Category: Hem/Onc Updates

FDA Approves TAGRISSO® for First-Line Treatment of Metastatic NSCLC

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SUMMARY: The FDA on April 19, 2018, approved TAGRISSO® (Osimertinib) for the first-line treatment of patients with metastatic Non Small Cell Lung Cancer (NSCLC), whose tumors have Epidermal Growth Factor Receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.

Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2018 about 234,030 new cases of lung cancer will be diagnosed and over 154,050 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), 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large cell carcinomas. 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. Approximately 10-15% of Caucasian patients and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR (Epidermal Growth Factor Receptor) mutations and 90% of these mutations are either exon 19 deletions or L858R point mutations in exon 21.EGFR-Tyrosine-Kinase-Inhibitors EGFR-Tyrosine Kinase Inhibitors (TKIs) such as TARCEVA® (Erlotinib), IRESSA® (Gefitinib) and GILOTRIF® (Afatinib), have demonstrated a 60-70% response rate as monotherapy when administered as first line treatment, in patients with metastatic NSCLC, who harbor the sensitizing EGFR mutations. However, majority of these patients experience disease progression within 9-14 months. This resistance to frontline EGFR TKI therapy has been attributed to acquired T790M “gatekeeper” point mutation in EGFR, identified in 50-60% of patients. Put another way, T790M is not relevant in about 40% of patients whose disease progression may be related to other mechanisms.

TAGRISSO® is a third-generation Epidermal Growth Factor Receptor (EGFR) TKI presently approved by the FDA, for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, who had progressed on prior systemic therapy, including an EGFR-TKI. Previously published studies had suggested that TAGRISSO® may also be effective as initial therapy for EGFR mutation-positive advanced NSCLC.

The recent new indication for TAGRISSO® was based on FLAURA, which is a randomized, double blind, phase III clinical trial, conducted to compare the efficacy and safety of first line TAGRISSO® to TARCEVA® or IRESSA® (which are considered standard first line therapies), in NSCLC patients with activating mutations EGFR exon 19 deletions or L858R substitution mutation on exon 21. This study randomized 556 advanced NSCLC treatment naïve patients, with EGFR exon 19 or 21 mutations in a 1:1 ratio, to TAGRISSO® 80 mg orally once daily (N=279) or Standard of Care EGFR-TKI, IRESSA® 250 mg or TARCEVA® 150 mg, orally once daily (N=277). Patients were stratified by mutation status (exon 19 vs 21 mutations) and race (Asian vs non-Asian). Patients with CNS metastases who were neurologically stable, were allowed in this study. The Primary endpoint was Progression Free Survival (PFS).

The median PFS was 18.9 months with TAGRISSO® compared to 10.2 months for the standard therapy (HR=0.46; P<0.001), suggesting a 54% reduction in the risk of disease progression, compared with Standard of Care. TAGRISSO® extended the median Time To Progression by about 9 months. This PFS benefit was consistent across all subgroups of patients, including those with and without CNS metastases at study entry. The Objective Response Rate (ORR) with TAGRISSO® was 80% compared with 76% for TARCEVA® and IRESSA®. The median Duration of Response with TAGRISSO® was 17.2 months versus 8.5 months in the comparator arm. The median Overall Survival was not reached. Grade 3 and 4 toxicities were lower for TAGRISSO® (34%) compared with 45% for TARCEVA® and IRESSA®. Toxicities led to treatment discontinuation for 13% and 18% of patients in the TAGRISSO® and comparator groups, respectively.

It was concluded that TAGRISSO® demonstrated superior efficacy, with a near doubling in median Progression Free Survival, and better tolerability, compared to the Standard of Care, when given as first-line therapy, for patients with advanced EGFR mutation positive NSCLC. Studies are underway, assessing treatments, following resistance to TAGRISSO®.

Osimertinib in Untreated EGFR-Mutated Advanced Non–Small-Cell Lung Cancer. Soria J-C, Ohe Y, Vansteenkiste J, et al. for the FLAURA Investigators. N Engl J Med 2018; 378:113-125

FDA Approves OPDIVO® plus YERVOY® Combination Immunotherapy for intermediate or Poor-risk Advanced Renal Cell Carcinoma

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SUMMARY: The FDA on April 16, 2018, granted approvals to OPDIVO® (Nivolumab) and YERVOY® (Ipilimumab) in combination, for the treatment of intermediate or poor-risk, previously untreated advanced Renal Cell Carcinoma (RCC). SUTENT® (Sunitinib) is a MultiKinase Inhibitor (MKI) which simultaneously targets the tumor cell wall, vascular endothelial cell wall as well as the pericyte/fibroblast/vascular/ smooth vessel cell wall and is capable of specifically binding to tyrosine kinases, inhibiting the earlier signaling events and thereby inhibits phosphorylation of VEGF receptor, PDGF receptor, FLT-3 and c-KIT. SUTENT® is the standard first-line intervention for treatment naïve patients with advanced Renal Cell Carcinoma. In a large, multi-center, randomized, phase III study, the median Progression Free Survival (PFS) with SUTENT® was 9.5 months, the Objective Response Rate (ORR) was 25%, and the median Overall Survival was 29.3 months, when compared with Interferon Alfa, in patients with treatment-naïve Renal Cell Carcinoma. This was however associated with a high rate of hematological toxicities.International-Metastatic-RCC-Database-Consortium-(IMDC)

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, whereas YERVOY® is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152). Blocking the Immune checkpoint proteins unleashes the T cells, resulting in T cell proliferation, activation and a therapeutic response. OPDIVO® was approved by the FDA in November 2015, for the treatment of advanced RCC in patients who had received prior anti-angiogenic therapy, based on an Overall Survival benefit. YERVOY® is approved for the treatment of metastatic melanoma. Combining OPDIVO® with YERVOY® (Combination immunotherapy) has shown promising efficacy in multiple tumor types, including advanced RCC, with higher Objective Response Rate than either agent alone, and is presently approved for the treatment of advanced malignant melanoma.

