Author: RR

Late Breaking Abstract – ESMO 2018 Treatment with a Combination of XOFIGO® and ZYTIGA® NOT Recommended in Metastatic Prostate Cancer

RR

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 174,650 new cases of Prostate cancer will be diagnosed in 2019 and 31,620 men will die of the disease. Over 90% of the patients with metastatic prostate cancer have bone metastases, and the tumor burden, is an independent predictor of death in this patient population. Agents such as ZOMETA® (Zoledronic acid) and XGEVA® (Denosumab) can prevent or delay Skeletal Related Events (SRE’s) and External Beam Radiation Therapy (EBRT) is often utilized to treat symptomatic SRE’s. EBRT can however damage the bone marrow in the radiated field, resulting in cytopenias, and consequently can potentially preclude patients from receiving cytotoxic chemotherapy.

Radium Ra 223 dichloride (XOFIGO®) is a bone seeking alpha particle emitter and by virtue of its chemical similarity to calcium is preferentially taken up by the bone and forms complexes with bone mineral, hydroxyapatite, in areas where there is increased bone turnover, such as bone metastases. XOFIGO® induces double stranded DNA breaks resulting in antitumor effects and has a very short range in tissues (around 2 and 10 cells), quickly losing energy, compared to beta or gamma radiation. The end result is less damage to the adjacent healthy tissues. Further, unlike Ra-226 which was first isolated by Madame Curie, XOFIGO® has a short half life of 11.4 days and rapidly decays, preventing significant radiation exposure.

XOFIGO® in a randomized, double-blind, Phase III trial (ALSYMPCA study) improved overall survival in patients with CRPC (Castrate Resistant Prostate Cancer) with bone metastases. Abiraterone acetate (ZYTIGA®) is a novel, targeted, oral androgen biosynthesis inhibitor that decreases androgen production in the adrenal glands, testes and prostate cancer cells by inhibiting a steroidal enzyme CYP17A. ZYTIGA® along with Prednisone in a double-blind, randomized, Phase III study (COU-AA-302 trial) significantly improved Overall Survival compared with Prednisone alone, in patients with chemotherapy-naive metastatic CRPC. This formed the basis for this present study.

ERA 223 is a randomized, double-blind, placebo controlled, Phase III trial in which 806 patients with asymptomatic or mildly symptomatic chemotherapy-naïve metastatic Castration Resistant Prostate Cancer with at least 2 bone metastases were randomly assigned in a 1:1 to ZYTIGA® plus concurrent XOFIGO® (N=401) versus ZYTIGA® plus matching placebo (N=405). Bone Health Agents (BHAs) (Bisphosphonates or XGEVA®) were only allowed in patients receiving them at baseline, and 39% of patients in the ZYTIGA® plus XOFIGO® and 42% in the ZYTIGA® plus placebo arms were receiving BHAs at baseline. The median age was 71 years in both treatment groups. The Primary endpoint was Symptomatic Skeletal Event-Free Survival (SSE-FS), defined as freedom from the use of External Beam Radiation to relieve symptomatic skeletal events, new symptomatic pathologic bone fracture, spinal cord compression, tumor-related orthopedic surgical intervention, or death. Secondary endpoints included Overall Survival, radiological Progression Free Survival (rPFS), time to cytotoxic chemotherapy, and time to opiate use for cancer pain. This study was unblinded prematurely due to more fractures and deaths in the ZYTIGA® plus XOFIGO® group. All patients had completed study-specified XOFIGO® /placebo treatment prior to unblinding. The treatment was however continued, and the protocol was amended to allow BHAs in patients who were not taking them at baseline.

At the primary analysis, it was noted that there was no significant difference between the two treatment arms for the Primary endpoint of Symptomatic Skeletal Event-Free Survival. The median Symptomatic Skeletal Event-Free Survival was 22.3 months in the ZYTIGA® plus XOFIGO® group versus 26 months in the ZYTIGA® plus placebo group (P=0.263). The Secondary endpoint of Overall Survival (OS) was 30.7 months with ZYTIGA® plus XOFIGO® and 33.3 months with ZYTIGA® plus placebo (P=0.128) and this was not significantly different. Fractures occurred in 29% of patients in the ZYTIGA® plus XOFIGO® group and 11% of patients in the ZYTIGA® plus placebo group respectively. Patients who were taking BHAs still sustained more fractures in the XOFIGO® containing arm. Baseline use of BHAs however was associated with lower fracture rates in both treatment groups. In patients receiving BHAs, 15% and 7% experienced a fracture in the ZYTIGA® plus XOFIGO® and ZYTIGA® plus placebo arms respectively, versus 37% and 15% without BHAs.

