Current situation in gastroesophageal cancer
According to DRGs proprietary Epidemiology, gastroesophageal cancer (which comprises cancer of the stomach, esophagus, and gastroesophageal junction [GEJ]) has one of the highest incidences of all cancers and is responsible for over one million annual deaths worldwide1. Clinical data shows that patients with advanced gastroesophageal cancer have a dismal prognosis. The current mainstay of treatment for this disease is doublet and triplet chemotherapy regimens. Additionally, there are two noncytotoxic agents which are approved for the treatment of gastric and GEJ adenocarcinoma; Roche/Genentech/Chugai’s HER2-targeting agent Herceptin (trastuzumab) used in combination with chemotherapy for the first-line treatment of advanced HER2-positive disease, and Eli Lilly’s anti-angiogenic agent Cyramza (ramucirumab) used as a monotherapy or in combination with paclitaxel for the treatment of advanced disease following prior fluoropyrimidine- or platinum-containing chemotherapy. No noncytotoxic agents are approved for the treatment of esophageal cancer.
Immune Checkpoint Inhibitors in Gastroesophageal Cancer
Despite the efforts of pharmaceutical companies to penetrate the gastroesophageal cancer market over the past decade, Phase III trial failures have been a common occurrence. High profile failures originate from a broad range of drug classes including PARP inhibitors, HER2-targeting agents, VEGF-targeting agents, mTOR inhibitors, c-MET inhibitors, EGFR inhibitors, and stem cell pathway inhibitors. Over the past few years, the gastroesophageal cancer development pipeline has transformed significantly, and there is optimism in the community regarding some of the emerging therapies, in particular the immune checkpoint inhibitors. Since October 2014, a staggering 15 Phase III studies investigating PD-1/PD-L1 inhibitors have commenced, and there is hope that these agents will come to fruition and revitalize the treatment of gastroesophageal cancer. Let’s consider the immune checkpoint inhibitors in late-phase development for gastroesophageal cancer:
- Keytruda (pembrolizumab): In May 2017, the FDA received an sBLA for Merck & Co’s Keytruda in previously treated recurrent or advanced gastric or GEJ adenocarcinoma patients who have received two or more lines of chemotherapy; the FDA granted it priority review, and the PDUFA data is September 22, 20172. This submission is based on promising ORR (11.6%) from one cohort of the Phase II KEYNOTE-059 study in heavily pretreated patients3. Keytruda has also shown promise in an early-Phase esophageal cancer trial (KEYNOTE-028)4. Phase III trials are ongoing in gastric and GEJ adenocarcinoma in a variety of populations: previously-untreated metastatic (KEYNOTE-062), second-line metastatic (KEYNOTE-061; KEYNOTE-063), resected (KEYNOTE-585). Similarly, Phase III trials are ongoing in esophageal cancer: first-line metastatic (KEYNOTE-590), second-line metastatic (KEYNOTE-181).
- Opdivo (nviolumab) with or without Yervoy (ipilimumab): Bristol-Myer’s Squibb/Ono Pharmaceutical’s PD-1 and CTLA-4 inhibitors are being assessed in a plethora of studies for gastroesophageal cancer. A supplemental application for Opdivo in Japan (submitted by Ono Pharmaceutical in December 2016) for unresectable advanced or recurrent gastric cancer was based on a Southeast Asian Phase III trial (ONO-4538-12). This study compared Opdivo to placebo in patients that had received two or more lines of chemotherapy and demonstrated a statistically significant OS benefit (5.32 months vs. 4.14 months, respectively; HR=0.63)5. There is also available data from CheckMate-032, which studied Opdivo with or without Yervoy in advanced or metastatic gastroesophageal cancer, in patients that had progressed on checmotherapy6,7. ORR was 12% for Opdivo monotherapy and 24% in a cohort of patients that received Opdivo and Yervoy. Although there are no data specifically from these trials, Opdivo (with Yervoy) is being assessed in multiple Phase III trials in a range of gastric and GEJ adenocarcinoma populations: resected (ONO-4538-38), previously-untreated metastatic (CheckMate-649, ONO-4538-37). Similarly, there are multiple ongoing Phase III trials in esophageal cancer: resected (CheckMate-577), previously-untreated metastatic (CheckMate-648), and second- and later-line metastatic (ONO-4538-24).
