OPDIVO® (Nivolumab)

The FDA on June 10, 2020 approved OPDIVO® for patients with unresectable, advanced, recurrent or metastatic Esophageal Squamous Cell Carcinoma (ESCC), after prior Fluoropyrimidine- and Platinum-based chemotherapy. OPDIVO® is a product of Bristol-Myers Squibb Co.

Late breaking Abstract – ESMO 2019 OPDIVO® Improves Overall Survival in Advanced Esophageal Cancer Regardless of PD-L1 Expression

SUMMARY: The American Cancer Society estimates that in 2019, about 17,650 new cases of esophageal cancer will be diagnosed in the US and about 16,080 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. About 20% of patients survive at least 5 years following diagnosis. Patients with advanced esophageal cancer following progression on first line chemotherapy have limited treatment options and have a poor prognosis, with a 5-year relative survival rate of 8% or less.

The FDA in July 2019 approved KEYTRUDA® (Pembrolizumab) for patients with recurrent, locally advanced or metastatic Squamous Cell Carcinoma of the Esophagus (ESCC), whose tumors express PD-L1 (Combined Positive Score-CPS of 10 or more). This approval was based on the Phase III KEYNOTE-181 global trial in which KEYTRUDA® significantly improved Overall Survival compared with chemotherapy, as second line therapy for patients with advanced esophageal cancer, with PD-L1 CPS of 10 or higher. The median Overall Survival in the Intent-To-Treat population was however was not statistically significant.

OPDIVO® (Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells. OPDIVO® in a Phase II study showed promising antitumor activity and safety profile among patients with advanced refractory Squamous Cell Carcinoma of the Esophagus (ESCC). ATTRACTION-3 is a multicentre, randomized, open-label, Phase III trial in which 419 patients with unresectable advanced or recurrent ESCC refractory or intolerant to one prior Fluoropyrimidine/Platinum-based chemotherapy, regardless of PD-L1 expression, were enrolled. Patients were randomly assigned (1:1) to either OPDIVO® 240 mg IV every 2 weeks (N=210) or investigator’s choice of Paclitaxel 100 mg/m2 IV once per week for 6 weeks then 1 week off or Docetaxel 75 mg/m2 IV every 3 weeks (N=209). Both treatment groups were well balanced and nearly 90% of the patients were male and 96% were Asian. Approximately 85% of patients were current or former smokers, about half of patients had prior surgery and about 70% had prior radiotherapy. Approximately 50% of patients had tumor PD-L1 expression of 1% or more. The Primary endpoint was Overall Survival (OS), in the intent-to-treat population that included all randomized patients.

At a minimum follow-up of 17.6 months, OPDIVO® showed a statistically significant improvement in OS, with a 23% reduction in the risk of death, compared to chemotherapy. The median Overall Survival was 10.9 months in the OPDIVO® group versus 8.4 months in the chemotherapy group (HR for death=0.77, P=0.019). The proportion of patients alive at 18 months was numerically larger with OPDIVO® versus chemotherapy (31% vs 21%). The OS benefit with OPDIVO® over chemotherapy was noted across tumor PD-L1 expression levels (PD-L1 1% or more, HR=0.69; PD-L1 less than 1%, HR=0.84). The Objective Response Rate was similar in both treatment groups (19% vs 22%). However the median duration of response with OPDIVO® was 6.9 months, versus 3.9 months with chemotherapy, suggesting that the responses were substantially more durable with OPDIVO® compared to chemotherapy. There was no significant difference in the Progression Free Survival between the treatment groups. Grade 3 or 4 adverse events occurred in 18% of the OPDIVO® group and 63% of the chemotherapy group.

It was concluded that OPDIVO® was associated with a significant improvement in Overall Survival with a favorable safety profile compared with chemotherapy, in previously treated patients with advanced Esophageal Squamous Cell Carcinoma, regardless of PD-L1 expression, and represents a potential new standard second-line treatment option for this patient group. Nivolumab versus chemotherapy in advanced esophageal squamous cell carcinoma (ESCC): the phase 3 ATTRACTION-3 study. Cho BC, Kato K, Takahashi M, et al. Presented at ESMO 2019: September 27-October 1, 2019; Barcelona, Spain. Abstract LBA 11.