This FDA approval was based on CheckMate 214, a randomized open-label phase III trial in which a combination of OPDIVO® plus YERVOY® (N=550) was compared with SUTENT® (N=546), among treatment naïve, clear-cell, advanced Renal Cell Carcinoma (RCC) patients. The authors randomly assigned 1096 patients in a 1:1 ratio to receive OPDIVO® 3 mg/kg IV plus YERVOY® 1 mg/kg IV every 3 weeks for four doses (induction phase) followed by OPDIVO® monotherapy at 3 mg/kg every 2 weeks (maintenance phase) or SUTENT® 50 mg orally once daily for 4 weeks, of each 6-week cycle. Four hundred and twenty five (425) patients in the combination group and 422 patients in the SUTENT® group had intermediate or poor-risk patients. It is estimated that approximately 75% of patients with advanced RCC have intermediate or poor-risk disease and have worse outcomes than those with favorable-risk disease. The coprimary end points were Overall Survival, Objective Response Rate and Progression Free Survival among patients with intermediate or poor prognostic risk disease.Unleashing-T-Cell-Function-with-Combination-Immunotherapy

At a median follow-up of 25.2 months, the combination of OPDIVO® and YERVOY® had a significant Overall Survival benefit over SUTENT®. The 18-month Overall Survival rate was 75% with combination immunotherapy and 60% with SUTENT®. The median Overall Survival was not reached with combination immunotherapy versus 26.0 months with SUTENT® (HR=0.63; P<0.001). The Objective Response Rate was 42% with combination immunotherapy versus 27% with SUTENT® (P<0.001), and the Complete Response rate was 9% versus 1% respectively. The median Progression Free Survival was 11.6 months and 8.4 months, respectively but this was not statistically significant per the prespecified threshold. The benefit with combination immunotherapy was not noted in patients with favorable-risk disease. The superior outcomes with combination immunotherapy in patients with intermediate and poor-risk RCC may very well be related to a higher tumor mutational load in this group of patients, compared to those with favorable-risk disease.

In exploratory analyses among 776 intermediate and poor-risk patients, who had quantifiable PD-L1 expression in this study, Overall Survival was longer with Immunotherapy combination compared with SUTENT®, across PD-L1 expression levels. In patients with PD-L1 expression of 1% or greater, the 18-month Overall Survival rate was 81% with combination immunotherapy and 53% with SUTENT®, and the median Overall Survival was not reached versus 19.6 months respectively (HR=0.45). Among patients with PD-L1 expression of 1% or greater, the Objective Response Rate was 58% versus 22% for SUTENT® (P<0.001), the median PFS was 22.8 and 5.9 months, respectively (HR=0.46). A similar trend was noted in patients with PD-L1 expression 5% or greater, as compared with patients with less than 5% PD-L1 expression. Treatment discontinuation, related to adverse events occurred in 22% of the patients in the combination immunotherapy group and 12% in the SUTENT® group.

It was concluded that treatment with a combination of OPDIVO® and YERVOY® resulted in a significantly higher Overall Survival and Objective Response Rates, compared with SUTENT®, among intermediate and poor-risk, previously untreated patients, with advanced Renal Cell Carcinoma. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. Motzer RJ, Tannir NM, McDermott DF, et al. N Engl J Med 2018; 378:1277-1290

Shorter Duration of Adjuvant Chemotherapy for Stage III Colon Cancer

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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 140,250 new cases of ColoRectal Cancer will be diagnosed in the United States in 2018 and over 50,630 patients are expected to die of the disease. Adjuvant chemotherapy for patients with resected, locally advanced, node-positive (stage III) colon cancer, has been the standard of care since the 1990s. Adjuvant treatment with an ELOXATIN® (Oxaliplatin) based chemotherapy regimen has been considered standard intervention since 2004, for patients with stage III colon cancer, following surgical resection, and has been proven to decrease the chance of recurrent disease. Chemotherapy regimens have included (FOLFOX – Leucovorin, 5-FluoroUracil, ELOXATIN®) or CAPOX/XELOX (XELODA®/Capecitabine and ELOXATIN®), given over a period of 6 months. ELOXATIN® can however be associated with neuropathy which can be long lasting or permanent, depending on the duration of therapy. Additional toxicities with longer duration of chemotherapy include diarrhea, fatigue as well as more office visits.

The IDEA Collaboration is a prospective, pre-planned pooled analysis of 6 concurrently conducted randomized phase III trials, which included 12,834 patients from 12 countries. The goal of this study was to determine if 3 months of adjuvant chemotherapy would be as effective as 6 months of therapy and would be non-inferior. Of the enrolled patients with stage III disease, 13% had T1-2 disease, 66% had T3 tumors and 21% had T4 tumors. Seventy one percent (71%) had N1 disease and 28% of the patients had N2 disease. Approximately 60% had low-risk disease (T1-3, N1) and 40% had high-risk (T4 or N2). Overall, about 40% of patients received CAPOX regimen and 60% received FOLFOX regimen. The primary endpoint was Disease Free Survival (DFS).