- Bavencio (avelumab): Merck KGaA/Pfizer’s Bavencio is being evaluated in two Phase III studies for gastric and GEJ adenocarcinoma—as a first-line maintenance treatment (JAVELIN Gastric 100) and as a third-line treatment for advanced or metastatic disease (JAVELIN Gastric 300). Data from the Phase Ib JAVELIN Solid Tumor trial showed patients treated with Bavencio maintenance had an ORR of 9% with two complete responses and a median PFS of 12 weeks, whereas those treated with the agent as a second-line treatment showed an ORR of 9.7% with no complete responses and a median PFS of six weeks8.
Future Treatment for Gastroesophageal Cancer
The data presented to date for PD-1 monotherapy intervention in gastroesophageal cancer is encouraging, so much so that this has led to regulatory submissions to the MHLW for Opdivo and to the FDA for Keytruda in pretreated gastric and GEJ adenocarcinoma. Furthermore, preliminary data suggests that Opdivo in combination with Yervoy is more efficacious than Opdivo monotherapy, which provides further optimism, as does the possibility to use these drugs in previously-untreated metastatic patients.
The immune checkpoint inhibitors will likely dominate the gastroesphageal cancer market within the next five years, and will provide all esophageal cancer patients and resectable gastric and GEJ adenocarcinoma patients with alternative treatment options to chemotherapy. Moreover, emerging immune checkpoint inhibitors will offer more tolerable treatment options for advanced gastroesophageal cancer patients, who may have refused or not have been able to tolerate toxic chemotherapy regimens. However, immune checkpoint inhibitors alone are insufficient to treat gastroesophageal cancer patients, and a diverse range of drug classes is required for optimal treatment. Fortunately, aside from immune checkpoint inhibitors, there are a number of drug classes being investigated in late-Phase studies for gastroesophageal cancer, including antiangiogenic agents, second-generation HER-targeting agents, matrix metalloproteinase inhibitors, therapeutic vaccines, and novel cytotoxic agents. In addition, earlier clinical studies are assessing an array of therapies including CAR T-cell therapy, Claudin 18.2-targeting agents, novel immune checkpoint inhibitors such as OX40 and 4-1BB, as well as combination treatments, for example, Keytruda in combination with Herceptin, and Opdivo in combination with Cyramza.
Taking into account the extensive and promising clinical development pipeline for gastroesophageal cancer, it is probable that the treatment of these patients is going to significantly improve over the coming years. However, undoubtedly further major developments will be necessary in order to satisfy the majority of patients, including the need for a broader spectrum of therapies in esophageal cancer (only PD-1 inhibitors are in late phase development), more efficacious treatments for resectable disease (particularly in Japan), and the stratifying of patients in order to receive the best treatment options, to name but a few.
Further insights and analysis of the clinical development of immune checkpoint inhibitors, including how they will shape the gastroesophageal cancer market over the next ten years, are available in our 2017: Gastroesophageal Cancer Disease Landscape and Forecast content (published in August 2017).
- Ferlay J, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015; 1;136(5):E359-86.
- Merck & Co, Press release, May 23, 2017.
- Fuchs CS, et al. KEYNOTE-059 cohort 1: Efficacy and safety of pembrolizumab (pembro) monotherapy in patients with previously treated advanced gastric cancer. J Clin Oncol 35. ASCO; 2017; Chicago, IL: Abstract #4003.
- Doi T, et al. Updated results for the advanced esophageal carcinoma cohort of the phase Ib KEYNOTE-028 study of pembrolizumab (MK-3475). J Clin Oncol. 2016;34 (suppl 4S; abstr 7).
- Kang YK, et al. Nivolumab (ONO-4538/BMS-936558) as salvage treatment after second or later-line chemotherapy for advanced gastric or gastro-esophageal junction cancer (AGC): A double-blinded, randomized, phase III trial. J Clin Oncol.2017;35 (suppl 4S; abstract 2).
- Janjigian YY, et al. Phase 1/2, Open-Label Study of Safety and Activity of Nivolumab alone or with Ipilmumab in Advanced and Metastatic Gastric Cancer: CheckMate-032. J Clin Oncol 34. ASCO; 2016; Chicago, IL: Abstract #4010.
- Janjigian YY, et al. Nivolumab ± ipilimumab in pts with advanced (adv)/metastatic chemotherapy-refractory (CTx-R) gastric (G), esophageal (E), or gastroesophageal junction (GEJ) cancer: CheckMate 032 study. J Clin Oncol 35. ASCO; 2017; Chicago, IL: Abstract #4014.
- Chung HC, et al. Avelumab (MSB0010718C; anti-PD-L1) in patients with advanced gastric or gastroesophageal junction cancer from JAVELIN solid tumor phase Ib trial: Analysis of safety and clinical activity. J Clin Oncol 34. ASCO; 2016; Chicago, IL: Abstract #4009.