Category: Meeting Updates

FDA Approves KEYTRUDA® for Cervical Cancer

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SUMMARY: The FDA on June 12, 2018, approved KEYTRUDA® (Pembrolizumab) for patients with recurrent or metastatic Cervical cancer with disease progression on or after chemotherapy, whose tumors express PD-L1 (Combined Positive Score-CPS, of 1 or more) as determined by an FDA-approved test. The American Cancer Society estimates that for Cervical cancer in the US for 2018, about 13,240 new cases of invasive Cervical cancer will be diagnosed and about 4,170 women will die of the disease. Cervical pre-cancers are diagnosed far more often than invasive Cervical cancer. Cervical cancer is most frequently diagnosed in women between the ages of 35 and 44 and in the US. Hispanic women are most likely to get Cervical cancer, followed by African-Americans, Asians and Pacific Islanders, and whites.

Approximately 5% of new diagnoses of Cervical cancer accounts for stage IV disease. However, metastatic disease develops in 15-60% of women, usually within the first two years of completing primary treatment. A select group of women with locally recurrent or limited metastatic disease may be potentially cured with surgical resection or radiotherapy. This however may not be feasible in the majority of cases. Patients with recurrent and metastatic Cervical cancer have a poor prognosis, with limited systemic treatment options. There is currently no consensus on the standard of care for second-line systemic treatment of recurrent or metastatic Cervical cancer, and as such represents a significant unmet clinical need.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells.

The FDA approval was based on KEYNOTE-158 study, which is a multicenter, non-randomized, open-label, multi-cohort phase II basket study trial, investigating the antitumor activity of KEYTRUDA® in 11 different advanced cancer types, who had progressed on standard-of-care therapy. Basket Trial by definition allows the testing of one drug on a single mutation in a variety of tumor types, at the same time, thereby potentially increasing the number of patients who are eligible to receive certain drugs. KEYTRUDA® was investigated in 98 patients with recurrent or metastatic Cervical cancer, enrolled in a single cohort of the KEYNOTE- 158 trial.

Key eligibility criteria for this cohort included patients with histologically or cytologically confirmed advanced Cervical cancer who had progressed on or intolerant to one or more lines of standard therapy and had tumor sample available for biomarker analysis. Patients were treated with KEYTRUDA® 200 mg IV every 3 weeks until documented disease progression or unacceptable toxicity..PD-L1 positivity, defined as a Combined Positive Score (CPS) of 1 or more, was evaluated retrospectively by ImmunoHistoChemistry (IHC) using the PD-L1 IHC 22C3 pharmDx Kit. Median age was 46 years and 77 patients (79%) of enrolled patients had PD-L1 positive tumors. Primary endpoint was Objective Response Rate (ORR) assessed by independent central review. Secondary endpoints included Duration of Response (DOR), Progression Free Survival (PFS), Overall Survival (OS) and safety.

With a median follow up time of 11.7 months, the ORR in the 77 PD-L1 positive patients was 14.3% including 2.6% Complete Responses and 11.7% Partial Responses. The estimated median response duration was not reached, 91% had response duration of 6 months or more, and no responses were observed in patients whose tumors did not have PD-L1 expression (CPS less than 1). The most common adverse reactions in at least 10% of patients were fatigue, fever, nausea, vomiting, diarrhea/colitis, abdominal pain, constipation, hypothyroidism, and dyspnea. KEYTRUDA® was discontinued due to adverse reactions in 8% of patients.

It was concluded that KEYTRUDA® is the first anti-PD-1 therapy approved for the treatment of advanced Cervical cancer, providing an important new second-line option for certain patients with this disease, with durable antitumor activity and manageable toxicity profile. Pembrolizumab treatment of advanced cervical cancer: Updated results from the phase 2 KEYNOTE-158 study. Chung HC, Schellens JH, Delord J, et al. J Clin Oncol 36, 2018 (suppl; abstr 5522)

KISQALI® plus FASLODEX® Improve Progression Free Survival in Advanced Breast Cancer

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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. Approximately 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors and these patients are often treated with anti-estrogen therapy as first line treatment. However, resistance to hormonal therapy occurs in a majority of the patients.

Cyclin Dependent Kinases (CDK) play a very important role to facilitate orderly and controlled progression of the cell cycle. Genetic alterations in these kinases and their regulatory proteins have been implicated in various malignancies. Cyclin Dependent Kinases 4 and 6 (CDK4 and CDK6) phosphorylate RetinoBlastoma protein (RB), and initiate transition from the G1 phase to the S phase of the cell cycle. RetinoBlastoma protein has antiproliferative and tumor-suppressor activity and phosphorylation of RB protein nullifies its beneficial activities. CDK4 and CDK6 are activated in hormone receptor positive breast cancer, promoting breast cancer cell proliferation. Further, there is evidence to suggest that endocrine resistant breast cancer cell lines depend on CDK4 for cell proliferation. The understanding of the role of Cyclin Dependent Kinases in the cell cycle, has paved the way for the development of CDK inhibitors.Cell-Cycle-Inhibition-by-RIBOCICLIB-A-CDK4-and-CDK6-Inhibitor