At a median follow up of 41.8 months, although non-inferiority of 3 months of therapy as compared with 6 months of therapy could not be confirmed in the overall treatment population, clinically relevant findings according to treatment were noted, in prespecified subgroups of patients. Among those patients who received FOLFOX regimen, 6 months of adjuvant therapy was superior to 3 months (HR=1.16; P=0.001 for superiority of 6-month therapy). However, among those patients who received CAPOX, the Disease Free Survival for 3 months versus 6 months was non-inferior (HR=0.95; P=0.006), and this was highly significant.

In an exploratory analysis, it was noted that among the patient group with low-risk cancers (T1-3, N1 cancers), 3 months of therapy was non-inferior to 6 months of therapy (HR= 1.01) with 3-year disease-free survival of 83.1% and 83.3%, respectively. However, among the patients with high-risk cancers (T4, N2, or both), 6 months of adjuvant therapy was superior to 3 months (HR= 1.12; P=0.01 for superiority).

When subgroup analysis was performed according to treatment and risk group, among the patients with low-risk tumors, 3 months of adjuvant therapy with CAPOX was non-inferior to 6 months of therapy. Outcomes after 3 months of adjuvant FOLFOX therapy were worse than those after 6 months, independent of risk group. For patients with high-risk tumors, 6 months of adjuvant therapy with FOLFOX was superior to 3 months, with a 3-year disease-free survival of 64.7% versus 61.5%. It has been hypothesized that the protracted delivery of a Fluoropyrimidine with CAPOX might have been more effective than the twice-monthly 5-FUinfusions with FOLFOX as an adjuvant therapy. Grade 2 or more neurotoxicity was significantly lower for patients who received 3 months of adjuvant therapy versus 6 months (P <0.0001), regardless of the treatment regimen (17% vs 48% for FOLFOX and 15% vs 45% for CAPOX/XELOX, respectively).

It was concluded by the IDEA collaboration that, a risk-based approach has to be taken when making adjuvant chemotherapy recommendations for patients with stage III colon cancer, taking into consideration choice of treatment regimen and duration of therapy. In patients treated with adjuvant CAPOX/XELOX regimen, 3 months of therapy was as effective as 6 months, particularly in the low risk subgroup. In patients treated with FOLFOX, 6 months of adjuvant therapy compared to 3 months, resulted in a higher rate of Disease Free Survival, particularly in the high-risk subgroup. Duration of Adjuvant Chemotherapy for Stage III Colon Cancer. Grothey A, Sobrero AF, Shields AF, et al. N Engl J Med 2018; 378:1177-1188

Frontline TECENTRIQ® along with AVASTIN® and Chemotherapy Improves Survival in Advanced NSCLC

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers. The American Cancer Society estimates that for 2018 about 234,030 new cases of lung cancer will be diagnosed and over 154,050 patients will die of the disease. 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), 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large cell carcinomas. Immunotherapy is an accepted second line intervention after platinum-based chemotherapy in patients with advanced NSCLC, and is an approved first line therapy, for patients with high PD-L1 expressing tumors (50% or more). Further, immunotherapy with KEYTRUDA® (Pembrolizumab), in combination with chemotherapy, has been approved for first line treatment of patients with advanced non-squamous NSCLC, irrespective of PD-L1 expression.

TECENTRIQ® (Atezolizumab) is an anti-PDL1 monoclonal antibody, designed to directly bind to PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, thereby blocking its interactions with PD-1 and B7.1 receptors and thus enabling the activation of T cells. TECENTRIQ® was approved by the FDA in October 2016 for the treatment of patients with metastatic Non Small Cell Lung Cancer (NSCLC) whose disease progressed during or following Platinum-containing chemotherapy. AVASTIN® (Bevacizumab) is a biologic antiangiogenic antibody, directed against Vascular Endothelial Growth Factor (VEGF), and prevents the interaction of VEGF to its receptors (Flt-1 and KDR) on the surface of endothelial cells. The interaction of VEGF with its receptors has been shown to result in endothelial cell proliferation and new blood vessel formation. Combining TECENTRIQ® and AVASTIN® is supported by the following scientific rationale. AVASTIN® in addition to its established anti-angiogenic effects, may further enhance the ability of TECENTRIQ® to restore anti-cancer immunity, by inhibiting VEGF-related immunosuppression, promoting T-cell tumor infiltration and enabling priming and activation of T-cell responses against tumor antigens.Unleashing-T-Cell-Function-with-PD-1-and-PD-L1-Antibodies

