August 19, 2022

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Nature: Anti-HER2 and PD-1 dual treatment of gastric cancer

Nature: Anti-HER2 and PD-1 dual treatment of gastric cancer



 

Nature: Anti-HER2 and PD-1 dual treatment of gastric cancer.

 

Type II human epidermal growth factor receptor ( HER2 ) is amplified or overexpressed in 20% of gastrointestinal malignancies [1-3] .

A few years ago, anti-HER2 antibody drug trastuzumab (trastuzumab) combined with chemotherapy has become clinically the first-line treatment for gastric cancer [4] .

Although the addition of anti-PD-1 antibody drugs (pembrolizumab) is not ideal for patients with HER2 recessive [5] , there are reports that trastuzumab can enhance the level of HER2 internalization and promote HER2-specific T Cell response [6-8] ;

In addition, trastuzumab can up-regulate the expression levels of PD-1 and its ligand PD-L1, induce tumor-infiltrating lymphocytes to differentiate, and regulate type II major histocompatibility complex Expression [9-13] .

 

Therefore, it is foreseeable that, both theoretically and clinically, the combination of trastuzumab and anti-PD-1 antibody is likely to have a good therapeutic effect on HER2-positive patients.

 

December 15, 2021, researchers from Memorial Sloan Cancer Center, and Katherine Cornell Medical College published a paper in Nature,  entitled:  The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer .   The research recruited 434 HER2-positive patients with gastrointestinal malignancies.

The PD-1 antibody drug was combined with trastuzumab and chemotherapy based on a randomized double-blind principle (https://clinicaltrials. gov, NCT03615326) , and found that this intervention has a better therapeutic effect than traditional trastuzumab combined with chemotherapy.

 

Nature: Anti-HER2 and PD-1 dual treatment of gastric cancer

 

Specifically, 434 patients were recruited between October 5, 2018 and June 17, 2020, of which 433 received one or more treatments.

All 217 patients in the treatment group took PD1 antibody drugs, while 217 patients in the placebo group, 216 took placebo.

In addition, the efficacy group includes 133 patients in the treatment group and 131 patients in the placebo group.

 

The follow-up time for the treatment group and the efficacy group was set at 9.9 months and 12 months, respectively.

In the treatment group, 81.3% were men, 68.4% suffered from gastrointestinal malignant tumors in situ, and 50.2% had intestinal tissue lesions; in addition, 88.6% of the chemotherapy regimens used capecitabine and oxaliplatin ) Combined administration, and the remaining 13.4% chemotherapy is combined administration of cisplatin and 5-fluorouracil .

 

From the point of view of effect, for the efficacy group, 74.4% of patients in the treatment group and 51.9% of patients in the placebo group have better intervention effects.

That is to say, the addition of PD-1 antibody drugs to the treatment plan increases the therapeutic effect by 22.7% (95%) Confidence interval 11.2~33.7) .

In addition, the response and duration of patients in the treatment group were significantly higher than those in the placebo group, that is, 11.3% of the patients in the treatment group responded to the drugs completely, and 70.3% of the patients had the drug effect lasting 6 months, and 58.4% lasting 9 Months; and for patients in the placebo group, the above data were 3.1%, 61.4%, and 51.1%, respectively.

 

For the treatment group, the median time of efficacy for patients in the treatment group and placebo group were 6.2 months and 5.3 months, respectively; while the side effects of the two groups were basically similar, that is, 57.1% and 57.4% of the side effects reached grades three to five, respectively.

Common side effects (treatment group vs placebo group) include diarrhea (52.5% vs 44.4%) , vomiting (48.8% vs 44.4%) and anemia (41% vs 44%) .

 

In addition, some work reports that adding PD-1 inhibitor drugs to the traditional diagnosis and treatment regimen for HER2-negative gastrointestinal malignancies can increase the efficacy by 10% to 15%, which also shows that there is a certain degree of synergy between HER2 and PD-1 .

Finally, the author also pointed out that throughout the clinical research process, the author kept tissue samples and blood samples of each volunteer, and tried to find more accurate biological diagnostic labels.

At present, the only identified tags are the high degree of microsatellite instability (MSI) of DNA fragments and the high expression of PD-L1.

 

In summary, the author through clinical analysis, the addition of PD-1 antibody drugs to the traditional diagnosis and treatment of HER2-positive gastrointestinal malignancies (trastuzumab plus chemotherapy ) can effectively improve the therapeutic effect. The author also determined that the addition of PD-1 antibody drugs is more effective and lasts longer.

At the same time, the safety and side effects of this new treatment plan (PD-1 antibody drug + trastuzumab + chemotherapy) are also completely controllable.

Based on the above results, certified by the U.S. Food and Drug Administration, the new diagnosis and treatment plan has become a first-line intervention for the treatment of HER2-positive gastric cancer and gastric-esophageal adenocarcinoma.

 

 

 

 

 

References:

https://doi.org/10.1038/s41586-021-04161-3
1. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513, 202–209 (2014).
2. Van Cutsem, E. et al. HER2 screening data from ToGA: targeting HER2 in gastric and gastroesophageal junction cancer. Gastric Cancer 18, 476–484 (2015).
3. Cancer Genome Atlas Research Network. Integrated genomic characterization of oesophageal carcinoma. Nature 541, 169–175 (2017).
4. Bang, Y. J. et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 376, 687–697 (2010).
5. Shitara, K. et al. Efficacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first-line, advanced gastric cancer: the KEYNOTE-062 phase 3 randomized clinical trial. JAMA Oncol. 6, 1571–1580 (2020).
6. Gall, V. A. et al. Trastuzumab increases HER2 uptake and cross-presentation by dendritic cells. Cancer Res. 77, 5374–5383 (2017).
7. Park, S. et al. The therapeutic effect of anti-HER2/neu antibody depends on both innate and adaptive immunity. Cancer Cell 18, 160–170 (2010).
8. Taylor, C. et al. Augmented HER-2 specific immunity during treatment with trastuzumab and chemotherapy. Clin. Cancer Res. 13, 5133–5143 (2007).
9. zum Buschenfelde, C. M., Hermann, C., Schmidt, B., Peschel, C. & Bernhard, H. Antihuman epidermal growth factor receptor 2 (HER2) monoclonal antibody trastuzumab enhances cytolytic activity of class I-restricted HER2-specific T lymphocytes against HER2-overexpressing tumor cells. Cancer Res. 62, 2244–2247 (2002).
10. Chaganty, B. K. R. et al. Trastuzumab upregulates PD-L1 as a potential mechanism of trastuzumab resistance through engagement of immune effector cells and stimulation of IFNγ secretion. Cancer Lett. 430, 47–56 (2018).
11. Varadan, V. et al. Immune signatures following single dose trastuzumab predict pathologic response to preoperative trastuzumab and chemotherapy in HER2-positive early breast cancer. Clin. Cancer Res. 22, 3249–3259 (2016).
12. Triulzi, T. et al. HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy. Oncoimmunology 8, e1512942 (2019).
13. Triulzi, T. et al. Early immune modulation by single-agent trastuzumab as a marker of trastuzumab benefit. Br. J. Cancer 119, 1487–1494 (2018).
14. Stagg, J. et al. Anti-ErbB-2 mAb therapy requires type I and II interferons and synergizes with anti-PD-1 or anti-CD137 mAb therapy. Proc. Natl Acad. Sci. USA 108, 7142–7147 (2011).

Nature: Anti-HER2 and PD-1 dual treatment of gastric cancer

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