KISQALI® (Ribociclib) is an orally bioavailable, selective, small-molecule inhibitor of CDK4/6 that blocks the phosphorylation of RetinoBlastoma protein, thereby preventing cell-cycle progression and inducing G1 phase arrest. KISQALI® in combination with an Aromatase Inhibitor has been approved by the FDA for pre and perimenopausal women with HR (Hormone Receptor)-positive, HER2-negative advanced or metastatic breast cancer, as initial endocrine-based therapy. The efficacy of KISQALI® was evaluated in two prior randomized phase III studies. In the MONALEESA-2 trial which evaluated KISQALI® in combination with FEMARA® (Letrozole) compared to FEMARA® alone, in postmenopausal women with HR-positive, HER2-negative advanced breast cancer who received no prior therapy for their advanced breast cancer, the addition of KISQALI® to FEMARA® significantly prolonged Progression Free Survival (PFS) compared to FEMARA® alone. In the MONALEESA-7 study, KISQALI® in combination with Tamoxifen or a Non-Steroidal Aromatase Inhibitor plus ZOLADEX® (Goserelin) was compared with Tamoxifen or an Aromatase Inhibitor plus ZOLADEX®, in premenopausal or perimenopausal women with HR-positive, HER2- negative advanced breast cancer, who had not previously received endocrine therapy for advanced disease. In this study of premenopausal women, KISQALI® plus endocrine therapy significantly improved PFS compared with placebo plus endocrine therapy

MONALEESA-3 is a randomized, double-blind, placebo-controlled Phase III study which compared the efficacy of KISQALI® in combination with FASLODEX® with FASLODEX® alone, among postmenopausal women with HR-positive, HER2-negative advanced breast cancer who received no prior or only one line of prior endocrine therapy for advanced disease. In this trial, 726 women were randomized, of whom 367 were treatment-naïve and 345 patients had received up to one line of prior endocrine therapy for advanced disease. . Patients were randomized 2:1 to receive KISQALI® plus FASLODEX® (N=484) or placebo plus FASLODEX® (N=242). Treatment consisted of KISQALI® 600 mg orally daily 3 weeks on and 1 week off and FASLODEX® 500 mg IM on day 1 of each 28-day cycle, with an additional dose given on day 15 of cycle 1. Patients were stratified by the presence or absence of lung or liver metastases and prior endocrine therapy (first-line versus second-line). The median age in both groups was 63 years. The Primary endpoint was Progression Free Survival. Secondary end points included Overall Survival, Overall Response Rate, and Safety. The median time from randomization to data cutoff was 20.4 months.

Among all randomized patients, the median PFS in the KISQALI® plus FASLODEX® group was 20.5 months compared to 12.8 months in the FASLODEX® plus placebo group (HR= 0.59; P<0.001). This represented a 41% reduction in the risk of disease progression. The PFS benefit was consistent among the 367 patients who were treatment-naïve (HR=0.57) and 345 patients had received up to one line of prior endocrine therapy for advanced disease (HR=0.56). In the subgroup of patients taking KISQALI® plus FASLODEX® as first-line treatment, the median PFS was not reached and 70% were estimated to remain Progression Free at median follow up of 16.5 months. Among those patients with measurable disease at baseline, the Overall Response Rate was 40.9% for the KISQALI® plus FASLODEX® arm versus 28.7% for FASLODEX® plus placebo group (P=0.003). At first interim analysis, the Overall Survival data were immature. The most common grade 3/4 Adverse Events in patients receiving KISQALI® plus FASLODEX® compared to FASLODEX® alone were neutropenia (53.4% versus 0%) and leukopenia (14.1% versus 0%).

It was concluded that KISQALI® plus FASLODEX® might represent a new, first or second-line treatment option for patients with Hormone Receptor-positive, Human Epidermal growth factor Receptor 2-negative advanced breast cancer. MONALEESA-3 is the only randomized Phase III trial to study a CDK4/6 inhibitor plus FASLODEX® in the first-line setting, with demonstrable efficacy in patients with de novo advanced breast cancer and those who had not received adjuvant therapy in more than a year. Ribociclib (RIB) + fulvestrant (FUL) in postmenopausal women with hormone receptor-positive (HR+), HER2-negative (HER2 –) advanced breast cancer (ABC): Results from MONALEESA-3. Slamon DJ, Neven P, Chia SKL, et al. J Clin Oncol. 2018: 36, (suppl; abstr 1000).

Late Breaking Abstract – ASCO 2018 Broad Range of MSI-H tumors Linked with Lynch Syndrome

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SUMMARY: The FDA in 2017 granted accelerated approval to KEYTRUDA® (Pembrolizumab), a PD-1 blocking antibody, for adult and pediatric patients with unresectable or metastatic, MicroSatellite Instability-High (MSI-H) or MisMatch Repair Deficient (dMMR) solid tumors that have progressed following prior treatment, and who have no satisfactory alternative treatment options. This has led to routine MSI-H/dMMR testing in advanced solid tumors. The DNA MisMatchRepair (MMR) system is responsible for molecular surveillance and works as an editing tool that identifies errors within the microsatellite regions of DNA and removes them. Defective MMR system leads to MSI (Micro Satellite Instability) and hypermutation, triggering an enhanced antitumor immune response. MSI is therefore a hallmark of defective/deficient DNA MisMatchRepair (dMMR) system and occurs in 15% of all colorectal cancers.Testing-for-MicroSatellite-Instability-and-MisMatch-Repair-Deficiency