IMpower150 is a multicenter, open-label, randomized, phase III study, conducted to evaluate the efficacy and safety of TECENTRIQ® in combination with Carboplatin and Paclitaxel with or without AVASTIN®, in patients with stage IV, treatment naïve, non-squamous NSCLC. This study enrolled 1,202 patients, who were randomized (1:1:1) to receive either TECENTRIQ® along with Carboplatin and Paclitaxel (Group A), TECENTRIQ® and AVASTIN® along with Carboplatin and Paclitaxel (Group B), or AVASTIN® plus Carboplatin and Paclitaxel (Group C – control arm). During the treatment-induction phase, patients in Group A received TECENTRIQ® 1200 mg IV along with Carboplatin AUC 6 and Paclitaxel 200mg/m2 IV on Day 1 of a 3-week treatment cycle for 4 or 6 cycles. Following the induction phase, patients received maintenance treatment with TECENTRIQ® on the same dose schedule until disease progression. Patients in Group B received AVASTIN® 15 mg/kg IV, along with TECENTRIQ®, Carboplatin and Paclitaxel IV, Day 1 of a 3-week treatment cycle for 4 or 6 cycles followed by maintenance treatment with the TECENTRIQ® and AVASTIN® until disease progression. Patients in the control Group C received AVASTIN® plus Carboplatin and Paclitaxel every 3 weeks for 4 or 6 cycles followed by AVASTIN® maintenance treatment until disease progression. Patients with tumors demonstrating ALK and EGFR mutations were excluded from the primary Intention-To-Treat (ITT) analysis. Patients were also tested for a tumor T-effector gene expression signature (based on phase II trial finding of prolonged Overall Survival in patients with high gene expression signature levels, treated with TECENTRIQ®). The median age was 63 years and the minimum follow up at the time of the analysis was 9.5 months. For the interim analysis, the study was only designed to compare Groups B and C. The co-Primary endpoints were Progression Free Survival (PFS) and Overall Survival in the Intention-to-Treat (ITT) population comparing patients in Group B and C. These end points were also evaluated in subgroup of people who had a specific biomarker (T-effector gene signature expression).

It was noted that at this interim analysis, the combination of TECENTRIQ® and AVASTIN® plus Carboplatin and Paclitaxel, significantly improved PFS and reduced the risk of disease worsening or death by 38% (HR=0.62; P<0.0001), compared to AVASTIN® plus Carboplatin and Paclitaxel alone. This PFS benefit was observed across key subgroups, regardless of PD-L1 expression status, including PD-L1–negative patients (HR 0.77). Further, the median PFS in the population of patients with defined expression of a T-effector gene signature expression in the tumor tissue, was 11.3 months versus 6.8 months (HR 0.51; P<0.0001). Roche on March 26, 2018 announced that the IMpower150 study met its co-primary endpoint of Overall Survival as well. Details will soon become available.

It was concluded that combining chemotherapy with immunotherapy and antiangiogenic agents significantly improved PFS as well as Overall Survival, in patients with treatment naïve, advanced non-squamous NSCLC. This strategy can completely eliminate the need for patient selection based on a particular biomarker, and could benefit larger number of patients with advanced NSCLC. Reck M. Primary PFS and safety analyses of a randomized Phase III study of carboplatin + paclitaxel +/− bevacizumab, with or without atezolizumab in 1L non-squamous metastatic NSCLC (IMpower150). Annals of Oncology, 2017;28(11). Abstract LBA1_PR. https://www.roche.com/media/store/releases/med-cor-2018-03-26.htm

FDA Approves RUBRACA® for Maintenance Treatment of Recurrent Ovarian Cancer

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SUMMARY: The FDA on April 6, 2018, approved RUBRACA® (Rucaparib), a Poly ADP-Ribose Polymerase (PARP) inhibitor, for the maintenance treatment of recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in a Complete or Partial Response to platinum-based chemotherapy. RUBRACA® was initially approved in December 2016 as monotherapy for the 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 an oral, small molecule inhibitor of Poly-Adenosine diphosphate [ADP] Ribose Polymerase (PARP), developed for treatment of ovarian cancer, associated with Homologous Recombination DNA repair deficiency (HRD). Previously published clinical data had suggested that ovarian cancer patients with and without evidence of a germline BRCA mutation, benefit from treatment with a PARP inhibitor, and that maintenance treatment with a PARP inhibitor following a response to platinum-based treatment increases Progression Free Survival (PFS), in patients with ovarian cancer. Even though patients with or without BRCA mutation benefited, the most benefit was derived in those with BRCA mutation.MOA-of-RUBRACA

The approval of RUBRACA® was based on ARIEL3, a randomized, double-blind, placebo-controlled, phase III trial, which evaluated the benefit of RUBRACA® versus placebo, after response to second-line or later platinum-based chemotherapy, in patients with high-grade, recurrent, platinum-sensitive ovarian carcinoma. In this trial, 561 patients were randomly assigned in a 2:1 ratio to receive RUBRACA® 600 mg orally twice daily (N=372) or placebo (N=189). Treatment was continued until disease progression or unacceptable toxicity. Eligible patients had recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, and had been treated with at least two prior treatments of platinum-based chemotherapy, and were in Complete or Partial Response to the most recent platinum-based chemotherapy. Patients had CA-125 level of less than the upper limit of normal. Using Next-Generation Sequencing assay, tumor tissue was examined to determine whether DNA contained a deleterious somatic or germline BRCA mutation (tBRCA), in addition to determining the percentage of genomic Loss of Heterozygosity (LOH). Positive Homologous Recombination Deficiency (HRD) status was defined as tBRCA-positive and/or LOH high. The Primary end point was Progression Free Survival in three patient cohorts – all patients, HRD subgroup, and tumor BRCA subgroup.

It was noted that there was a statistically significant improvement in median Progression Free Survival (PFS) for all patients assigned to RUBRACA®, compared with placebo (median PFS 10.8 versus 5.4 months, HR=0.36; P<0.0001). In the HRD subgroup, the median PFS was 13.6 months for those assigned to RUBRACA®, versus 5.4 months for the placebo group (HR=0.32; P<0.0001), and in the tumor BRCA subgroup, the median PFS was 16.6 versus 5.4 months (HR=0.23; P <0.0001), respectively. The most common adverse reactions were fatigue, rash, nausea, vomiting, diarrhea, abdominal discomfort, cytopenias and abnormal liver function studies. Discontinuation due to adverse reactions occurred in 15% of patients receiving RUBRACA®.