It was concluded that concurrent ZYTIGA® plus XOFIGO® treatment did not improve Symptomatic Skeletal Event-Free Survival or Overall Survival but on the contrary led to a higher fracture rate. Based on these results, the authors recommended against the use of XOFIGO® in combination with ZYTIGA®. ERA 223: A phase 3 trial of radium-223 (Ra-223) in combination with abiraterone acetate and prednisone/prednisolone for the treatment of asymptomatic or mildly symptomatic chemotherapy-naïve patients (pts) with bone-predominant metastatic castration-resistant prostate cancer (mCRPC). Smith MR, Parker CC, Saad F, et al. Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA30.

Late Breaking Abstract – ESMO 2018 LONSURF® Improves Overall Survival in Heavily Pretreated Gastric and GE Junction Cancers

RR

SUMMARY: The American Cancer Society estimates that in the US, about 27,510 cases of Gastric Cancer will be diagnosed in 2019 and about 11,140 people will die of the disease. The average age at diagnosis is 68 years and Gastric Cancer is one of the leading causes of cancer-related deaths in the world. Patients with localized disease (Stage II and Stage III) are often treated with multimodality therapy and 40% of the patients may survive for 5 years or more. However, majority of the patients with Gastric and GastroEsophageal (GE) Adenocarcinoma have advanced disease at the time of initial presentation and have limited therapeutic options with little or no chance for cure. Following progression after first line treatment for metastatic disease, the median survival is approximately 3 months.

LONSURF® (TAS-102) is a combination of two agents – a novel oral nucleoside Trifluridine and a thymidine phosphorylase inhibitor, Tipiracil hydrochloride. This combination has a unique mechanism of action. Trifluridine, the active ingredient of LONSURF® incorporates into DNA resulting in DNA damage. Degradation of Trifluridine which occurs when taken orally is prevented by Tipiracil hydrochloride. In a previously published Phase II study, LONSURF® demonstrated promising efficacy and was well tolerated among pretreated patients with advanced Gastric cancer. TAGS study was conducted to confirm these findings.

The TAGS (TAS-102 Gastric Study) trial is a pivotal Phase III multinational, randomized, double-blind study evaluating LONSURF® (Trifluridine and Tipiracil) plus Best Supportive Care (BSC) versus placebo plus BSC, in patients with metastatic Gastric Cancer, refractory to standard treatments. Enrolled patients (N=507) with histologically confirmed, non-resectable metastatic Gastric cancer including GastroEesophageal junction cancer, who had received 2 or more prior chemotherapy regimens, were randomly assigned in a 2:1 ratio to receive LONSURF® 35 mg/m2 BID on days 1-5 and 8-12 of each 28-day cycle (N=337) or placebo plus Best Supportive Care (N=170). Prior treatments included Fluoropyrimidine, Platinum, Taxane, Irinotecan, or a HER2 inhibitor. Both treatment groups were well balanced and 63% of patients had received 3 or more lines of prior systemic therapy. The Primary endpoint was Overall Survival.

At a median follow-up was 10.7 months, the Primary endpoint was met with a median OS of 5.7 months with LONSURF&rg; versus 3.6 months for those in the placebo group (HR=0.69; P=0.0003). This suggested a 31% reduction in the risk of death when treated with LONSURF®. This benefit was noted across all prespecified subgroups. Treatment with LONSURF® was also associated with 43% lower risk of disease progression or death compared with placebo (HR=0.57; P<0.0001). This Progression Free Survival benefit was again noted in all subgroups. Further, patients in the LONSURF® group had a higher Disease Control Rate (44% versus 14%; P<0.0001) and lower risk of deterioration in Performance Status (HR=0.69; P=0.0005), compared to placebo.

The authors concluded that LONSURF® provided clinically meaningful and statistically significant prolongation in Overall Survival and was well tolerated in patients with heavily pretreated metastatic Gastric Carcinoma. TAGS: a phase 3, randomised, double-blind study of trifluridine/tipiracil (TAS-102) versus placebo in patients with refractory metastatic gastric cancer. Arkenau H-T, Tabernero J, Shitara K, et al. Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA25.

