For patients with PD-L1 expression less than 1%, median OS was 5.7 with OPDIVO® versus 5.8 months, for the control group (HR=0.89). HPV status also had an impact on outcomes. HPV-positive patients had a median OS of 9.1 months with OPDIVO® compared with 4.4 months with investigator’s choice of therapy (HR=0.56), whereas those who were HPV-negative and receiving OPDIVO®, had a median OS of 7.5 months compared to 5.8 months with investigator’s choice of therapy (HR=0.73). Grade 3 or 4 adverse events were significantly lower with OPDIVO®, compared with investigator’s choice of therapy(13.1% vs 35.1%).

The authors concluded that OPDIVO® is the first agent to demonstrate a significant improvement in Overall Survival, in patients with advanced head and neck cancer following progression on platinum-based chemotherapy, and fulfills an unmet need for this patient group. Gillison ML, Blumenschein G, Fayette J, et al. Nivolumab Versus Investigator’s Choice (IC) for Recurrent or Metastatic (R/M) Head and Neck Squamous Cell Carcinoma (SCCHN): CheckMate-141. Presented at: AACR 2016 Annual Meeting, New Orleans; April 16-20, 2016. Abstract CT099.

Left Sided Colon Cancer Patients Have Better Outcomes than Those with Right Sided Tumors

May 6, 2016March 21, 2017 RR

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 135,000 new cases of ColoRectal Cancer will be diagnosed in the United States in 2016 and over 49,000 patients are expected to die of the disease. Even though prognosis for patients with Colon Cancer has improved over the past two to three decades, it has remained unclear if improvement in survival was greater for Left sided Colon Cancer versus cancer originating in the Right hemicolon. To address this question, the authors in this study used the Geneva population-based registry and collected the data on all Colon Cancer patients from 1980-2006. They then compared outcomes ided Tumorsin 3396 patients with proximal (Right-sided) and distal (Left-sided) Colon Cancer. In the study population, 1,334 patients (39%) had Right-sided tumors and 2,062 (61%) had Left-sided tumors. Colon Cancer specific survival was then determined and compared, taking into consideration tumor and treatment characteristics of Left and Right sided tumors, as well as putative confounding variables. The authors also compared changes in survival between Colon Cancer location in early and late years of this observation study.

At the beginning of the study period (1980s), the 5-year specific survival was identical for Right and Left sided Colon Cancers (49% versus 48%). However, over the course of the study period, there was a marked improvement in survival, for patients with Left-sided cancers (HR=0.42; P<0.001), but this benefit was not noted in Right-sided Colon Cancer patients (HR=0.76; P=0.69). As such, distal Colon Cancer (Left sided) had a better prognosis than patients with proximal or Right sided Colon Cancer (Hazard Ratio for Left versus Right Colon Cancer = 0.81; P<0.001).

The authors concluded from this study that survival of patients with Right Colon Cancer did not improve since 1980, and tend to have the worse prognosis of all Colon Cancer patients. Therefore, change in treatment strategy is warranted for this patient subgroup. Right colon cancer: left behind. Gervaza P, Usel M, Rapiti E, et al. European Journal of Surgical Oncology 2016;doi:10.1016/j.ejso.2016.04.002

Impact of Treatment Delay on Clinical Outcomes in Breast Cancer Patients

April 29, 2016September 15, 2017 RR

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, 246,660 new cases of invasive breast cancer will be diagnosed in 2016 and 40,450 women will die of the disease. Patients with early stage breast cancer often receive adjuvant chemotherapy and this is even more so true for HER positive and triple negative (ER, PR and HER negative) breast cancer patients, who are at an increased risk to develop recurrent disease. Even though majority of the patients start their adjuvant chemotherapy within 4-6 weeks following surgery, the impact of delay in the initiation of adjuvant therapy on outcomes, has remained unclear. Preclinical models have suggested that there is phase of increased angiogenesis and accelerated growth of micrometastases, as well as development of drug resistant clones, following removal of the primary tumor. Previously published data from a large meta-analysis had suggested that a four week delay in the initiation of adjuvant chemotherapy resulted in a 6% increase in the risk of death and an 8% increase in the risk of relapse. Nonetheless, over the past 2 decades, there has been increasing delay for both surgery and adjuvant chemotherapy treatment intervention, following diagnosis of breast cancer. These delays have been attributed to the increasing use of prognostic tools prior to treatment intervention, in order to optimize breast cancer care, germ-line genetic testing to plan appropriate surgical intervention, as well as patients seeking immediate reconstructive surgical options. Two studies addressed the impact of delay in treatment intervention following diagnosis of breast cancer, by investigating outcomes, in a very large group of patients with breast cancer.