KEYTRUDA® (Pembrolizumab)

The FDA on July 30, 2019 approved KEYTRUDA® for patients with recurrent, locally advanced or metastatic Squamous Cell Carcinoma of the Esophagus (ESCC), whose tumors express PD-L1 (Combined Positive Score-CPS of 10 or more), as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy. FDA also approved a new use for the PD-L1 IHC 22C3 pharmDx kit as a companion diagnostic device for selecting patients for the above indication. KEYTRUDA® is a product of Merck & Co., Inc.

KEYTRUDA® versus Chemotherapy as Second-Line Treatment for Advanced Esophageal Cancer

SUMMARY: The American Cancer Society estimates that in 2019, about 17,650 new cases of esophageal cancer will be diagnosed in the US and about 16,080 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. About 20% of patients survive at least 5 years following diagnosis. Patients with advanced esophageal cancer following progression on first line chemotherapy have limited treatment options and have a poor prognosis.

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. KEYTRUDA® in the Phase II KEYNOTE-180 study demonstrated durable responses among heavily pretreated patients with advanced metastatic Adenocarcinoma or Squamous Cell Carcinoma of the Esophagus as well as tumors with PD-L1 Combined Positive Score (CPS) of 10 or higher.

KEYNOTE-181 is a global, open-label, Phase III study which included 628 patients with advanced or metastatic adenocarcinoma or squamous cell carcinoma of the esophagus, or Siewert Type I adenocarcinoma of the esophagogastric junction that had progressed after first-line standard therapy. [Adenocarcinomas arising in the vicinity of the EsophagoGastric Junction are classified (Siewert classification) into adenocarcinoma of the distal esophagus (Type I), true carcinoma of the cardia (Type II) and subcardial carcinoma (Type III)].

Patients were randomized 1:1 to KEYTRUDA® 200 mg Q3W for up to 35 cycles (approximately2 years) or investigator’s choice chemotherapy with Docetaxel 75 mg/m2 IV on day 1 of each 21 day cycle, OR Paclitaxel 80-100 mg/m2 IV on days 1, 8 and 15 of each 28-day cycle, OR Irinotecan 80 mg/m2 IV on day 1 of each 14-day cycle. Randomization was stratified by histology and region (Asia vs rest of world). The majority of patients (N=401; 64%) had Squamous Cell Carcinoma (SCC), and 222 patients had PD-L1 Combined Positive Score (CPS) of 10 or higher. The three Primary end points were Overall Survival (OS) in patients with SCC, patients with PD-L1 CPS of 10 or higher and Intent-To- Treat populations. The median follow up was 7 months.

It was noted that among the patients with a PD-L1 CPS of 10 or higher (35% of the study population), the median Overall Survival was 9.3 months with KEYTRUDA® versus 6.7 months with chemotherapy (HR=0.69; P=0.0074). The 12-month survival rate in this group was 43% versus 20% respectively. In the Squamous Cell Carcinoma subgroup (N=401), the median Overall Survival was 8.2 months with KEYTRUDA® versus 7.1 months with chemotherapy (HR=0.78; P=0.0095). These differences favoring KEYTRUDA® however, did not meet the study’s prespecified statistical boundary. In the Intent-To- Treat population, the median Overall Survival was 7.1 months in each treatment group (HR=0.89; P=0.0560), and was not statistically significant. The Progression Free Survival at 12 months among patients with a PD-L1 CPS of 10 or higher was 21% versus 7% for KEYTRUDA® and chemotherapy, respectively. Further, in this patient group, KEYTRUDA® more than doubled the Response Rates than those achieved with chemotherapy, with a longer median duration of response (9.3 versus 7.7 months respectively). Fewer patients had any grade drug-related adverse events with KEYTRUDA®, compared with chemotherapy.

