In the previous two issues, we have presented the latest news on the surgical, perioperative, and metastatic treatment of gastric cancer. I’m sure you’ve noticed that the promising progress in these areas cannot be separated from the exploration and breakthroughs made by chemotherapy and immunotherapy researchers. Currently, research experts are experimenting with the use of immune drugs in the first-line treatment of advanced gastric cancer to find the most suitable population and to further enhance chemotherapy regimens.
Next, let’s look back at 2019 and focus on the latest achievements in chemotherapy and immunotherapy!
First-line immunotherapy for advanced gastric cancer
At the 2019 American Society of Clinical Oncology Annual Meeting, a study on first-line treatment of gastric cancer caused a huge stir and controversy when it was presented. The study is considered by industry insiders to be a landmark for immunotherapy in gastric cancer. In this study, 763 HER2-negative and PD-L1-positive patients were enrolled in the trial. They were randomly assigned to either the pabolizumab immunotherapy group, the chemotherapy group, or the “pabolizumab + chemotherapy” group. The results showed that the combination of chemotherapy and pabolizumab performed poorly, with overall survival rates even worse than pabolizumab alone. In fact, the effect of chemotherapy on the body’s immunity is very complex, and different combination regimens, doses, and timing of administration may affect the final outcome. Another study of immunotherapy in combination with XELOX chemotherapy is still ongoing, and it may change the chemotherapy regimen and alter the outcome of the combination therapy.
On the other hand, while pabolizumab alone achieved the overall “no worse than other regimens” goal and the survival curve won after 12 months due to a trailing effect, there was a significant survival curve crossover before that, meaning that 46.9% of patients had impaired initial survival. Even though the overall survival in the pabolizumab group performed better than patients in the chemotherapy group in the population with a combined positive score (CPS, which reflects the degree of PD-L1 expression in cells and is related to treatment efficacy) ≥10, there was still a survival curve crossover, intersecting at 8 months after the randomized trial, so that more than 1/3 of patients in the pabolizumab group had impaired initial survival. Possible explanations could be due to the relatively slow onset of hyperprogression or immunotherapy. In conclusion, a “CPS≥1” index is not sufficient to screen for those who would benefit from immunotherapy, and a “CSP≥10” might be better as a watershed, but it still does not completely avoid hyperprogression. Therefore, there is an urgent need to identify more precise predictive markers of efficacy.
The MSI-H population is dominant in immunotherapy
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On the way to finding new metrics, a study presented at the 2019 European Conference on Medical Oncology did instead excel because they used microsatellite status MSI as a predictor.
The study showed that for a population with advanced gastric cancer with a microsatellite status of “MSI-H,” patients on pabolizumab always had better overall survival than those on chemotherapy in first-line treatment, regardless of whether the patient had a CPS score greater than 1 or 10. Despite the small sample size, there was little crossover of survival curves in this population, providing strong evidence that the MSI-H population is a superior population for immunotherapy in gastric cancer. In the chemotherapy-only group, the overall survival of the MSI population was 8.5 months, which was significantly shorter than the overall population of 11.1 months. Therefore, the survival benefit of chemotherapy alone in the immunotherapy-dominant MSI-H population is questionable.
In conclusion, we should probably rely more on MSI status than on CPS values when predicting the efficacy of immunotherapy. In the MSI-H population, the survival benefit of pabolizumab alone and tumor regression were better than chemotherapy alone, which had a very limited benefit. In addition, the “pabolizumab+chemotherapy” regimen achieved maximal tumor regression in both the total and MSI-H populations, so the combination strategy remains essential in neoadjuvant chemotherapy and translational therapy.
Regretfully defeated, Avelumab maintenance therapy is not very useful
Avelumab is a PD-L1 inhibitor that has been progressively available in Europe and the United States since 2017, and was initially used to treat lung cancer. So how well does it work in maintenance therapy for gastric cancer?
A phase III study published in 2019 answered this question. The investigators included 805 patients with never-chemotherapy, HER-2-negative progressive gastric or esophagogastric junction (GEJ) adenocarcinoma (inoperable, locally advanced, or metastatic), and patients’ PD-L1 expression status was not taken into account. After a total of 12 weeks of induction chemotherapy with FOLFOX or XELOX, 499 patients without disease progression were randomly assigned to receive either the maintenance treatment arm with Avelumab or to continue treatment with the original regimen until disease progression. The primary evaluation metric for the study was the endpoint of overall survival in the intention-to-treat population and in the PD-L1-positive (≥1%) population.
The results showed that although a clinical benefit for Avelumab was seen in the intention-to-treat population on maintenance therapy, it did not reach a statistically significant level of difference. In the 54 PD-L1-positive patients, Avelumab was even found to be less effective on maintenance than continued chemotherapy. A recent Meta-analysis showed that PD-1 monoclonal antibody was generally more effective than PD-L1 monoclonal antibody, but the failure of this study was more due to various factors such as heterogeneity of gastric cancer, lack of screening of the patient population, possible changes in PD-L1 expression after treatment, and the effect of chemotherapy on immunotherapy. This implies that the immunotherapy screening population needs to focus not only on the genetic alterations of the tumor and the tumor microenvironment, but also on the body’s own immune function.