Radical Prostatectomy Lowers the Risk of Death in Clinically Detected Localized Prostate Cancer

RR

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 174,650 new cases of Prostate cancer will be diagnosed in 2019 and 31,620 men will die of the disease. The widespread use of PSA testing in the recent years has resulted in a dramatic increase in the diagnosis and treatment of prostate cancer. The management of clinically localized prostate cancer that is detected based on Prostate Specific Antigen (PSA) levels remains controversial and management strategies for these patients have included Surgery, Radiotherapy or Active Monitoring. However, it has been proposed that given the indolent nature of prostate cancer in general, majority of the patients do not benefit from treatment intervention and many patients die of competing causes. Further, treatment intervention can result in adverse effects on sexual, urinary, or bowel function. The U.S. Preventive Services Task Force (USPSTF) has recommended that population screening for prostate cancer should not be adopted as a public health policy, because the risks appeared to outweigh benefits, from detecting and treating PSA-detected prostate cancer. 

In the Prostate Testing for Cancer and Treatment (ProtecT) study which is a prospective, randomized trial, management with Active Monitoring, Radical Prostatectomy, and External Beam Radiotherapy were compared, among patients with PSA-detected clinically localized prostate cancer. This study at a median follow up of 10 yrs concluded that prostate cancer-specific mortality was low, irrespective of the treatment given, with similar efficacy outcomes, but with a variable impact on quality of life. In this study, it was noted that patients assigned to Active Monitoring were significantly more likely to have metastatic disease than those assigned to treatment. This in turn would warrant salvage treatment, which could result in toxicities as well. Long term survival results are not mature. In the Prostate Cancer Intervention versus Observation Trial (PIVOT), at 19 years of follow up, the relative risk of death from prostate cancer was 0.65 (65% lower with intervention) but the absolute difference in risk was only 4%. However, long term follow up results are not mature. These data suggested that Radical Prostatectomy reduces mortality among men with clinically detected localized prostate cancer, but evidence from long-term follow-up is lacking.

The Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) is a randomized trial in which 695 men with localized prostate cancer were randomly assigned to the Radical Prostatectomy group (N=347) and to the watchful-waiting group (N=348), between 1989 and 1999. This trial opened before the era of Prostate Specific Antigen (PSA) testing. Enrolled patients were younger than 75 years of age and had localized tumor Stage T1, or T2. Tumors had to be well differentiated to moderately well differentiated according to the WHO classification, and were required to have a serum PSA level of less than 50 ng/ml and a negative bone scan. The baseline characteristics were similar in both groups. The mean age was 65 years, the mean PSA level was approximately 13 ng/ml, and only 12% of the patients had nonpalpable stage T1c tumors. Patients were followed up every 6 months for the first 2 years and then annually. The Primary end points were death from any cause, death from prostate cancer, and the risk of metastases. Secondary end points included the initiation of Androgen Deprivation Therapy. The median follow up time was 23.6 years.

The cumulative incidence of death from prostate cancer at 23 years was 19.6% in the Radical Prostatectomy group and 31.3% in the watchful-waiting group (difference of 11.7%) and the relative risk for the complete follow up period was 0.55, meaning 55% lower risk of death with Radical Prostatectomy (P<0.001). The mean years of life gained, in the Radical Prostatectomy group at 23 years of follow up was 2.9 years. The cumulative incidence of distant metastases at 23 years was 26.6% in the Radical Prostatectomy group and 43.3% in the watchful-waiting group (difference of 16.7%) and the relative risk based on data from the complete follow up period was 0.54, meaning 54% lower risk of distant metastases (P<0.001). Among those who underwent Radical Prostatectomy, extracapsular extension was associated with a risk of death from prostate cancer that was 5 times as high as that among men without extracapsular extension. A Gleason score higher than 7 was associated with a risk, that was 10 times as high as that with a score of 6 or lower.

It was concluded that among men with clinically detected localized prostate cancer, Radical Prostatectomy resulted in a mean gain of almost 3 years of life after 23 years of follow up, and a high Gleason score and the presence of extracapsular extension in the Radical Prostatectomy specimens were highly predictive of death from prostate cancer. In the current day clinical practice however, with widespread PSA testing and PSA-detected tumors utilizing multiparametric Magnetic Resonance Imaging with targeted biopsies, the lead time induced by screening and definition of risk groups becomes increasing relevant when recommending treatment. Radical Prostatectomy or Watchful Waiting in Prostate Cancer – 29-Year Follow-up. Bill-Axelson A, Holmberg L, Garmo H, et al. N Engl J Med 2018; 379:2319-2329