The authors concluded that KEYTRUDA® significantly improved Overall Survival compared with chemotherapy, as second line therapy for patients with advanced esophageal cancer, with PD-L1 CPS of 10 or higher and also had a more favorable safety profile. They added that these data support KEYTRUDA® as a new second line standard of care for esophageal cancer with PD-L1 CPS of 10 or higher. A Phase III study of KEYTRUDA® plus chemotherapy as first line therapy for advanced esophageal cancer is underway. Pembrolizumab versus chemotherapy as second-line therapy for advanced esophageal cancer: Phase III KEYNOTE-181 study. Kojima T, Muro K, Francois E, et al. J Clin Oncol 37, 2019 (suppl 4; abstr 2)

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

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)

Preoperative Chemoradiotherapy for Esophageal or Junctional Cancer Improves Overall Survival

SUMMARY: The American Cancer Society estimates that in the US, about 16,910 new esophageal cancer cases will be diagnosed in 2016 and about 15,690 patients will die of the disease. Squamous Cell Carcinoma is the most common type of cancer of the esophagus among African Americans, while Adenocarcinoma is more common in caucasians. Previously published trials comparing neoadjuvant concurrent chemoradiation plus surgery to surgery alone, with Cisplatin and 5-FU chemotherapy, have shown conflicting results and this may have been due to small numbers of patients enrolled in these trials. Based on positive outcomes in phase II studies, the ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) was conducted, to compare neoadjuvant chemoradiotherapy plus surgery to surgery alone, in patients with Squamous Cell Carcinoma and Adenocarcinoma of the esophagus or esophagogastric junction. Enrolled patients (N=368) were randomly assigned in a 1:1 ratio and had locally advanced (clinical stage T1N1M0 or clinical stage T2-3N0-1M0) disease. Locoregional sites included mediastinum, supraclavicular and celiac trunk lymph nodes.

Treatment consisted of PARAPLATIN® (Carboplatin) at AUC-2, IV and TAXOL® (Paclitaxel) 50 mg/m2 IV, given weekly for 5 weeks, on days 1,8,15,22 and 29 with concurrent radiotherapy (41.4 Gy, given in 23 fractions of 1.8 Gy, 5 days per week) followed by surgery (N=180), or surgery alone (N=188). The median age was 60 years and patients in the surgery alone group underwent surgery as soon as possible, whereas those receiving neoadjuvant chemoradiation underwent surgery 4-6 weeks following completion of chemoradiation. The primary endpoint of this study was Overall Survival (OS) and secondary endpoints included Progression Free Survival (PFS).

After a median follow up of 84.1 months, the median Overall Survival (OS) for all histologies was 48.6 months in the neoadjuvant chemoradiation plus surgery group and 24 months in the surgery alone group (HR=0.68; P=0.003). The median OS for patients with Squamous Cell Carcinomas was 81.6 months in the neoadjuvant chemoradiation plus surgery group and 21.1 months in the surgery alone group (HR=0.48; P=0.008) and for patients with Adenocarcinomas was 43.2 months in the neoadjuvant chemoradiotherapy plus surgery group and 27.1 months in the surgery alone group (HR=0.73; P=0.038). It is of interest to note that the improvement in distant disease control occurred within the first 2 years following treatment initiation, whereas improvement in locoregional control continued for a longer period of time.