It was concluded that RUBRACA® significantly improved Progression Free Survival in patients with platinum-sensitive ovarian cancer who had achieved a response to platinum-based chemotherapy, and could be considered a new standard of care for women with platinum-sensitive ovarian cancer, following a complete or partial response to second-line or later lines of platinum-based chemotherapy. The FDA also concurrently approved the complementary diagnostic test, FoundationFocusTM CDx BRCA LOH for tumor samples, to determine HRD status.

Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Coleman RL, Oza AM, Lorusso D, et al. The Lancet 2017;390:1949-1961

CABOMETYX® Improves Overall Survival in Advanced Hepatocelluar Carcinoma

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SUMMARY: The American Cancer Society estimates that for 2018, about 42,220 new cases of primary liver cancer will be diagnosed in the US and 30,200 patients will die of their disease. Liver cancer is seen more often in men than in women and the incidence has more than tripled since1980. This increase has been attributed to the higher rate of Hepatitis C virus (HCV) infection among baby boomers (born between 1945 through 1965). Obesity and type II diabetes have also likely contributed to the trend. Other risk factors include alcohol, which increases liver cancer risk by about 10% per drink per day, and tobacco use, which increases liver cancer risk by approximately 50%. HepatoCellular Carcinoma (HCC) is the second most common cause of cancer-related deaths worldwide. NEXAVAR® (Sorafenib) was approved by the FDA in 2007 for the treatment of unresectable HepatoCellular Carcinoma (HCC). Patients with advanced HCC, who progress on NEXAVAR®, have a poor prognosis, with limited treatment options.

CABOMETYX® (Cabozantinib) is an oral, small-molecule Tyrosine Kinase Inhibitor (TKI) which targets the Vascular Endothelial Growth Factor Receptors (VEGFR), and additionally inhibits the action of tyrosine kinases MET and AXL. Increased expression of MET and AXL is associated with tumor progression and development of resistance to VEGFR inhibitors. Previously published studies demonstrated clinical activity of CABOMETYX® in patients with advanced HepatoCellular Carcinoma (HCC).

The CELESTIAL trial is a global, randomized, double-blind, phase III study, which evaluated the benefit of CABOMETYX® in patients with advanced HCC, whose disease progressed on prior treatment with NEXAVAR® or other systemic therapies. NEXAVAR® is considered the standard first line treatment for patients with advanced HCC. In this study, 707 patients were randomized in a 2:1 ratio to receive CABOMETYX® 60 mg daily (N= 470) or placebo (N=237). Eligible patients had an ECOG performance status of 0 or 1, a Child-Pugh score of A, and had progressed on at least one prior systemic therapy for advanced HCC, with 70% having received only prior treatment with NEXAVAR® and 27% having received two prior systemic therapy regimens for advanced HCC.. The median age was 64 years, 38% had Hepatitis B Virus, 24% had Hepatitis C Virus, 78% had ExtraHepatic Spread (EHS), 30% had MacroVascular Invasion (MVI) and 85% had both EHS and MVI. Both treatment groups were well balanced and patients were stratified based on etiology of disease, geographic region, and the presence of EHS and/or MVI. The Primary endpoint was Overall Survival (OS) and Secondary endpoints included Progression Free Survival (PFS) and Objective Response Rate (ORR).

This study met the Primary endpoint at the second planned interim analysis and the median Overall Survival was 10.2 months with CABOMETYX®, compared with 8.0 months with placebo (HR=0.76; P=0.0049) , which meant a 24% reduction in the risk of death. Among patients who received NEXAVAR® alone and received CABOMETYX® as second-line treatment, the median survival was 11.3 months versus 7.2 months with placebo. (HR =0.70). CABOMETYX® also improved PFS compared to placebo and the median PFS was 5.2 months with CABOMETYX® versus 1.9 months with placebo (HR=0.44; P<0.0001). Although the Objective Response Rate was only 4% with CABOMETYX® versus 0.4% with placebo (P=0.0086), stable disease rates however, were doubled (60% vs 33%). The most common grade 3 adverse events in the CABOMETYX® group was hand-foot skin reaction, hypertension, elevated liver enzymes, fatigue and diarrhea.

It was concluded that CABOMETYX® significantly improved Overall Survival and PFS, compared with placebo, in previously treated patients with advanced HCC, and CABOMETYX® represents a new treatment option for this patient group. Cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC) who have received prior sorafenib: Results from the randomized phase III CELESTIAL trial. Abou-Alfa GK, Meyer T, Cheng A-L, et al. J Clin Oncol 36, 2018 (suppl 4S; abstr 207)

FDA Approves 4-Week Dosing Schedule for OPDIVO®

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SUMMARY: The FDA on March 6, 2018 approved a supplemental Biologics License Application (sBLA) updating the OPDIVO® (Nivolumab) dosing schedule to include 480 mg infused every four weeks (Q4W) for a majority of approved indications. OPDIVO® is an immune checkpoint PD-1 (Programmed cell Death 1) targeted, fully human, immunoglobulin G4 monoclonal antibody approved by the FDA for multiple tumor types. 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. They therefore suppress antitumor immunity. OPDIVO® by targeting immune checkpoint PD-1, unleashes the T cells, resulting in T cell proliferation, activation and a therapeutic response.

The clinical pharmacology of OPDIVO® is well established and the clinical data regarding the efficacy and safety of OPDIVO® when administered at 3 mg/kg Q2W (every 2 weeks) across multiple tumor types is well characterized. However, alternative dosing schedules would provide flexibility and other benefits both to patients as well as prescribers.