Defective MisMatchRepair can be a sporadic or heritable event. Defective MisMatchRepair can manifest as a germline mutation occurring in MisMatchRepair genes including MLH1, MSH2, MSH6, PMS2 and EPCAM. This produces Lynch Syndrome often called Hereditary Nonpolyposis Colorectal Carcinoma – HNPCC, an Autosomal Dominant disorder, that is often associated with a high risk for Colorectal and Endometrial carcinoma, as well as several other malignancies including Ovary, Stomach, Small bowel, Hepatobiliary tract, Brain and Skin. MSI is a hallmark of Lynch Syndrome-associated cancers. MSI tumors tend to have better outcomes and this has been attributed to the abundance of tumor infiltrating lymphocytes in these tumors from increase immunogenicity. These tumors therefore are susceptible to blockade with immune checkpoint inhibitors. MSI testing is performed using a PCR based assay and MSI-High refers to instability at 2 or more of the 5 mononucleotide repeat markers and MSI-Low refers to instability at 1 of the 5 markers. Patients are considered Micro Satellite Stable (MSS) if no instability occurs. MSI-L and MSS are grouped together because MSI-L tumors are uncommon and behave similar to MSS tumors. Tumors considered MSI-H have deficiency of one or more of the DNA MisMatchRepair genes. MMR gene deficiency can be detected by ImmunoHistoChemistry (IHC). NCCN Guidelines recommend MMR or MSI testing for all patients with a history of Colon or Rectal cancer. Unlike Colorectal and Endometrial cancer, where MSI-H/dMMR testing is routinely undertaken, the characterization of Lynch Syndrome across heterogeneous MSI-H/dMMR tumors is unknown.

The aim of the study was to determine the prevalence of germline mutations in the DNA mismatch repair genes diagnostic of Lynch Syndrome, across MSI-H tumors. The researchers in this study analyzed 15,045 tumor samples collected from patients with more than 50 different types of cancer using a comprehensive genomic test called MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets), a next-generation sequencing platform. The MSK-IMPACT assay is a qualitative in-vitro diagnostic test that uses targeted next-generation sequencing of Formalin Fixed Paraffin-Embedded (FFPE) tumor tissue matched with normal specimens, from patients with solid tumors, to detect tumor gene alterations in a broad multigene panel. It is the first multiplex tumor profiling test to receive FDA authorization. The MSK-IMPACT test can look for gene mutations and other errors in all solid tumors, regardless of their origin.

Scores of less than 3, 3-9 and 10 or more were designated MSS, MSI-Indeterminate (MSI-I) or MSI-H status, respectively. Germline mutations were assessed in MLH1, MSH2, MSH6, PMS2, EPCAM. ImmunoHistoChemical staining (IHC) for dMMR, and tumor signatures in Lynch Syndrome patients were assessed.

Of the tumor samples analyzed, 93.2% were MSS, 4.6% were MSI-I, and 2.2% were MSI-H. Germline mutations indicative of Lynch Syndrome were identified in 0.3% of microsatellite-stable tumors, 1.9% of MSI-I tumors, and 16.3% of MSI-H tumors (P<0.001). The authors noted that nearly 50% of patients with MSI-H/MSI-I tumors identified as having Lynch Syndrome, had cancers other than colorectal or endometrial carcinoma – the two malignancies that are typically seen with Lynch Syndrome. The cancer types identified that were previously not linked to or rarely, linked to the Lynch Syndrome, included Mesothelioma, Sarcoma, Adrenocortical cancer, Melanoma, Prostate and Ovarian germ cell cancer. Nearly 40% of these patients did not meet the genetic testing criteria for Lynch Syndrome. MMR-deficiency was found in 98.3% of MSI-I/MSI-H tumor samples.

It was concluded that MSI-H/dMMR tumors, regardless of cancer type and irrespective of the family history, should prompt germline testing for the evaluation of Lynch Syndrome. This will increase the ability to recognize Lynch Syndrome, not only in the patients tested, but also in at-risk family members, thus enabling the implementation of enhanced surveillance and risk reduction measures. Pan-cancer microsatellite instability to predict for presence of Lynch syndrome. Schwark AL, Srinivasan P, Kemel Y, et al. J Clin Oncol 36, 2018 (suppl; abstr LBA1509)

POMALYST® Combination Significantly Improves Progression Free Survival in Relapsed/Refractory Myeloma

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 30,770 new cases will be diagnosed in 2018 and 12,770 patients are expected to die of the disease. Multiple Myeloma in 2018 remains an incurable disease. The therapeutic goal therefore is to improve Progression Free Survival (PFS) and Overall Survival (OS). POMALYST® (Pomalidomide) is a novel, oral, immunomodulatory drug which is far more potent than THALOMID® (Thalidomide) and REVLIMID® (Lenalidomide), and has been shown to be active in REVLIMID® and VELCADE® (Bortezomib) refractory patients. POMALYST® is approved by the FDA for use in combination with Dexamethasone for the treatment of patients with Multiple Myeloma who have received at least 2 prior therapies including REVLIMID® and a Proteasome Inhibitor, and have had disease progression on or within 60 days of completing their last therapy.

POMALYST® has demonstrated synergistic anti-myeloma activity with Dexamethasone and Proteasome Inhibitors. It has been shown to inhibit proliferation of REVLIMID® resistant cells in preclinical studies. With the increasing use of REVLIMID® as first line treatment for patients with Multiple Myeloma, there is a clinically relevant unmet medical need for patients who have progressed on REVLIMID®. The authors herein report the outcomes of a first phase III trial, comparing a combination of POMALYST®, VELCADE® and low dose Dexamethasone (PVd) with VELCADE® and Dexamethasone (Vd), in an entirely post-REVLIMID® treated population.