FDA Approves CABOMETYX® for Hepatocellular Carcinoma

RR

SUMMARY: The FDA on January 14, 2019 approved CABOMETYX® (Cabozantinib) for patients with HepatoCellular Carcinoma (HCC) who have been previously treated with NEXAVAR® (Sorafenib). The American Cancer Society estimates that for 2019, about 42,030 new cases of primary liver cancer will be diagnosed in the US and 31,780 patients will die of their disease. Liver cancer is seen more often in men than in women and the incidence has more than tripled since 1980. 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® 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® 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).MOA-of-CABOZANTINIB

The present FDA approval was based on the CELESTIAL trial, which 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 Progression Free Survival, compared with placebo, in previously treated patients with advanced HCC, and CABOMETYX® represents a new treatment option for this patient group. Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma. Abou-Alfa GK, Meyer T, Cheng A-L, et al. N Engl J Med 2018;379:54-63

ONTRUZANT® (Trastuzumab-dttb)

RR

The FDA on January 18, 2019 granted approval to ONTRUZANT®, a Trastuzumab (HERCEPTIN®) biosimilar, for the treatment of patients with HER2-overexpressing Breast cancer or metastatic Gastric or GastroEsophageal Junction adenocarcinoma. The newly approved biosimilar will also eventually compete with 2 prior FDA approved biosimilars, OGIVRI® (Trastuzumab-dkst) and HERZUMA® (Trastuzumab-pkrb). ONTRUZANT® is a product of Samsung Bioepis and will be marketed by Merck&Co.

Radiotherapy plus ERBITUX® Inferior to Radiotherapy plus Cisplatin in HPV-Positive Oropharyngeal Squamous Cell Carcinoma

RR

SUMMARY: The Centers for Disease Control and Prevention estimates that in the US, there are more than 16,000 cases of Human PapillomaVirus (HPV)-positive OroPharyngeal Squamous Cell Carcinoma (OPSCC) per year and there has been a significant increase in incidence during the past several decades, due to changes in sexual practices. They represent approximately 70% of all OPSCC in the United States and Canada. HPV-positive oropharyngeal squamous cell carcinoma is an entirely distinct disease entity from HPV-negative oropharyngeal squamous cell carcinoma. Patients with HPV-positive OPSCC tend to be younger males, who are former smokers or nonsmokers, with risk factors for exposure to High Risk HPV (HR-HPV). The HPV-positive primary Squamous Cell Carcinoma tend to be smaller in size, with early nodal metastases, and these patients have a better prognosis compared with patients with HPV-negative Head and Neck Squamous Cell Carcinoma (HNSCC), when treated similarly. Expression of tumor suppressor protein, known as p16, is highly correlated with infection with HPV in HNSCC. Accurate HPV assessment in head and neck cancers is becoming important as it significantly impacts clinical management. HPV status is considered the most important prognostic indicator in patients with head and neck cancer and p16 status is now included in the American Joint Committee on Cancer (AJCC) Staging System.
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HPV-positive Oropharyngeal Squamous Cell Carcinoma is more sensitive to chemotherapy and radiotherapy than is HPV-negative Oropharyngeal Squamous Cell Carcinoma, which translates to a much better prognosis and survival, when treated with a combination of Cisplatin chemotherapy and radiotherapy. This treatment however can be associated with substantial morbidity and lifelong toxicities such as dry mouth, difficulty swallowing, and loss of taste. Patients deemed unable to tolerate Cisplatin chemotherapy such as the elderly, and those with poor kidney function, receive ERBITUX® (Cetuximab), an Epidermal Growth Factor Receptor (EGFR) inhibitor with radiotherapy.

ERBITUX® is an EGFR targeted monoclonal antibody and the goal of this present study was to find an alternative to Cisplatin, and this study was designed to see if ERBITUX® with radiation would be less toxic than Cisplatin with radiation, without compromising survival among HPV-positive OPSCC patient population. RTOG 1016 is a randomized, multicentre, non-inferiority, phase III trial which included patients with Human PapillomaVirus (HPV)-positive Oropharyngeal Squamous Cell Carcinoma. This study enrolled 987 patients (N=987) at 182 centers in the US and Canada and enrollees had histologically confirmed HPV-positive Oropharyngeal carcinoma and clinical categories included T1-T2, N2a-N3 M0 or T3-T4, N0-N3 M0 groups. Patients were randomly assigned in a 1:1 ratio to receive either radiotherapy plus ERBITUX®, or radiotherapy plus Cisplatin. Treatment groups were well balanced and were stratified by T (T1–T2 vs T3–T4), N category (N0-N2a vs N2b-N3), and smoking history (10 pack-years or less vs more than 10 pack-years). Patients were randomized to receive either ERBITUX® at a loading dose of 400 mg/m2 IV 5-7 days before radiotherapy initiation, followed by ERBITUX® 250 mg/m2 IV weekly for seven doses (N=425) or Cisplatin 100 mg/m 2 on days 1 and 22 of radiotherapy (N=424). All patients received accelerated Intensity-Modulated RadioTherapy (IMRT) delivered at 70 Gy in 35 fractions over 6 weeks at six fractions per week (with two fractions given on one day, at least 6 hours apart). The Primary endpoint was Overall Survival.