The authors in this study, using a combination of quantitative clinical pharmacology analyses and safety assessments, evaluated the feasibility of extending the dosing interval of OPDIVO®, and administering it every 4 weeks instead of every 2 weeks. They examined the predicted risk/benefit profile of OPDIVO® 480 mg Q4W compared to 3 mg/kg Q2W by

(1) Comparing OPDIVO® exposures produced by 3 mg/kg Q2W and 480 mg Q4W across tumor types

(2) Evaluating OPDIVO® exposure margins for safety, relative to the well-tolerated dose of 10 mg/kg Q2W

(3) Comparing the predicted risk of experiencing grade 3 adverse events with 480 mg Q4W relative to 3 mg/kg Q2W across the various tumor types for which it is indicated

(4) Comparing the predicted Objective Response Rate (ORR) and Overall Survival with OPDIVO® 480 mg Q4W compared to 3 mg/kg Q2W, in patients with Melanoma, Non Small Cell Lung Cancer (NSCLC), and Renal Cell Carcinoma (RCC).

The researchers noted that among patients with Melanoma, NSCLC, or RCC, there was a less than 1% difference in the predicted probability of achieving a response. The predicted 1 and 2-year survival probabilities were also similar among patients with these tumor types receiving either of the two dose schedules of OPDIVO®, with differences ranging between 0-4.6% at the end of the first year and 1.9-6.9% at the end of second year, across tumor types.

Based on this data, OPDIVO® 480 mg Q4W flat dose option was approved by the FDA for the following indications:

• Metastatic melanoma (monotherapy or monotherapy phase after combination treatment with YERVOY® (Ipilimumab)

• Previously treated metastatic Non Small Cell Lung Cancer

• Advanced Renal Cell Carcinoma following prior Anti-angiogenic therapy

• Previously treated locally advanced or metastatic Urothelial carcinoma following disease progression during or after Platinum-based chemotherapy

• Classical Hodgkin lymphoma following relapse/progression after autologous Hematopoietic Stem Cell Transplantation (HSCT) and Brentuximab vedotin, or three or more lines of systemic therapy that includes autologous HSCT

• Recurrent/metastatic Squamous Cell Carcinoma of the Head and Neck following Platinum-based therapy

• Hepatocellular carcinoma after prior Sorafenib therapy

• Adjuvant therapy for patients with completely resected Melanoma with lymph node involvement or metastatic disease

It was concluded that based on the clinical pharmacology of OPDIVO® and well characterized Exposure-Response relationships for efficacy and safety, the differences in exposures produced by a OPDIVO® schedule of 480 mg Q4W relative to 3 mg/kg Q2W dosing schedule, should not result in clinically meaningful differences in the safety and efficacy of OPDIVO®. This alternate, flexible dosing option may further help tailor patient care. A model-based exposure-response (E-R) assessment of a nivolumab (NIVO) 4-weekly (Q4W) dosing schedule across multiple tumor types [abstract]. Zhao X, Ivaturi V, Gopalakrishnan M, et al. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract CT101. doi:10.1158/1538-7445.AM2017-CT101

ASTRO Issues New Updated Clinical Guideline for Whole Breast Radiation Therapy

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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 266,120 new cases of invasive breast cancer will be diagnosed in 2018 and about 40,920 women will die of the disease. When it comes to adjuvant radiation therapy in breast cancer, the standard of care has been Whole Breast Irradiation (WBI), administered in Conventional Fractions (CF-WBI) of 180 to 200 cGy daily, to approximately 4500 to 5000 cGy, with or without a tumor bed boost. More recently, with clinical trials supporting the safety and effectiveness of HypoFractionated Whole Breast Irradiation (HF-WBI), the American Society for Radiation Oncology (ASTRO) task force, has issued a new clinical guideline for the use of whole-breast radiation therapy for breast cancer, which replaces the existing ASTRO Whole Breast Irradiation guideline published in 2011. With HypoFractionated Whole Breast Irradiation, patients receive larger doses of radiation over a shorter period of time, typically completing treatment in 3-4 weeks, compared with 5-7 weeks for CF-WBI.

The guideline recommendations were based on a systematic literature review, between January 2009 and May 2016, and created using ASTRO-approved tools, for grading evidence quality and recommendation strength. The ASTRO convened a task force to address 5 key questions focused on dose-fractionation for WBI, indications and dose fractionation for tumor bed boost, and treatment planning techniques for WBI and tumor bed boost. The recommendations are summarized below.

Whole-Breast Irradiation (without irradiation of regional lymph nodes) – Delivery and Dosing

1) Treatment decisions, including radiation techniques (Hypofractionated versus Conventional Fractions) should be a shared decision between patient and physician and should be individualized to each patient.

2) For women with invasive breast cancer receiving WBI with or without inclusion of the low axilla, the preferred dose-fractionation scheme is HF-WBI to a dose of 4000 cGy in 15 fractions or 4250 cGy in 16 fractions.

3) The decision to offer HF-WBI should be independent of age, tumor grade, hormone receptor status, HER2 receptor status, surgical margin status, breast size, breast cancer laterality, chemotherapy received prior to radiation and trastuzumab or endocrine therapy received prior to or during radiation.

4) HF-WBI may be used as an alternative to CF-WBI in patients with DCIS.

5) CF-WBI may be preferred over HFWBI when treating primary breast cancers with rare histologies that are most commonly treated with CF when arising in other parts of the body.

6) In patients with breast augmentation, either HF-WBI or CF-WBI may be used.