In the study by Bleicher, et al., the relationship between the time from diagnosis to breast cancer surgery and survival was investigated, by collecting data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database and the National Cancer Database (NCDB). The SEER-Medicare cohort had 94,544 patients 66 years or older, diagnosed between 1992 and 2009 and the NCDB cohort included 115,790 patients 18 years or older, diagnosed between 2003 and 2005. Patients included in this analysis underwent surgery as initial treatment and had a diagnosis of non-inflammatory, non-metastatic, invasive breast cancer. The primary outcome was Overall and Disease-Specific Survival, as a function of time between diagnosis and surgery, measured in 30 day increments. They noted that with each interval of treatment delay increase, Overall Survival was lower (HR=1.09; P<0.001 in the SEER-Medicare cohort and HR=1.10; P<0.001 in the NCDB cohort). This relationship was statistically significant only in stages I and II breast cancer. The authors in this study concluded that longer time to surgery is associated with lower Overall and Disease-Specific Survival.

Chavez-MacGregor et al. analyzed the outcomes of 24,â€¯843 patients in the California Cancer Registry with stage I-III invasive breast cancer, diagnosed between January 2005 and December 2010, and treated with adjuvant chemotherapy. Time to chemotherapy was defined as the number of days between surgery and the first dose of chemotherapy, and delayed treatment was defined as 91 or more days from surgery to the first dose of adjuvant chemotherapy. Median age at the time of diagnosis was 53 years, and median time to adjuvant chemotherapy was 46 days. Patients were evaluated for Overall Survival and Breast Cancer-Specific Survival. They noted that patients receiving adjuvant chemotherapy 91 or more days following surgery experienced worse Overall Survival (HR=1.34) and worse Breast Cancer-Specific Survival (HR=1.27) compared with patients receiving adjuvant chemotherapy within 31 days from surgery and these adverse outcomes were even more so, among patients with triple negative breast cancer (HR=1.53). Factors associated with adjuvant therapy delays included, low socioeconomic status, breast reconstruction, non-private insurance, and Hispanic or African American ethnicity. The authors in this study concluded that delaying initiation of adjuvant chemotherapy 91 days or more, results in adverse outcomes and this may be even more detrimental, in patients with triple negative breast cancer.

These two studies strongly suggest that treatment delays should be avoided in patients with early stage breast cancer and if surgery is to be delayed, neoadjuvant treatment approach may be reasonable, to avoid adverse outcomes.

Time to Surgery and Breast Cancer Survival in the United States. Bleicher RJ, Ruth K, Sigurdson ER, et al. JAMA Oncol. 2016;2:330-339.

Delayed Initiation of Adjuvant Chemotherapy Among Patients With Breast Cancer. Chavez-MacGregor M, Clarke CA, Lichtensztajn DY, et al. JAMA Oncol. 2016;2:322-329.

Liquid Biopsy Can Rapidly Detect EGFR Mutations and KRAS mutations with High Specificity

April 29, 2016March 10, 2017 RR

SUMMARY: It has been well established that treatment with EGFR TKIs results in superior outcomes, for patients with tumors harboring exon 19 deletions and exon 21 mutations. The application of precision medicine with targeted therapy, requires detection of molecular abnormalities in a tumor specimen, following progression or recurrence. Archived biopsy specimens may not be helpful as it is important to identify additional mutations in the tumor at the time of recurrence or progression, in order to plan appropriate therapy. Further, recurrent tumors may be inaccessible for a safe biopsy procedure or the clinical condition of the patient may not permit a repeat biopsy. Additionally, the biopsy itself may be subject to sampling error due to tumor heterogeneity. Genotyping cell free DNA in the plasma can potentially overcome the shortcomings of repeat biopsies and tissue genotyping, allowing the detection of many more targetable gene mutations, thus resulting in better evaluation of the tumor genome landscape.