The third and final interim analysis was done after a median follow-up of 4.5 years. Radiotherapy plus ERBITUX® did not meet the non-inferiority criteria for Overall Survival and the estimated 5-year Overall Survival was 77.9% in the ERBITUX® group versus 84.6% in the Cisplatin group, suggesting that the Overall Survival on the ERBITUX® arm was significantly inferior to the Cisplatin arm. Progression Free Survival (PFS) was also significantly lower in the ERBITUX® group compared with the Cisplatin group, with a 5-year PFS of 67.3% versus 78.4%, respectively. Five year locoregional failure rates were significantly higher in the ERBITUX® group compared with the Cisplatin group (17.3% versus 9.9%, respectively. Serious (grade 3-5) adverse events were similar for patients in both treatment groups and as expected, toxicities were different, with adverse events of renal toxicity, hearing loss, and bone marrow suppression more common in patients in the Cisplatin group, where as body rash was more common in the ERBITUX® group. All patients in this study were able to complete therapy at the time of this analysis.

It was concluded that this trial is the first randomized clinical trial specifically designed for patients with HPV-positive Oropharyngeal cancer, and among this patient group, radiotherapy plus ERBITUX® showed inferior Overall Survival and Progression Free Survival compared with radiotherapy plus Cisplatin. Radiotherapy plus Cisplatin should therefore be the standard of care for eligible patients with HPV-positive Oropharyngeal carcinoma. Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial. Gillison ML, Trotti AM, Harris J, et al. Published:November 15, 2018. DOI:https://doi.org/10.1016/S0140-6736(18)32779-X

Late Breaking Abstract – ESMO 2018 Frontline KEYTRUDA® Improves Overall Survival in Advanced Head and Neck Cancer

RR

SUMMARY: The American Cancer Society estimates that 65,410 people will be diagnosed with Head and Neck cancer in 2019 and 14,620 patients will die of the disease. Patients with Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck have a poor prognosis with a short median Overall Survival. The treatment paradigm for Head and Neck cancer has been rapidly evolving with the recognition and better understanding of immune evasion and the role of Immune checkpoints or gate keepers in suppressing antitumor immunity. Blocking the Immune checkpoints unleashes the T cells, resulting in T cell proliferation, activation and a therapeutic response. KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells.

KEYNOTE-048 is an open-label, three arm, randomized, phase III trial, in which KEYTRUDA® monotherapy and KEYTRUDA® plus chemotherapy was compared to ERBITUX® (Cetuximab) plus chemotherapy, as first-line systemic therapy, among patients with Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma. A total 882 patients were randomized in a 1:1:1 ratio to receive either KEYTRUDA® 200 mg IV every 3 weeks for 24 months (N=301), KEYTRUDA® 200 mg IV every 3 weeks for 24 months plus Cisplatin 100 mg/m2 IV or Carboplatin AUC 5 IV (investigator’s choice) on day 1, along with 5-FU 1,000 mg/m2/day IV, days 1-4 of each 3-week cycle, for a maximum of 6 cycles (N=281) or the control arm (EXTREME) consisting of ERBITUX® 400 mg/m2 loading dose followed by 250 mg/m2 weekly, plus Cisplatin 100 mg/m2 or Carboplatin AUC 5 IV on day 1 along with 5-FU 1000 mg/m2/day IV, days 1-4 of each 3-week cycle, for a maximum of 6 cycles (N=300).

Enrolled patients had Recurrent or Metatastic Squamous Cell Carcinoma of the Oral cavity, Oropharynx, Hypopharynx or Larynx, and had not received prior systemic therapy for their recurrent or metastatic disease. Patients were stratified by PD-L1 expression, HPV p16 status, and ECOG Performance Status. PD-L1 expression was measured using the Combined Positive Score (CPS) and Tumor Proportion Score and a CPS of 20 or more indicated high PD-L1 expression, whereas a CPS of 1 or more was the lower threshold of positivity. (CPS measures high PD-L1 expression in the tumor and surrounding immune cells, whereas TPS only captures PD-L1 expression on tumor cells). Approximately 21% of patients were positive for Human Papillomavirus Virus (HPV) p16.