OPTIMISMM is an international, open label phase III study in which 559 patients with Relapsed/Refractory Multiple Myeloma were randomized in a 1:1 ratio to receive POMALYST® in combination with VELCADE® and low dose Dexamethasone (PVd – N=281) or VELCADE® and Dexamethasone (Vd – N=278). Patients in both treatment groups received VELCADE® 1.3 mg/m² SC, on days 1, 4, 8, and 11 of cycles 1 thru 8, and on days 1 and 8 of cycle 9 and beyond, of each 21 day cycle. Dexamethasone was given to all patients at 20 mg orally daily (10 mg/day if more than 75 years of age) on the days of and after VELCADE® treatment. In the experimental arm, patients received POMALYST® 4 mg orally daily on days 1 thru 14, of each 21 day cycle. The median age was 67.5 years and both treatment groups were well balanced. All patients had prior treatment with REVLIMID® and 70% were refractory to this agent, whereas 72% of the patients had prior treatment with VELCADE® and 68% were refractory to the last treatment. The median number of prior treatment lines was 2 and approximately 40% of the patients in both treatment groups had one prior line of therapy. The percentage of patients with high-risk cytogenetics such as del(17p), t(4;14), and or t(14;16]), was similar in both treatment groups. The Primary endpoint was Progression Free Survival (PFS) and Secondary endpoints included Overall Survival (OS), Overall Response Rate (ORR), Duration of Response, and Safety.

At a median follow up of 16 months, the median PFS was 11.2 months with PVd compared with 7.1 months with Vd alone (HR=0.61; P<0.0001). This meant a 39% reduction in the risk of progression or death with POMALYST®, VELCADE® and low dose Dexamethasone combination, compared with VELCADE® and low dose Dexamethasone alone. This PFS benefit was noted regardless of age, performance status, high-risk cytogenetics, number of prior therapies, and types of prior therapy. The OS data are not mature. The most common side effects of the drug combinations were neutropenia, infections, and thrombocytopenia, which were manageable.

It was concluded that in the treatment of Multiple Myeloma, there remains an unmet medical need for those patients who have received REVLIMID® based therapies and are in early relapse. OPTIMISMM is the only phase III study to date in early Relapsed/Refractory Multiple Myeloma, that has demonstrated a significant and clinically meaningful PFS improvement in patients who have previously received REVLIMID® and especially those who are refractory to REVLIMID®, suggesting that the combination of POMALYST®, VELCADE® and low dose Dexamethasone may be a new standard of care in patients with Relapsed/Refractory Multiple Myeloma, with prior exposure to REVLIMID®. Pomalidomide (POM), bortezomib, and low‐dose dexamethasone (PVd) vs bortezomib and low-dose dexamethasone (Vd) in lenalidomide (LEN)-exposed patients (pts) with relapsed or refractory multiple myeloma (RRMM): Phase 3 OPTIMISMM trial. Richardson PG, Rocafiguera AO, Beksac M, et al. J Clin Oncol 36, 2018 (suppl; abstr 8001)

Late Breaking Abstract – ASCO 2018 Chemoprevention of Esophageal Cancer with NEXIUM® and Aspirin

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SUMMARY: The American Cancer Society estimates that in 2018, about 17,290 new cases of esophageal cancer will be diagnosed in the US and about 15,850 individuals will die of the disease. It is the sixth most common cause of global cancer death. Squamous Cell Carcinoma is the most common type of cancer of the esophagus among African Americans, while Adenocarcinoma is more common in caucasians. In those with esophageal adenocarcinoma detected through symptoms, 5-year survival is less than 10%.

Barrett esophagus, defined as intestinal metaplasia in the distal esophagus, is a complication of GastroEsophageal Reflux Disease (GERD) and affects 2% of the adult population in western countries. In patients with Barrett’s esophagus, a portion of the esophagus that is usually lined with squamous epithelium undergoes metaplastic change to become columnar mucosa. Barrett esophagus predisposes patients to esophageal adenocarcinoma through a series of pathological events which include esophagitis, metaplasia, dysplasia and subsequently adenocarcinoma. Patients with Barrett’s esophagus are often screened for early malignancy with endoscopic evaluation with modest benefit. This is unlike screening for colorectal cancer that has proved successful in reducing colorectal cancer deaths.

It has been shown in observational studies that powerful acid suppression with Proton Pump Inhibitors (PPIs) could reduce risk of neoplastic progression in patients with Barrett’s esophagus, by downregulating cylcogoxygenase-2 expression. Esomeprazole (NEXIUM®) is the most commonly used PPI in the USA, and allows the healing of esophagitis without promoting clonal expansion of Barrett’s esophagus. Aspirin use in observational studies has been associated with reduced risk of esophageal adenocarcinoma. Based on these findings, the authors evaluated the efficacy and safety of these two drugs in the Aspirin and Esomeprazole Chemoprevention in Barrett’s metaplasia Trial (AspECT).

AspECT is a prospective, factorial design, multicenter, randomized, phase III study of chemoprevention by Aspirin and NEXIUM®, in patients with Barrett’s esophagus. Patients with Barrett’s esophagus of 1 cm or more (N=2557) were randomised 1:1:1:1 to Low-dose NEXIUM® (20 mg qd) and no Aspirin (N=705), High-dose NEXIUM® (40 mg bid) and no Aspirin (N=704), Low-dose NEXIUM® with Aspirin 300 mg qd (N=571) and High-dose NEXIUM® with Aspirin (N=577). The median follow up and treatment duration was 8.9 years. The Primary composite endpoint was time to all-cause mortality, esophageal adenocarcinoma, or high-grade dysplasia. The co-primary end points were the efficacy of High-dose PPI versus Low-dose PPI, and the efficacy of Aspirin versus no Aspirin.

