Published: August 09, 2020
Public Summary
- Immunotherapy has revolutionized the therapeutic landscape of gastrointestinal cancer, based on a series of clinical trials conducted in recent years.
- The next level of predictive biomarker of the response to immune checkpoint inhibitors (ICIs) should address the integration of current multi-omics biomarkers with an interdisciplinary approach.
- The emerging combination strategies based on ICIs should be more defined in the specific population.
- It is imperative to understand mechanism of acquired resistance to ICIs and explore therapeutic strategies to reverse it.
Gastrointestinal (GI) cancers represent a major public health problem worldwide. Due to the late detection and high heterogeneity of GI cancers, traditional treatments, including surgery, radiotherapy, chemotherapy, and targeted therapy, have shown limited effects, and the overall prognosis of these patients remains poor. Recently, immunotherapy, involving programmed cell death-1 (PD-1) and its ligand (PD-L1), has shown promising efficacy in several solid cancers and seems to have become a potential treatment option for GI cancers This review focuses on data on the development of immunotherapy-based clinical trials in esophageal cancer, gastric cancer, and colorectal cancer. The predictive biomarkers and combination strategies in clinical trials and translational medicine are also discussed. Finally, prospects for immunotherapy in the treatment of GI cancers are described. Although only a small proportion of patients with GI cancers respond to PD-1/PD-L1 blockade, we strongly believe that precision immunotherapy might improve the overall survival of many more GI cancer patients in the future.
Graphical Abstract
Main Text
Background
According to the GLOBOCAN database, there were 18.1 million newly diagnosed cases and 9.6 million deaths from cancer worldwide in 2018. Notably, more than 15% of cancer incidence and 17% of cancer-caused deaths were attributed to gastrointestinal (GI) tract cancers.
Moreover, GI malignancies are the most common cancers and have a huge impact on cancer-associated mortality in China., The mainstreams of therapeutic approaches for such patients are still surgery, radiation therapy, chemotherapy, and targeted therapy. However, the effectiveness of these treatments is not satisfactory due to the late diagnosis. The emergence of cancer immunotherapy has revolutionized the landscape of cancer treatment, currently driven by the application of monoclonal antibodies targeting immune checkpoint such as programmed cell death-1 (PD-1) and cytotoxic T lymphocyte-associated protein-4 (CTLA-4) that release cellular brakes on T cells. Since the first approval of immune checkpoint inhibitors (ICIs) in melanoma in 2011, and afterward in more than 20 different indications, ICIs have become a promising treatment option for patients with cancer. In the field of GI cancers, despite the response rate of ICIs not being as high as for some immunogenic tumors, immunotherapy was still considered as the potentially curative therapeutic approach evidenced by a series of clinical trials. Here, we discuss the current status and prospects for immunotherapy in the treatment of GI cancers.
Current Status of Immune Checkpoint Blockade in GI Cancers
Esophageal Cancer
Squamous cell carcinoma and adenocarcinoma are the two main histological types of esophageal cancer. Patients with esophageal squamous cell carcinoma (ESCC) seemed to benefit more from ICIs than those with adenocarcinoma. Regarding esophageal adenocarcinoma (EAC), data on ICI efficacy are limited. In the esophageal cancer cohort of the KEYNOTE-028 trial, the overall response rate (ORR) was 40% in EAC patients (n = 5) with a positive PD-L1 expression. However, among patients who progressed after 2 or more lines of systemic therapy, only 5.2% of EAC patients (n = 58) achieved partial response (PR), and no patient achieved complete response (CR) in the phase 2 KEYNOTE-180 trial. In the phase 3 KEYNOTE-181 trial, subgroup analysis demonstrated that pembrolizumab had no overall survival (OS) advantage over chemotherapy for EAC patients, even those with a PD-L1 combined positive score (CPS) ≥10 (n = 55).7 Therefore, it is currently unclear whether patients with EAC might benefit from ICIs and whether determination of the PD-L1 status could identify potential candidates for ICI therapy. Concerning ESCC, three phase 3 trials led to landmark changes in second-line treatment. In the KEYNOTE-181 trial, pembrolizumab did not show a survival benefit in the whole population (n = 628); however, pembrolizumab was superior to chemotherapy in terms of OS (8.2 versus 7.1 months, p = 0.0095) and ORR (16.7% versus 7.4%, p = 0.0022) for patients with ESCC (n = 401). Similarly, nivolumab showed a statistically significant extension in OS for PD-L1 unselected advanced ESCC patients in the ATTRACTION-3 trial, as did camrelizumab in the ESCORT study. According to these three trials, it seems that the relationship between PD-L1 status and the response to immunotherapy is still controversial. Table 1Efficacy of Immune Checkpoint Inhibitors in Esophageal Squamous Cell Carcinoma
| KEYNOTE-1817 | ATTRACTION-38 | ESCORT9 | ||||
|---|---|---|---|---|---|---|
| Regimen | Pembrolizumab | chemotherapy | nivolumab | chemotherapy | camrelizumab | chemotherapy |
| Sample size | 198 | 203 | 210 | 209 | 228 | 220 |
| Prior treatment lines | ≥1 | ≥1 | ≥1 | ≥1 | ≥1 | ≥1 |
| ORR, n (%) | 33 (16.7) | 15 (7.4) | 33/171a (19) | 34/158a (22) | 46 (20.2) | 14 (6.4) |
| PFS, months | 2.2 | 3.1 | 1.7 | 3.4 | 1.9 | 1.9 |
| OS, months | 8.2 | 7.1 | 10.9 | 8.4 | 8.3 | 6.2 |
a Randomly assigned patients who had target lesion measurements at baseline.