In this analysis, the authors compared the outcomes with KEYTRUDA® alone versus EXTREME (ERBITUX® plus chemo combination) in patients stratified for PD-L1 expression as well as KEYTRUDA® plus chemotherapy versus ERBITUX® plus chemotherapy in all patients with any PD-L1 status. The Primary endpoints were Progression Free Survival (PFS) and Overall Survival (OS) in patients with a PD-L1 CPS of 20 or more and CPS of 1 or more in all enrolled patients. The Secondary endpoints of the study were PFS at 6 months and 12 months, Objective Response Rate (ORR), and time to deterioration in Quality of Life. The minimum follow up was about 17 months.

It was noted that in patients with PD-L1 CPS of 20 or more (high expressors, N=255), single agent KEYTRUDA® was superior to ERBITUX® combination, with a median OS of 14.9 months in patients who received single agent KEYTRUDA® versus 10.7 months in patients who received ERBITUX® with combination chemotherapy (HR=0.61; P=0.0007). There was however no difference in PFS in this PD-L1 subset between the 2 treatment groups (HR=0.99; P=0.5). Similar benefit was seen for patients with a PD-L1 CPS of 1 or more subset (low expressors, N= 512), in which the median OS for KEYTRUDA® monotherapy versus ERBITUX® plus chemotherapy was 12.3 months versus 10.3 months respectively (HR=0.78; P=0.0086). The OS for KEYTRUDA® monotherapy was noninferior to ERBITUX® plus chemotherapy in the total population of patients (N=601). The ORRs were 23% and 36%, with single agent KEYTRUDA® and ERBITUX® combination respectively, in the high expressor subgroup and 19% and 35%, respectively in the low expressor subgroup. However, the median Duration of Response was almost 5 times longer with KEYTRUDA® monotherapy compared to ERBITUX® combination.

When KEYTRUDA® plus chemotherapy was compared with ERBITUX® plus chemotherapy, KEYTRUDA® combination was non-inferior and in fact was superior to ERBITUX® combination for OS in the total population (N = 559), with a median OS of 13.0 versus 10.7 months respectively (HR=0.77; P=0.0034).

It was concluded that among patients with Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma, KEYTRUDA® monotherapy significantly improved Overall Survival compared to ERBITUX® plus chemotherapy in patients with PD-L1 Combined Positive Score of 1 or more. Additionally, KEYTRUDA® plus chemotherapy significantly improved Overall Survival in the total patient population, compared to ERBITUX® plus chemotherapy. Responses associated with single agent KEYTRUDA® and KEYTRUDA® chemotherapy combination, were durable. These data support KEYTRUDA®, as well as KEYTRUDA® plus platinum and 5-FU as the new first-line standards of care for this patient group. KEYNOTE-048: Phase 3 study of first-line pembrolizumab (P) for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Burtness B, Harrington KJ, Greil R, et al. Proceedings from the 2018 ESMO Congress: October 19-23, 2018; Munich, Germany. Abstract LBA8_PR.

ASH 2018 Four Cycles of Chemotherapy Equally Effective as Six Cycles in Diffuse Large B-Cell Lymphoma

RR

SUMMARY: The American Cancer Society estimates that in 2019, about 74,200 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 19,970 individuals will die of this disease. Diffuse Large B-Cell Lymphoma (DLBCL) is the most common of the aggressive Non-Hodgkin lymphoma’s in the United States, and the incidence has steadily increased 3-4% each year. More than half of patients are 65 or older at the time of diagnosis and the incidence is likely to increase with the aging of the American population. The etiology of Diffuse Large B-Cell Lymphoma is unknown. Contributing risk factors include immunosuppression (AIDS, transplantation setting, autoimmune diseases), UltraViolet radiation, pesticides, hair dyes, and diet. DLBCL is a neoplasm of large B cells and the most common chromosome abnormality involves alterations of the BCL-6 gene at the 3q27 locus, which is critical for germinal center formation. Two major molecular subtypes of DLBCL arising from different genetic mechanisms have been identified, using gene expression profiling: Germinal Center B-cell-like (GCB) and Activated B-Cell-like (ABC). Patients in the GCB subgroup have a higher five year survival rate, independent of clinical IPI (International Prognostic Index) risk score, whereas patients in the ABC subgroup have a significantly worse outcome. Regardless, R-CHOP regimen (RITUXAN®-Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone), given every 21 days, for 6 cycles, delivered with curative intent, is the current standard of care for patients of all ages, with newly diagnosed DLBCL, regardless of molecular subtype. The MInT trial (MabThera International Trial Group) published in The Lancet Oncology in 2006 established that for a subgroup of young DLBCL patients with favorable prognosis (age-adjusted International Prognostic Index (aaIPI) of 0 and no bulky disease, 6 cycles CHOP-like chemotherapy plus RITUXAN® resulted in a 3-year Event Free Survival of 89%, Progression Free Survival of 95% and Overall Survival of 98% (Lancet Oncol 2006;7:379-391).