It was noted that High-dose PPI was superior to Low-dose PPI (P=0.038). Aspirin was not significantly better than no Aspirin (P=0.068). However, if patients using Non-Steroidal Anti-Inflammatory Drugs (NSAIDS) were censored at the time of first use, Aspirin was significantly better than no Aspirin (P=0.043). The most benefit was noted when High-dose PPI was combined with Aspirin compared with Low-dose PPI without Aspirin (P=0.0068). It appeared that the use of Aspirin and NEXIUM® (Proton Pump Inhibitor) would improve outcomes in Barrett’s esophagus, if given for at least 9 years. Serious adverse events were reported in only 1% of the participants.

It was concluded that in this largest randomized, controlled, chemoprevention trial in patients with Barrett’s esophagus, High dose NEXIUM® (given twice daily) along with Aspirin significantly reduces rates of death, esophageal adenocarcinoma, or high-grade dysplasia, with twice-daily NEXIUM® producing more effective suppression of acid reflux than once-daily dosing. Chemoprevention of esophageal cancer with esomeprazole and aspirin therapy: Efficacy and safety in the phase III randomized factorial ASPECT trial. Jankowski J, de Caestecker J, Love S, et al. J Clin Oncol 36, 2018 (suppl; abstr LBA4008)

Six Months Adjuvant HERCEPTIN® Safer and Efficacious in Early Stage HER2+ Breast Cancer

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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. The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. HERCEPTIN® (Trastuzumab) is a humanized monoclonal antibody targeting HER2, and adjuvant chemotherapy given along with HERCEPTIN® reduces the risk of disease recurrence and death, among patients with HER2-positive, early stage breast cancer. The duration of adjuvant HERCEPTIN® therapy has been 12 months and this length of treatment was empirically adopted from the pivotal registration trials.HER2-Directed-Therapy

PERSEPHONE is a randomized, phase III, noninferiority trial in which a 6-month course of adjuvant HERCEPTIN® was compared with the standard 12-month course, among patients with HER2-positive early breast cancer. This study was conducted based on the hypothesis that shorter course of treatment with HERCEPTIN® could reduce cardiotoxicities as well as cost without compromising efficacy. This trial randomized 4089 patients across 152 sites in a 1:1 ratio to receive HERCEPTIN® for 6 months (N=2044) or 12 months (N=2045). In this trial, 69% of patients had ER-positive tumors, 41% received Anthracycline-based chemotherapy, 49% received Anthracycline and Taxane-based chemotherapy, 10% received Taxane-based chemotherapy, 85% received adjuvant chemotherapy, and sequential HERCEPTIN® was administered in 54% of patients. This study also included assessment of Left Ventricular Ejection Fraction (LVEF) every 3 months until month 12, as well as continued Quality of Life and health economic assessments at months 18 and 24. The Primary endpoint was Disease Free Survival (DFS) from the time of diagnosis.

At a median follow-up period of 5 years, the 4-year DFS rate was identical in both treatment groups. DFS was 89.8% with 12 months of HERCEPTIN® compared with 89.4% with the 6-month course, which met the criteria for noninferiority (P=0.01). Further, only 4% of the patients enrolled in the 6-month HERCEPTIN® group discontinued HERCEPTIN® treatment due to cardiotoxicities compared with 8% in the 12-month group (P<0.0001), suggesting that the number of patients stopping treatment due to cardiac toxicities was cut in half with the shorter duration of treatment with HERCEPTIN®. Patients receiving shorter course of HERCEPTIN® also had a more rapid recovery of their cardiac LVEF following treatment, compared with the standard of care group (P=0.02).

It was concluded from this largest, reduced duration, noninferiority trial that a shorter 6-month course of adjuvant HERCEPTIN® was noninferior for Disease Free Survival, compared with the standard 12-month schedule, among patients with HER2-positive early breast cancer, with an additional benefit of reduction in cardiac toxicities, as well as cost both to the patients and healthcare systems. Overall Survival data was not available at the time of this analysis. PERSEPHONE: 6 versus 12 months (m) of adjuvant trastuzumab in patients (pts) with HER2 positive (+) early breast cancer (EBC): Randomised phase 3 non-inferiority trial with definitive 4-year (yr) disease-free survival (DFS) results. Earl HM, Hiller L, Vallier A-L, et al. J Clin Oncol 36, 2018 (suppl; abstr 506)

Late Breaking Abstract – ASCO 2018 Blood Test Demonstrates High Specificity for Detection of Early Stage Lung Cancer

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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 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. Survival rates however are significantly higher when lung cancer is diagnosed early. 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.

Although the U.S. Preventive Services Task Force (USPSTF) has recommended annual screening for lung cancer with Low-Dose Computed Tomography (LDCT) for individuals with significant smoking history, screening is vastly underutilized, with a screening rate of less than 2% among smokers eligible for screening. Screening for lung cancer using a peripheral blood sample may improve lung cancer screening rates. Analysis of cell-free DNA (cfDNA) from peripheral blood (Liquid Biopsy), is presently approved to select EGFR targeted therapies (cobas EGFR mutation test), in patients with advanced Non Small Cell Lung Cancer. However, the role of cell-free DNA analysis for early detection of lung cancer is not well established.