The authors concluded that in patients with resectable, locally advanced, esophageal or esophagogastric junctional cancer, neoadjuvant chemoradiotherapy when added to surgery, confers Overall Survival benefit for both Squamous Cell Carcinoma and Adenocarcinoma histological subtypes and should therefore be regarded as the standard of care, for this patient population. Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Shapiro J, van Lanschot JB, Hulshof MM, et al. The Lancet Oncology 2015;16:1090-1098

Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17) final results of a randomised, phase 2/3 trial

SUMMARY: It is estimated that in 2014, over 18,000 new cases of esophageal carcinoma will be diagnosed in the U.S. and over 15,000 will die of the disease. There has been a rise in the incidence of esophageal cancer in recent decades. Even though stage 0, I, and II and most stage III esophageal cancers are potentially resectable, a significant number of these patients have associated comorbid conditions that may preclude them from undergoing surgical intervention. In this group of patients, as well as those with inoperable esophageal cancer, cisplatin based chemoradiation treatment has been associated with improved survival. Cisplatin however is associated with significant toxicities. The rationale for substituting ELOXATIN® for Cisplatin is based on its lower emetogenicity, lack of nephrotoxicity and lack of need for IV hydration. Prior phase II trials have demonstrated that ELOXATIN® (Oxaliplatin) based chemotherapy given alone or in combination with radiation therapy improved response rates with acceptable toxicities, in patients with advanced esophageal cancer. Based on this information, the authors conducted an open labeled, multicenter study to assess the efficacy and safety of the FOLFOX chemotherapy regimen (Fluorouracil plus Leucovorin and Oxaliplatin) compared to Fluorouracil and Cisplatin, when administered as a part of chemoradiotherapy treatment, in patients with locally advanced esophageal cancer. Patients with stage I—IVA esophageal carcinoma (adenocarcinoma, squamous-cell, or adenosquamous) who were not candidates for surgical intervention were randomly assigned to receive FOLFOX chemotherapy (N=131) or Cisplatin and Fluorouracil (N=128), with concurrent radiation. FOLFOX chemotherapy consisted of 6 cycles of ELOXATIN® 85 mg/m2 IV, Leucovorin 200 mg/m2 IV, Fluorouracil 400 mg/m2 IV bolus given on day 1, and infusional Fluorouracil 1600 mg/m2 given over 46 hours, every 2 weeks, with the first 3 cycles given concurrently with radiation therapy. Chemotherapy with Cisplatin and Fluorouracil consisted of 4 cycles of Cisplatin 75 mg/m2 IV given on day 1 and infusional Fluorouracil 1000 mg/m2 per day, given for 4 days, with the first 2 cycles given concurrently with radiation therapy at 4 week intervals and the remaining 2 cycles given 3 weeks apart after completion of radiation therapy. Both treatment groups received 50Gy radiotherapy, in 25 fractions, at five fractions per week. The primary endpoint was Progression Free Survival (PFS). At a median follow up of 25.3 months, the median PFS was 9.7 months in the FOLFOX group and 9.4 months in the Cisplatin group and this was not statistically significant (P=0.64), suggesting that FOLFOX in combination with radiation may be an alternative to Cisplatin and Fluorouracil. FOLFOX chemotherapy may alleviate Cisplatin related toxicities such as nausea and vomiting, nephrotoxicity and the need for IV hydration, making this a much more tolerable regimen in advanced esophageal carcinoma. Conroy T, Galais M, Raoul J, et al. Lancet Oncol, 2014;15: 305-314

Preoperative Chemoradiotherapy for Esophageal or Junctional Cancer

SUMMARY: In this trial, neoadjuvant chemoradiation followed by surgery was compared with surgery alone, in patients with esophageal or GE junction tumors. Three hundred and sixty six (366) patients were randomized and chemoradiotherapy consisted of weekly PARAPLATIN® (Carboplatin) and TAXOL® (Paclitaxel) for 5 weeks with concurrent radiotherapy followed by surgery. Complete resection was feasible in 92% of the patients receiving chemoradiation compared to 69% in the surgery alone group (P<0.001). Overall survival was 49 months in the chemoradiation/surgery group compared to 24 months in the surgery alone group (HR=0.65, P<0.003). This benefit was seen regardless of histology and postoperative complications were similar in both treatment groups. This study has conclusively established that chemoradiation followed by surgery is superior to surgery alone, in patients with esophageal and GE junction tumors. van Hagen P, Hulshof MCCM, van Lanschot JJB, et al. for the CROSS Group. N Engl J Med 2012; 366:2074-2084