The International Prognostic Index includes the following risk factors and one point is assigned to each risk factor (Age greater than 60 years, ECOG PS of 2, 3 or 4, elevated serum LDH, more than one Extranodal site and Stages III or IV disease). Age-Adjusted IPI is a simplified version and can be used when comparing patients within an age group (i.e. 60 years or younger, or over 60 years) and includes only 3 of the above factors (Performance Status, LDH and Stage).

Treatment with CHOP-like chemotherapy can result in delayed toxicities including cardiotoxicity and second malignancies. De-escalating chemotherapy can reduce toxicities and cost, while improving patient convenience. The authors conducted the FLYER trial to evaluate whether a shorter chemotherapy course of 4 cycles of R-CHOP plus 2 cycles of RITUXAN® alone was non-inferior to the standard treatment of 6 cycles of R-CHOP.

The FLYER trial is an international, multicenter, randomized phase III study in which 592 treatment naïve patients with favorable risk (age 18-60 years, tumor size less than 7.5 cm), Stage I or II DLBCL, were randomly assigned to receive either 6 cycles of R-CHOP, or 4 cycles of R-CHOP plus 2 cycles of RITUXAN®. For this final analysis, 588 patients were evaluable. Each treatment cycle was 21 days. Radiotherapy was not part of the planned treatment, with the exception of prophylactic radiotherapy of the contralateral testis, in patients with Testicular lymphoma. Both treatment groups were well balanced. The mean age was 48 years, 99% were classified as IPI = 0 and 1% as IPI = 1. The Primary endpoint was Progression Free Survival (PFS).

At a median follow up of 66 months, there was no significant difference in the PFS between the two treatment groups (P=0.76). The 3-year Progression Free Survival (PFS) rate was 94% for patients who received 6 cycles of R-CHOP (N=295) compared with 96% for those who received 4 cycles of R-CHOP followed by 2 cycles of RITUXAN® (N=293). The 3-year Overall Survival (OS) rate was 98% among those who received 6 cycles of R-CHOP versus 99% for those who received 4 cycles of R-CHOP followed by 2 cycles of RITUXAN® (P=0.89). There was also no significant difference in the Relapse Rate between the two treatment groups (4-5%). Grade 3 and 4 nonhematologic as well as hematologic Adverse Events were higher in those patients who received 6 cycles of R-CHOP versus the 4 cycles of R-CHOP.

The authors concluded that in this randomized, noninferiority, phase III study, 2 fewer cycles of R-CHOP greatly reduced toxicity without compromising efficacy, in young treatment naïve patients, with low-risk Diffuse Large B-Cell Lymphoma. Data on outcomes in the Germinal Center B-cell-like (GCB) versus Activated B-Cell-like (ABC) subsets is not available. Excellent outcome of young patients (18-60 years) with favourable-prognosis diffuse large B-cell lymphoma (DLBCL) treated with 4 cycles CHOP plus 6 applications of rituximab: results of the 592 patients of the FLYER trial of the Dshnhl/GLA. Poeschel V, Held G, Ziepert M, et al. Presented at ASH Annual Meeting and Exposition: December 4-8, 2018; San Diego, California. Abstract 781.

Late Breaking Abstract – ESMO 2018 Targeting PIK3CA Mutations Improves Outcomes 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 268,600 new cases of female breast cancer will be diagnosed in 2019 and about 41,760 women will die of the disease. About 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.