The Circulating Cell-Free Genome Atlas (CCGA) is a prospective, multi-center, observational study and is the largest study ever initiated, to develop a noninvasive, liquid biopsy assay for early cancer detection, based on cell-free DNA (cfDNA). This study has currently enrolled 10,012 of a planned 15,000 participants, including people with a recent cancer diagnosis and also a control group of individuals with no known malignancy (70% with cancer, 30% without cancer), across 141 sites in the United States and Canada. This report is one of the first pre-planned sub-studies from the CCGA, involving investigation of blood samples from 1,627 participants (878 patients with newly diagnosed untreated cancer including 127 patients with lung cancer and 749 controls – 580 controls and 169 technical assay controls ), across 20 tumor types and all clinical stages.

The cell-free DNA was isolated from the peripheral blood and analyzed using the following three sequencing methods that were designed to detect cancer-defining signals (mutations and other genomic changes), that could be utilized for early cancer detection.

Targeted sequencing to detect somatic (non-inherited) mutations, such as Single Nucleotide Variants and small insertions and/or deletions, in specific sections of the genome.

Whole-Genome Sequencing (WGS) to detect somatic gene copy number changes across the genome.

Whole-Genome Bisulfite Sequencing (WGBS) of cfDNA to detect abnormal patterns of cfDNA methylation (epigenetic changes)

In this initial sub-study, the authors explored the ability of the above three different assays to detect cancer in 127 people with stage I-IV lung cancer. It was noted that biologic signals suggesting lung cancer were detected and comparable across all assays, and the signal increased with cancer stage. At 98% specificity, the Targeted sequencing detected 51% of early-stage (stage I-IIIA) lung cancers and 89% of late-stage (stage IIIB-IV) lung cancers. Whole-Genome Sequencing detected 38% of early-stage cancers and 87% of late-stage cancers. Whole-Genome Bisulfite Sequencing had similar efficacy, detecting 41% of early stage lung cancers and 89% of late-stage cancers. Similar sensitivities were noted across all assays for adenocarcinoma, squamous cell and small cell lung cancer. False positive rates were low. Of the 580 control participants without cancer at study enrollment, less than 1% (five participants) had cancer-like signal across all three assays, of whom two were subsequently diagnosed with cancer. This highlights the potential for these assays to detect early stage cancers. The authors caution that a large proportion of cell-free DNA is derived from White Blood Cells (WBCs) and DNA mutations in the WBC population can also be generated by processes other than cancer such as clonal hematopoiesis during human aging. In this study, signal generated from the WBCs was subtracted resulting in a cleaner signal, only from tumor related variants.

It was concluded that based on the initial results from the CCGA study, it is possible to detect early-stage lung cancer, with a high degree of specificity, from a simple blood test, using genome sequencing. The authors plan to further optimize the assays and validate results in a larger group of people. Genome-wide sequencing for early stage lung cancer detection from plasma cell-free DNA (cfDNA): The Circulating Cancer Genome Atlas (CCGA) study. Oxnard GR, Maddala T, Hubbell E, et al. J Clin Oncol. 2018;36(suppl; abstr LBA8501)

Late Breaking Abstract – ASCO 2018 First Line TECENTRIQ® plus Chemotherapy in Advanced Squamous 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 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. Non Small Cell Lung Cancer patients with Squamous Cell histology have been a traditionally hard- to-treat, patient group, and less than 15% of patients with advanced Squamous NSCLC survive a year after diagnosis and less than 5% of patients survive for five years or longer. 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).

TECENTRIQ® (Atezolizumab) is an anti PD-L1 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. In this present publication, the authors studied the efficacy of TECENTRIQ® given along with combination chemotherapy, in patients with advanced Squamous NSCLC.Unleashing-T-Cell-Function-with-Anti-PDL1-Antibodies

IMpower131 is a multicenter, open-label, phase III study, in which 1021 chemotherapy-naïve patients with stage IV Squamous NSCLC were randomly assigned in 1:1:1 ratio to receive TECENTRIQ® along with Carboplatin, and Paclitaxel (Group A, N=338), TECENTRIQ® along with Carboplatin, and ABRAXANE® (nab-paclitaxel) (Group B, N=343) and the control arm of Carboplatin and ABRAXANE® (Group C, N=340). Patients in Group A received TECENTRIQ® 1200 mg IV along with Carboplatin AUC 6 and TAXOL® (Paclitaxel) 200 mg/m2 IV, all drugs given on Day 1, every 21 days. Patients in Group B received TECENTRIQ® 1200 mg IV along with Carboplatin AUC 6 IV on Day 1 and ABRAXANE® 100mg/m2 IV on Days 1, 8, and 15 of each 21-day cycle. Patients in Group C (control group) received Carboplatin AUC 6 IV on Day 1 and ABRAXANE® 100mg/m2 IV on Days 1, 8, and 15 of each 21-day cycle. Patients received 4-6 cycles of this combination treatment and in Groups A and B, TECENTRIQ® alone was continued as long as there was a clinical benefit, without evidence of disease progression. Tumors were tested for PD-L1 expression, but patients were included in the study regardless of PD-L1 expression level. Patients with tumors demonstrating EGFR or ALK gene changes should have received molecularly targeted treatments before enrolling in this study. The co-Primary endpoints for this study were Progression Free Survival (PFS) and Overall Survival (OS). As per the study design, the current analysis compared the outcomes of patients in Group B with Group C. Outcomes data comparing Group A with Group C are not yet available.