Tumor Bed Boost

1) A tumor bed boost is recommended for patients with invasive breast cancer 50 years or younger with any grade tumor, age 51-70 years with high grade tumor, or a positive margin. Omitting a tumor bed boost is suggested in patients with invasive breast cancer who are older than 70 years with hormone receptor-positive tumors of low or intermediate grade, resected with widely negative (2 or more mm) margins.

2) A tumor bed boost may be used for patients with DCIS, 50 years and younger, high grade tumors, or close (less than 2 mm) or positive margins following resection. A tumor bed boost may be omitted for patients with DCIS who are older than 50 years, screen detected tumor, total size 2.5 cm or less, low to intermediate nuclear grade, and have widely negative surgical margins (3 mm or more).

3) The decision to use a tumor bed boost should be based on the clinical indications for a boost and should be independent of whether the patient received Conventional or Hypofractionated WBI.

Preferred Techniques for WBI Treatment Planning

1) Three-dimensional conformal radiotherapy planning with a field-in-field technique is recommended to achieve radiation dose homogeneity and full coverage of the tumor bed.

2) Techniques that incorporate deep inspiration breath hold, prone positioning, and/or heart blocks are recommended to minimize heart dose. Treatment techniques should also minimize dose to the contralateral breast, lung, and other normal tissues.

3) Treatment plans should be individualized after consideration of many factors, including tumor characteristics, patient anatomy and comorbidities.

Radiation therapy for the whole breast: Executive summary of an American Society for Radiation Oncology (ASTRO) evidence-based guideline. Smith BD, Bellon JR, Blitzblau R, et al. DOI: https://doi.org/10.1016/j.prro.2018.01.012

Gut Bacteria May Promote Pancreatic Cancer by Inducing Immune Suppression

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SUMMARY: The American Cancer Society estimates that in 2018, about 55,440 people will be diagnosed with pancreatic cancer and about 44,330 people will die of the disease. Pancreatic cancer is the fourth most common cause of cancer-related deaths in the United States and Western Europe. Unfortunately, unlike other malignancies, very little progress has been made and outcomes for patients with advanced pancreatic cancer, has been dismal. Diagnosis is often made late in the course of the disease, as patients are often asymptomatic and early tumors cannot be detected during routine physical examination. Research has been underway evaluating the role of modifiable risk factors, early screening biomarkers, and tumor microenvironment and their influence on outcomes.

Recent published studies have shown the influence of gut microbiome alterations, in the carcinogenesis of pancreatic cancer. A commensal microbiome in a healthy individual maintains a symbiotic relationship conferring protection by its inflammatory-modulating activity, detoxification, hormonal homeostatic and metabolic effects of bacterial metabolites. An imbalanced microbiome can result in dysbiosis, and microbiome alteration has been reported to contribute to carcinogenesis of multiple malignancies. One classic example of influence of microbiome alteration contributing to carcinogenesis is Helicobacter pylori (H. pylori). Eradication of H. pylori causes regression of MALT lymphoma and decreases risk of metachronous gastric carcinoma after endoscopic resection for early stage gastric cancer.

An abundance and alteration of certain microbiomes has been shown to suppress monocytic cellular differentiation in pancreatic cancer leading to T-cell anergy. Targeting the microbiome and bacterial ablation has been shown to be associated with immunogenic reprogramming of the pancreatic tumor microenvironment, by reducing the myeloid-derived suppressor cells and increasing macrophage differentiation. Additionally, bacterial ablation also upregulates PD-1 expression, and enables the efficacy for checkpoint-based immunotherapy and reverses intratumoral immune tolerance. These findings have led to the conclusion that, endogenous microbiota promote immune suppression, characteristic of pancreatic ductal adenocarcinoma, and targeting microbiome potentially can modulate disease progression.

The present study was based on preclinical findings that cancerous pancreas harbors a population of bacteria that is a 1000 fold more, compared with normal pancreas in both mice and humans, and these select bacteria are differentially increased in the tumorous pancreas compared with the gut. The authors in this study noted that bacteria that are more abundant in pancreatic cancers include proteobacteria, actinobacteria, and fusobacteria species. These bacteria release cell membrane components such as lipopolysaccharides and proteins such as flagellins that shift macrophages into immune suppression and prevent the immune system from attacking tumor cells. Their study showed that eliminating these bacteria using antibiotics restored the ability of immune cells to recognize cancer cells, slowed pancreatic tumor growth, and reduced the cancer cell tumor burden by 50% in study animals. Specifically, it was noted that eradicating these bacteria from the gut and pancreas, by treating mice with antibiotics, slowed cancer growth and allowed the recognition of tumor cells by the immune system. Oral antibiotics also increased the efficacy of checkpoint inhibitors roughly 3 fold, thereby strongly improving antitumor immunity.

The researchers further pointed out that even though alterations in genes such as KRAS can result in abnormal cell growth and development of pancreatic cancer, the present study showed that bacteria can change the immune environment around cancer cells and facilitate rapid tumor growth in some patients more so than others, despite their similar genetic alterations. The authors hypothesized that changes in the genes that cause abnormal cell growth in the pancreas might also change the immune response, favoring the growth of different bacterial species, other than those found in healthy individuals. Environmental factors like diet, other medical conditions, or common medications, might also cause bacterial changes in the gut, that influence the pancreatic microbiome.