The PhosphoInositide 3-Kinase (PI3K) pathway is an intracellular signaling pathway important in the regulation of cancer cell proliferation and metastasis. PI3K is a lipid kinase and has four distinct isoforms – alpha, beta, gamma and delta, which play a unique role in the survival of different tumor types and establishment of supportive tumor microenvironments. The alpha and beta isoforms are expressed in a wide variety of tissues whereas the gamma and delta isoforms are primarily expressed in hematopoietic cells such as B and T cells. The PI3K alpha isoform is particularly important in breast cancer and plays an important role in tumorigenesis, supporting tumor angiogenesis and stromal interactions, making this a viable target. PIK3CA is an oncogene that codes for the alpha isoform of PI3K, (PI3Kα), more specifically for the alpha isoform of p110. The PI3k pathway is the most frequently altered pathway in human cancers including breast cancer, and has been implicated in disease progression in a significant number of patients with breast cancer. Activation of the PI3K pathway in breast cancer has been associated with resistance to endocrine therapy and disease progression. Approximately 40% of patients with Hormone Receptor positive (HR+), HER2 negative breast cancers, harbor activating mutations in the PIK3CA isoform of PI3K, which is the most common mutation in HR+ breast cancer. Patients with advanced breast cancer harboring PIK3CA mutations typically have a poor prognosis. This provides a strong rationale for targeting the PI3K pathway in breast cancer.Alpelisib - Mechanism-of-Action

Alpelisib is an oral, alpha-specific PI3K inhibitor that specifically inhibits PIK3 in the PI3K/AKT kinase signaling pathway. Further, it was shown in preclinical studies that cancer cells with PIK3CA mutations are more sensitive to Alpelisib than those without the mutation, across a broad range of tumor types. SOLAR-1 clinical trial was conducted to test this hypothesis.

SOLAR-1 is a global, double-blind, placebo-controlled, randomized phase III trial, which studied the benefit of Alpelisib in combination with FASLODEX® (Fulvestrant) among postmenopausal women and men with PIK3CA-mutated HR+/HER2 negative advanced or metastatic breast cancer, who had progressed on or following prior Aromatase Inhibitor treatment with or without a Cyclin-Dependent Kinase (CDK) 4/6 inhibitor. In this study, 572 patients were randomized in a 1:1 ratio to receive Alpelisib 300 mg orally daily or placebo once daily, in combination with FASLODEX® 500mg IM on days 1 and 15 of the first cycle and day 1 of each subsequent 28-day cycle. Patients were stratified based on visceral metastases and prior CDK4/6 inhibitor treatment. A total of 341 patients had PIK3CA mutations upon testing of the tumor tissue with 169 patients receiving the Alpelisib combination and 172 patients receiving FASLODEX® alone. Enrolled patients had received one or more prior lines of hormonal therapy, but no chemotherapy for advanced breast cancer. They had not previously received FASLODEX® or any PI3K, Akt or mTOR inhibitor, and were not on concurrent anticancer therapy. Approximately half of the patients in each treatment group had lung or liver metastases and 6% had received prior CDK4/6 inhibitor therapy. The Primary endpoint was Progression Free Survival (PFS) for patients with the PIK3CA mutation. Secondary endpoints included Overall Survival (OS), Overall Response Rate (ORR), Clinical Benefit Rate, Health-Related Quality of Life, Efficacy in PIK3CA non-mutant cohort, Safety and Tolerability.

The Primary endpoint was met and at a median follow up of 20 months, the PFS was nearly twice as long in patients with PIK3CA mutations randomized to Alpelisib plus FASLODEX® compared to the placebo plus FASLODEX® group. The median PFS was 11.0 months in the Alpelisib group compared to 5.7 months in the placebo group (HR=0.65; P=0.00065). In patients with measurable, PIK3CA-mutated advanced breast cancer (N=262), the Overall Response Rate was 36% for the Alpelisib plus FASLODEX® group versus 16% for placebo plus FASLODEX® group (P=0.0002). There was no significant PFS benefit noted in the PIK3CA-nonmutant patient group receiving Alpelisib plus FASLODEX®. The most frequent toxicities with Alpelisib were hyperglycemia which could be managed with Metformin, nausea, decreased appetite and rash.

It was concluded that Alpelisib given along with FASLODEX® significantly improved Progression Free Survival compared to Placebo plus FASLODEX®, with manageable toxicities. The authors commented that this is the first study to show statistically significant, clinically meaningful PFS improvement with an alpha-specific PI3K inhibitor in PIK3CA-mutated HR+, HER2 negative advanced breast cancer, highlighting the importance of clinical genomics in advanced breast cancer. It however remains unclear whether Alpelisib should be incorporated into the current treatment paradigm upfront, along with endocrine therapy and a CDK 4/6 inhibitor, or sequentially following disease progression on a combination of endocrine therapy and a CDK 4/6 inhibitor. Alpelisib (ALP) + fulvestrant (FUL) for advanced breast cancer (ABC): results of the phase 3 SOLAR-1 trial. André F, Ciruelos EM, Rubovszky G, et al. Presented during the Presidential Symposium 1 at: 2018 ESMO Congress; October 19-23; Munich, Germany. Abstract LBA3_PR.