At the time of primary analysis, with a median follow up of 17.1 months, the median PFS across all PD-L1 subgroups was 6.3 months with the addition of TECENTRIQ® to chemotherapy (Group B) versus 5.6 months in Group C, with chemotherapy alone (HR=0.71; P=0.0001). This represented a 29% reduction in the risk of disease progression or death, with the addition of TECENTRIQ® to chemotherapy. The 12-month PFS rates in Groups B and C were 24.7% versus 12.0%, respectively, suggesting a doubling of PFS benefit with the addition of TECENTRIQ® to chemotherapy. The PFS benefit was more pronounced in those with higher tumor PD-L1 expression. Overall Survival data are not yet mature. The most common side effects with the addition of TECENTRIQ® to chemotherapy included skin rash, colitis, and hypothyroidism.

The authors concluded that this is the first phase III trial of an immunotherapy-based treatment regimen, to demonstrate a significant improvement in Progression Free Survival, in advanced Squamous NSCLC. IMpower131: Primary PFS and safety analysis of a randomized phase III study of atezolizumab + carboplatin + paclitaxel or nab-paclitaxel vs carboplatin + nab-paclitaxel as 1L therapy in advanced squamous NSCLC. Jotte RM, Cappuzzo F, Vynnychenko I, et al. J Clin Oncol 36, 2018 (suppl; abstr LBA9000)

REVLIMID® plus RITUXAN®, A Potential Chemo-Free Frontline Therapy for Follicular Lymphoma

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SUMMARY: The American Cancer Society estimates that in 2018, about 74,680 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 19,910 individuals will die of this disease. Indolent Non Hodgkin Lymphomas are mature B cell lymphoproliferative disorders and include Follicular Lymphoma, Nodal Marginal Zone Lymphoma (NMZL), Extranodal Marginal Zone Lymphoma (ENMZL) of Mucosa-Associated Lymphoid Tissue (MALT), Splenic Marginal Zone Lymphoma (SMZL), LymphoPlasmacytic Lymphoma (LPL) and Small Lymphocytic Lymphoma (SLL).

Follicular Lymphoma is the most indolent form and second most common form of all NHLs and they are a heterogeneous group of lymphoproliferative malignancies. Approximately 20% of all NHLs are Follicular Lymphomas. Advanced stage indolent NHL is not curable and as such, prolonging Progression Free Survival (PFS) and Overall Survival (OS), while maintaining Quality of Life, have been the goals of treatment intervention. Asymptomatic patients with indolent NHL are generally considered candidates for “watch and wait” approach. Patients with advanced stage symptomatic Follicular Lymphoma are often treated with induction chemoimmunotherapy followed by maintenance RITUXAN® (Rituximab).

REVLIMID® (Lenalidomide) is an oral immunomodulatory agent (IMiD) with activity in lymphoid malignancies, primarily through immune modulation (repair T-cell immune synapse dysfunction and Natural Killer cell/T-cell effector augmentation). It additionally has antiproliferative effects. Chemo-free combination immunotherapy with REVLIMID® and RITUXAN® or the R2 regimen, has shown promising activity in phase II studies.GELF-Criteria-for-Initiating-Treatment-of-Follicular-Lymphoma

RELEVANCE is a global, randomized, open-label, phase III study, conducted in partnership with the Lymphoma Academic Research Organisation (LYSARC). This study evaluated the investigational regimen of REVLIMID® plus RITUXAN® (R2), followed by RITUXAN® maintenance, compared to the standard of care treatment of RITUXAN® plus chemotherapy, followed by RITUXAN® maintenance, in patients with previously untreated Follicular Lymphoma.

In this study, 1030 patients with treatment naïve, advanced Follicular Lymphoma, were randomized to R2 regimen (N=513) and R-Chemo regimen (N=517). Patients had Grade 1-3a Follicular Lymphoma, requiring therapy according to GELF criteria. Patients in the R2 group received REVLIMID® 20 mg orally daily on Days 2 thru 22 every 28 days for 6-12 cycles and continued responders received REVLIMID® 10 mg orally daily on Days 2 thru 22 every 28 days, for a total of 18 cycles. RITUXAN® was administered at 375 mg/m2 IV on Days 1, 8, 15, and 22 of cycle 1 and Day 1 of cycles 2 thru 6, and then continued in responders for 12 additional cycles every 8 weeks. R-Chemo group received investigators choice of standard R-CHOP (72%), R-Bendamustine (23%) or R-CVP (5%), and responding patients continued with RITUXAN® 375 mg/m2 IV every 8 weeks, for 12 cycles. The median age of the patients was 59 years. The co-Primary endpoints were Complete Response/unconfirmed Complete Response at 120 weeks and Progression Free Survival (PFS) during the preplanned analysis.

At a median follow up of 37.9 months, PFS was similar in both treatment groups and the 3-year PFS rate was 77% in the R2 group compared with 78% for the R-Chemo group (HR=1.10; P=0.48). The Complete Response/unconfirmed Complete Response at 120 weeks were 48% in the R2 group and 53% in the R-chemo group and this was also not statistically significant (P=0.13). Preliminary Overall Survival outcomes (Secondary endpoint) showed a 3-year survival rate of 94% in both treatment groups. Adverse events were different in the two treatment groups, with a higher incidence of neutropenia and febrile neutropenia in the R-Chemo group, and higher incidence of cutaneous events in the R2 group.