Gastric Cancer
A randomized, double-blind, placebo-controlled, phase 3 trial, ATTRACTION-2, first showed the efficacy of nivolumab in patients with advanced gastric cancer (AGC) (including gastroesophageal junction cancer) for whom no current standard-of-care therapy was available. The median OS (5.26 versus 4.14 months, p < 0.0001) and ORR (11.2% versus 0%) of nivolumab were both significantly better than those of placebo. The survival benefit from nivolumab was independent of PD-L1 positivity. In a later-line setting, 259 patients who failed to respond to at least two lines of systemic therapies were enrolled in the KEYNOTE-059 trial. The ORR was 11.6%, with 2.3% achieving CR. Among patients with a PD-L1 CPS ≥1, the ORR was 15.5%, while the ORR of patients with PD-L1 negative expression was only 6.4%. The phase 3 KEYNOTE-061 trial included patients with one prior line of treatment and compared pembrolizumab with paclitaxel. Updated results presented at the ASCO 2020 meeting indicated that pembrolizumab prolongs OS relative to paclitaxel in PD-L1 positive patients. The ORR was higher for pembrolizumab in the CPS ≥10 group, and the response duration was longer in the pembrolizumab group using all PD-L1 CPS cutoff values (CPS ≥1, CPS ≥5, and CPS ≥10). Meanwhile, in the JAVELIN Gastric 300 study, avelumab failed to demonstrate its priority as top physicians’ choice of chemotherapy as a third-line treatment for unresectable, recurrent, or metastatic gastric or gastroesophageal junction adenocarcinoma patients. In the first-line setting, the phase 3 KEYNOTE-062 study demonstrated that pembrolizumab showed clinically meaningful efficacy in patients with a PD-L1 CPS ≥10 as well as more durable responses than chemotherapy. Globally, 256 patients received pembrolizumab monotherapy and 250 patients received chemotherapy. Pembrolizumab was non-inferior to chemotherapy for OS in tumors with a PD-L1 CPS ≥1 per prespecified margins (median OS, 10.6 versus 11.1 months; hazard ratio [HR], 0.91; 99.2% confidence interval [CI], 0.69–1.18). The Asian subpopulation analysis demonstrated that OS was longer with pembrolizumab than with chemotherapy regardless of the cutoff value used (CPS ≥1, 22.7 versus 13.8 months; CPS ≥10, 28.5 versus 14.8 months). These data indicate that ICIs might be a new option for patients with AGC regardless of treatment lines. Moreover, PD-L1 positivity was associated with a pronounced survival benefit of patients who underwent ICI treatment, especially those with a PD-L1 CPS ≥10. However, given the modest additional benefit of pembrolizumab plus chemotherapy versus chemotherapy alone, the combinational regimen of an anti-PD-1 antibody plus chemotherapy still needs to be explored.1
Colorectal Cancer
Deficient Mismatch Repair and Microsatellite Instability-High
Microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR) was first identified as an excellent predictive biomarker of PD-1 blockade in a phase 2 trial with a small sample size. Since then, an increasing number of studies have demonstrated the activity of monotherapy anti-PD-1 antibodies (nivolumab and pembrolizumab) in patients with MSI-H/dMMR. In the second- or later-line setting (Table 2), the ORR and disease control rate (DCR) were 32%–52% and 57%–82%, respectively. The survival data showed that the 1-year progression-free survival (PFS) rate ranged from 41% to 44% and the 1-year OS rate ranged from 72% to 76%.
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