The purpose of this study was to prospectively validate plasma droplet digital PCR (ddPCR) for the rapid detection of common Epidermal Growth Factor Receptor (EGFR) and KRAS mutations, as well as the EGFR T790M acquired resistance mutation. The authors prospectively evaluated the feasibility and accuracy of this assay in patients with newly diagnosed advanced non-squamous Non Small Cell Lung Cancer (NSCLC) who either were newly diagnosed and initial therapy was planned (N=120) or had developed acquired resistance to an EGFR kinase inhibitor and rebiopsy was planned (N=60). The median age was 62 years and 62% were females.

Following initial blood sampling of all patients, plasma droplet digital Polymerase Chain Reaction (ddPCR) for EGFR and KRAS mutations, including EGFR exon 19 deletion, EGFR L858R, KRAS G12X and EGFR T790M acquired resistance mutation, was performed. All patients underwent biopsy for tissue genotyping, and this was used as a reference standard for comparison with the liquid biopsy results. Important study outcomes included sensitivity and specificity of plasma ddPCR assay, as well as test turnaround time, which was defined as the number of business days between blood sampling and test reporting.

Tumor genotypes identified included 80 EGFR exon 19 or L858R mutations, 35 EGFR T790M mutations, and 25 KRAS G12X mutations. The ddPCR assay median turnaround time was 3 days compared with 12 days for tissue genotyping and 27 days for patients with acquired resistance. Plasma ddPCR exhibited a positive predictive value of 100% for EGFR 19 del, 100% for EGFR L858R mutation and 100% for KRAS. The positive predictive value for EGFR T790M was lower at 79%. The sensitivity of plasma ddPCR assay was 82% for EGFR exon19 del, 74% for EGFR L858R mutation, and 77% for EGFR T790M acquired resistance mutation, but lower for KRAS at 64%. Sensitivity for EGFR or KRAS was higher in patients with multiple metastatic sites (P=0.001), specifically in those with bone and hepatic metastases.

The authors concluded that in this first prospective study, plasma ddPCR assay can rapidly detect EGFR and KRAS mutations with high specificity, allowing treatment selection, without repeat biopsies. Additionally, this assay may also detect EGFR T790M mutation, missed by tissue genotyping, due to tumor heterogeneity in resistant disease. Prospective Validation of Rapid Plasma Genotyping for the Detection of EGFR and KRAS Mutations in Advanced Lung Cancer. Sacher AG, Paweletz C, Dahlberg SE, et al. JAMA Oncol. Published online April 07, 2016. doi:10.1001/jamaoncol.2016.0173

FDA Approves VENCLEXTA®, a BCL2 Inhibitor for the Treatment of Chronic Lymphocytic Leukemia

April 22, 2016March 3, 2017 RR

SUMMARY: The FDA on April 11, 2016, granted an accelerated approval to Venetoclax (VENCLEXTA®) for the treatment of patients with Chronic Lymphocytic Leukemia (CLL) with 17p deletion, as detected by an FDA-approved test, who have received at least one prior therapy. The FDA also approved Vysis CLL FISH probe kit, as a companion diagnostic to VENCLEXTA®, for detection of the del(17p). There are two main types of lymphocytes, B and T lymphocytes. B-cell CLL is the most common type of leukemia in adults. Normal B-cell activation and proliferation is dependent on B-cell receptor (BCR) signaling. This signaling is also important for initiation and progression of B-cell lymphoproliferative disorders. Bruton's Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. Following binding of antigen to the B-Cell Receptor, kinases such as Syk (Spleen Tyrosine Kinase), Lyn (member of the Src family of protein tyrosine kinases) and BTK (Bruton's Tyrosine Kinase) are activated, with subsequent propagation through PI3K/Akt, MAPK, and NF-κB pathways. This results in B-cell activation and proliferation. PI3K (PhosphoInositide 3-Kinase) delta signaling, is hyperactive in B-cell malignancies and is important for the activation, proliferation, homing of malignant B cells in the lymphoid tissues and their survival. The delta isoform of PI3K enzyme is predominantly expressed in leukocytes. Targeting proteins in key pathways of B-cell biology has fundamentally changed the management and outcomes of CLL, over the past 5 years. IMBRUVICA® (Ibrutinib) is an oral, irreversible inhibitor of BTK and inhibits cell proliferation and promotes programmed cell death (Apoptosis) by blocking B-cell activation and signaling. ZYDELIG® (Idelalisib) is a highly selective oral inhibitor of the enzyme PI3K and specifically blocks the delta isoform of PI3K enzyme and its signaling pathway. The pro-survival (anti-apoptotic) protein BCL2, is over expressed by CLL cells and regulates clonal selection and cell survival. A new class of anticancer agents known as BH3-mimetic drugs are in development that mimic the activity of the physiologic antagonists of BCL2 and related proteins and promote apoptosis (programmed cell death).