It was concluded that in this first randomized phase III comparison of a chemo-free regimen (R2) with standard R-Chemo, in previously untreated Follicular Lymphoma, a combination of REVLIMID® and RITUXAN® (R2) showed similar efficacy, with a more favorable safety profile, making it a potential chemo-free, firstline option, for patients with Follicular Lymphoma. RELEVANCE: Phase III randomized study of lenalidomide plus rituximab (R2) versus chemotherapy plus rituximab, followed by rituximab maintenance, in patients with previously untreated follicular lymphoma. Fowler NH, Morschhauser F, Feugier P, et al. J Clin Oncol 36, 2018 (suppl; abstr 7500)

Late Breaking Abstract – ASCO 2018 First-Line KEYTRUDA® Superior to Chemotherapy in 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 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.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells. High level of Programmed Death-Ligand 1 (PD-L1) expression is defined as membranous PD-L1 expression on at least 50% of the tumor cells, regardless of the staining intensity. It is estimated that based on observations from previous studies, approximately 25% of the patients with advanced NSCLC have a high level of PD-L1 expression and high level of PD-L1 expression has been associated with significantly increased response rates to KEYTRUDA®. The FDA approved KEYTRUDA® for the first-line treatment of advanced NSCLC with high PD-L1 expression (Tumor Proportion Score of 50% or more), as well as in combination with Pemetrexed and Carboplatin, as first-line treatment of patients with metastatic nonsquamous NSCLC and for previously treated advanced NSCLC with a PD-L1 Tumor Proportion Score of 1% or more. Currently, KEYTRUDA® is the only FDA approved immunotherapy for initial treatment of NSCLC as monotherapy (KEYNOTE-024) or in combination with chemotherapy. In KEYNOTE-024, KEYTRUDA® significantly improved Progression Free Survival and Overall Survival compared to chemotherapy, as first-line treatment for metastatic NSCLC, without targetable mutations and PD-L1 TPS of 50% or more. KEYNOTE-042 trial evaluated the benefit of KEYTRUDA® in patients whose tumors had a much lower level of PD-L1 expression (TPS of 1% or higher).Unleashing-T-Cell-Function-with-KEYTRUDA-(Pembrolizumab)-for-Advanced-Non-Small-Cell-Lung-Cancer

KEYNOTE-042 is a large, international, multicenter, randomized phase III trial in which 1274 patients with untreated locally advanced or metastatic NSCLC were randomly assigned to KEYTRUDA® or chemotherapy with Paclitaxel plus Carboplatin or Pemetrexed plus Carboplatin. In this study, both squamous and non-squamous cancers with PD-L1 Tumor Proportion Score (TPS) of 1% or more were included, but tumors with sensitizing Epidermal Growth Factor Receptor (EGFR) or Anaplastic Lymphoma Kinase (ALK) mutations cancers with genetic changes, that could be treated with targeted therapies such as EGFR and ALK inhibitors, were excluded. Eligible patients were randomly assigned in a 1:1 to receive either KEYTRUDA® 200 mg IV every 3 weeks for up to 35 cycles or investigator’s choice of up to 6 cycles of chemotherapy with Paclitaxel plus Carboplatin or Pemetrexed plus Carboplatin, with optional Pemetrexed maintenance for nonsquamous NSCLC. Patients were divided into 3 treatment groups based on their PD-L1 Tumor Proportion Score (TPS): TPS 50% or more (N=599), TPS 20% or more (N=818), and TPS 1% or more (N=1274). Each PD-L1 expression group had equal numbers of patients receiving KEYTRUDA® and chemotherapy. The Primary end points were Overall Survival (OS) in patients with TPS 50% or more, 20% or more, and 1% or more.

At a median follow up of 12.8 months, 13.7% of patients were still receiving KEYTRUDA® compared with 4.9% on Pemetrexed maintenance therapy. It was noted that KEYTRUDA® was significantly superior to chemotherapy in all PD-L1 expression subsets. In patients with a PD-L1 TPS 50% or more, the median OS with KEYTRUDA® was 20 months versus 12.2 months for chemotherapy (HR=0.69, P=0.0003), for patients with PD-L1 TPS 20% or more, the median OS was 17.7 months versus 13 months respectively (HR=0.77, P=0.002), and for those with PD-L1 TPS 1% or more, the median OS was 16.7 months versus 12.1 months respectively (HR=0.81, P = 0.0018). The Response Rates (RR) were also higher among patients who received KEYTRUDA®, with RR of 39.5% for KEYTRUDA® versus 32% for chemotherapy in patients with a TPS 50% or more, 33.4% and 28.9% respectively in patients with TPS 20% or more and 27.3% and 26.5%, respectively, in patients with TPS of 1% or more. The duration of response was also superior with KEYTRUDA® in all three PD-L1 subgroups compared to chemotherapy (20.2 months versus 8-11 months). Patients receiving KEYTRUDA® experienced fewer severe Adverse Events, compared with chemotherapy (17.8% versus 41%).

The authors concluded that this is the largest clinical trial of KEYTRUDA® as a stand-alone therapy, and is the first study with a Primary end point of OS to demonstrate superiority of KEYTRUDA® over platinum-based chemotherapy, in patients with previously untreated advanced/metastatic NSCLC, without sensitizing EGFR or ALK alterations and a PD-L1 TPS of 1% or more. These data confirmed the benefit of KEYTRUDA® monotherapy as a standard first-line treatment, for PD-L1-expressing advanced/metastatic NSCLC. Pembrolizumab (pembro) versus platinum-based chemotherapy (chemo) as first-line therapy for advanced/metastatic NSCLC with a PD-L1 tumor proportion score (TPS) ≥ 1%: Open-label, phase 3 KEYNOTE-042 study. Lopes G, Wu Y-L, Kudaba I, et al. J Clin Oncol 36, 2018 (suppl; abstr LBA4)