It was concluded that in pancreatic cancer, a distinct and abundant group of bacteria provide an immune suppressed environment, and addition of antibiotics improved the efficacy of a checkpoint inhibitor, in a mouse model of pancreatic ductal adenocarcinoma, as demonstrated by an increase in T cells that could attack the tumor. Studies are planned to evaluate the role of antibiotic combinations such as Ciprofloxacin and Metronidazole and their benefit in improving the efficacy of PD-1 inhibitors, in patients with pancreatic ductal adenocarcinoma. The Pancreatic Cancer Microbiome Promotes Oncogenesis by Induction of Innate and Adaptive Immune Suppression. Pushalkar S, Hundeyin M, Daley D, et al. DOI: 10.1158/2159-8290.CD-17-1134

Treatment Sequencing with STIVARGA® before ERBITUX® Improves Survival in Metastatic Colorectal Cancer

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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 140,250 new cases of CRC will be diagnosed in the United States in 2018 and about 50,630 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 21 (4.7%). 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 (PFS) and Overall Survival (OS). The benefit with anti EGFR agents however is only demonstrable in patients with metastatic CRC, whose tumors do not harbor KRAS mutations in codons 12 and 13 of exon 2 (KRAS Wild Type). It is now also clear that even among the KRAS Wild Type patients, about 15-20% have other rare mutations such as NRAS and BRAF mutations, which confer resistance to anti EGFR agents. Therefore, pan RAS (expanded RAS) testing is now recommended.

STIVARGA® (Regorafenib), is an oral multi-kinase inhibitor approved by the FDA for the treatment of patients with metastatic CRC, who have progressed on 5FU, ELOXATIN® (Oxaliplatin), CAMPTOSAR® (Irinotecan), anti-VEGF and anti-EGFR therapies. STIVARGA® inhibits multiple kinases including VEGF1, VEGF2, VEGF3, PDGFR, FGFR involved in tumor angiogenesis and KIT, RET, RAF-1, BRAF involved in oncogenesis. The approval was based on a phase III trial in which patients receiving STIVARGA® had a statistically significant improvement in the Overall Survival and Progression Free Survival, compared to placebo.

Both STIVARGA® and ERBITUX® are approved for metastatic CRC. The optimal sequencing of these drugs however, has remained unclear. The current standard of care is to offer an ERBITUX® based regimen followed by STIVARGA®. STIVARGA® however has demonstrated activity in patients with metastatic CRC, when given earlier in the course of the disease. Further preclinical data suggests that downregulation of MAP kinase and Akt with STIVARGA® was shown to sensitize metastatic CRC cells to anti-EGFR therapies, such as ERBITUX®.

The REVERCE trial is a multicenter, randomized phase II trial which enrolled patients with KRAS wild-type metastatic CRC, after failure on combination chemotherapy with Fluoropyrimidine, Oxaliplatin, and Irinotecan. A total of 101 patients were randomized in a 1:1 ratio to receive sequential treatment with STIVARGA® followed by ERBITUX® with or without Irinotecan or reverse sequence of ERBITUX® with or without Irinotecan followed by STIVARGA®. Patients were stratified by prior use of AVASTIN® and intent to use ERBITUX® in combination with Irinotecan. Patients continued each sequence until disease progression or unacceptable toxicity, at which time patients switched to the alternative drug. The Primary endpoint was Overall Survival. Secondary endpoints included Progression Free Survival (PFS) with initial treatment (PFS1), PFS with second treatment (PFS2), Time to sequential Treatment Failure (TTF), Response Rate, Safety, and Quality of Life (QOL). The authors further investigated possible biomarkers including oncogenic mutations from circulating cell free DNA by liquid biopsy, with serial measurements.

It was noted that giving STIVARGA® before ERBITUX® resulted in a significantly longer median Overall Survival of 17.4 months, compared with 11.6 months with ERBITUX® followed by STIVARGA®. After a median follow up of 29 months, there was a 39% reduction in the risk of death with the STIVARGA®-ERBITUX® sequence (HR=0.61; P=0.029). The benefit with STIVARGA®-ERBITUX® sequence was consistently noted across all patient subgroups. In the subgroup of patients with left-sided primary tumors (N=81), patients who started treatment with STIVARGA® first followed by ERBITUX®, had a median Overall Survival of 20.5 months compared with 11.9 months for those receiving ERBITUX® first, and this meant a 49% reduction in mortality risk, which was statistically significant (P=0.01).

The first Progression Free Survival (PFS1) did not differ significantly according to the drug sequence, but the second PFS (PFS2) was more prolonged in those receiving ERBITUX® after STIVARGA®, with a 71% reduction in the risk of progression or death following the second treatment (HR=0.29; P<0.0001). The time to treatment failure was a median of 7.4 months with STIVARGA® followed by ERBITUX® and 6.1 months with ERBITUX® followed by STIVARGA® (HR=0.60; P=0.017). Safety and quality of life were comparable between the two treatment groups.

It was concluded that data from this study suggest that treatment with STIVARGA® first, followed by ERBITUX® resulted in longer survival than that of the current standard sequence and the longer Progression Free Survival following the second treatment period with ERBITUX® may have contributed to the improvement in Overall Survival with the STIVARGA®-ERBITUX® sequence. A biomarker analysis is still ongoing. Randomized phase II study of regorafenib followed by cetuximab versus reverse sequence for wild-type KRAS metastatic colorectal cancer previously treated with fluoropyrimidine, oxaliplatin, and irinotecan (REVERCE). Shitara K, Yamanaka T, Denda T, et al. DOI: 10.1200/JCO.2018.36.4_suppl.557 Journal of Clinical Oncology 36, no. 4_suppl (February 2018) 557-557.