VENCLEXTA® is a second generation, oral, selective, small molecule inhibitor of BCL2 and restores the apoptotic processes in tumor cells. VENCLEXTA® causes markedly less thrombocytopenia but more neutropenia compared to its first generation predecessor, Navitoclax. In the phase I study by Roberts, et al. (N Engl J Med 2016;374:311-322), high response rates of 71 to 79% were observed in CLL patients with poor prognostic features, when treated with VENCLEXTA®, with a 15-month Progression Free Survival (PFS) of 69%.

Based on this phase I data, a pivotal phase II, single-arm, multicenter study was conducted, to evaluate the efficacy of VENCLEXTA® monotherapy in patients with Relapsed/Refractory del(17p) CLL. This study included 106 patients with a median age of 67 years and patients had received a median of 2 prior chemotherapy regimens. More than a third of the patients were refractory to prior therapy with Fludarabine and Bendamustine. Treatment consisted of VENCLEXTA® tablets given once daily with a weekly dose ramp-up schedule (20 mg for 1 week, followed by 1 week at each dose level of 50 mg, 100 mg, and 200 mg and then the recommended daily dose of 400 mg), over a period of 5 weeks, given along with Tumor Lysis Syndrome (TLS) prophylaxis. Patients were treated with the daily 400 mg dosing until disease progression or unacceptable toxicity. The primary endpoint was Overall Response Rate (ORR). Secondary endpoints included Complete Response (CR), Partial Response (PR) rates, Time to first response, Duration of Response (DoR), Progression Free Survival (PFS), Overall Survival (OS), the proportion of patients proceeding to allogeneic Stem Cell Transplant (allo-SCT) and Safety.

The ORR was 79.4% with 8% Complete Response (including 2% Complete Response with incomplete marrow recovery-CRi). Minimal Residual Disease (MRD) was evaluated in peripheral blood and bone marrow for patients who achieved CR or CRi, following treatment with VENCLEXTA®. Forty five (N=45) patients were evaluated for MRD and 18 attained MRD-negative status in their peripheral blood. The median time to first response was 0.8 months (range: 0.1 to 8.1 months) and median time to CR/CRi was 8.2 months. With a median follow up of 12 months, the median Duration of Response (DoR) has not been reached (2.9-19.0 months).

The most common adverse reactions of any grade were neutropenia, diarrhea, nausea, anemia, upper respiratory tract infection, thrombocytopenia, and fatigue. Patients should be closely monitored and should receive prophylaxis for Tumor Lysis Syndrome, which can occur as a result of rapid reduction in tumor volume.

The authors concluded that monotherapy with VENCLEXTA® resulted in a high ORR and sustained remissions, in high risk patients with CLL. Undetectable Minimal Residual Disease was noted in more than 20% of responders, with more than 10% of all patients achieving a deep response. Venetoclax (ABT-199/GDC-0199) monotherapy induces deep remissions, including complete remission and undetectable MRD, in ultra-high risk relapsed/refractory chronic lymphocytic leukemia with 17p deletion: results of the pivotal international phase II study. Stilgenbauer S, Eichhorst BF, Schetelig JS, et al. Presented at: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract LBA6.

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Author: RR