REGONIVO research has been excellent, can the saga be renewed?
At the 2019 American Society of Clinical Oncology meeting, another study called REGONIVO made quite a splash, trying a “multi-targeted TKI regorafenib + Nivolumab” regimen. In this phase Ib study, a total of 25 patients each with metastatic gastric and intestinal cancers were enrolled in last-line therapy, of which only 1 patient with intestinal cancer had MSI-H microsatellite status and the rest had MSS type. During the dose creep phase, Nivolumab was administered at a fixed dose of 3 mg/kg every 2 weeks, and the finalized dose of regorafenib was 80 mg/d.
The trial results showed an objective remission rate of 44% in patients with gastric cancer and 36% in patients with bowel cancer, with that figure being 33% in patients with MSS-type bowel cancer. Even more surprisingly, seven of the gastric cancer patients in the trial had already been treated with PD-1 monoclonal antibody and failed, while three of them achieved partial remission in this trial. Also in terms of progression-free survival, it was 5.8 months in patients with gastric cancer and 6.3 months in patients with colorectal cancer.
The reason the REGONIVO study did so well in patients with endline MSS gastrointestinal cancer may be related to regorafenib targets of action, including CSF1R, which modulates tumor-associated macrophage function. Of course, this may also be related to the high level of patient screening in small sample studies. Furthermore, although we note that the final efficacy is independent of PD-L1 expression, a decrease in Treg-like cells in tumor-infiltrating lymphocytes can still be observed in effective patients. A follow-up phase III study is currently underway and we expect it to further validate such amazing efficacy of these two classes of drugs. In the meantime, there are clinical studies of anti-PD-1/PD-L1 in combination with furoquinitinib, apatinib, and aprotininib, and it is not clear which regimen will ultimately win.
Optimal management of chemotherapy regimens, with evidence-based dose adjustments for older and frailer patients
In clinical practice, chemotherapy regimens for elderly or frail patients are subjectively influenced. This is primarily due to the lack of trial evidence to support this area and the need to rely on physician experience and patient family opinion for tailoring. A phase III study is being conducted at 61 centers in the United Kingdom to provide evidence for chemotherapy dosing in elderly and frail patients. Based on the Comprehensive Geriatric Assessment Scale, the team enrolled 514 untreated frail patients who could not tolerate three-drug chemotherapy. They had advanced gastric cancer or adenocarcinoma of the esophagogastric junction and were randomized to chemotherapy in the full-dose, 80%-dose, and 60%-dose groups.
The median overall survival for the three groups was 7.5 months, 6.7 months, and 7.6 months, respectively. Progression-free survival in the lower-dose patients was not as long as in the remaining full-dose patients, and patients in the 60%-dose group had a better quality of life and slower progression of symptoms. It can be said that this study provides a more objective reference range and basis for proactive dose adjustment in elderly frail patients, which I believe could be reflected in the update of drug treatment guidelines. However, we should also note that in addition to the CGA scale 9 latitude assessment, antitumor therapy needs to take into account factors such as tumor biological behavior, tumor load, pathological staging, microsatellite instability status, or biomarker expression such as HER2.
How to choose a platinum-based drug?Lauren typing to guide
Gastric cancer is a highly heterogeneous tumor, and staging it is extremely important. One such approach, Lauren typing, represents information on the different sites of gastric cancer, its biological behavior, and patterns of metastatic recurrence. In general, gastric cancers can be classified as diffuse gastric cancer and intestinal gastric cancer according to the Lauren typing method.
Diffuse gastric cancer is often associated with high expression of DPD enzymes, and a small phase II study suggested that oxaliplatin was more effective and better tolerated than cisplatin in this group of patients. In another randomized open phase III study, investigators enrolled 558 patients with diffuse or mixed gastric/gastroesophageal junction adenocarcinoma in first-line therapy to compare the median overall survival of SOX versus SP chemotherapy modalities. The results showed longer overall survival with SOX treatment than SP treatment (13 months vs 11.8 months), slightly improved progression-free survival and time to tumor treatment failure (5.7 months vs 4.9 months, and 5.2 months vs 4.7 months, respectively), and, except for neurotoxicity The incidence of adverse reactions was much lower. Although this study shows that oxaliplatin has an advantage over cisplatin if the patient does not have intestinal gastric cancer, we also have to consider that Lauren staging is still relatively crude and the diagnosis of mixed type may change with treatment. Therefore, precision drug management of gastric cancer still needs to be guided by more definitive molecular markers.
Conclusion
Looking back at 2019, we see the field of gastric cancer making steady progress toward precision therapy. Medical researchers are attempting to first achieve precise diagnosis, move from precise staging to precise staging, standardize different procedures and refine management of D2 radical surgery, and establish and validate a model for neoadjuvant chemotherapy, all of which lay a solid foundation for subsequent research.
In precision therapy, we need to actively screen the MSI-H and HER2-positive populations, manage them individually, and use combination regimens appropriately to optimize outcomes. In the future, it is hoped that the exploration of other populations and targets will never end, and that more attention will be paid to precision evaluation and precision monitoring of recurrence in gastric cancer.