Pembrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction cancer

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Published: 14 Jun 2021
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Dr Yelena Janjigian - Memorial Sloan Kettering Center, New York, USA

Dr Yelena Janjigian speaks to ecancer about the initial findings of the global phase 3 KEYNOTE-811 trial.

The trial investigates pembrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction (G/GEJ) cancer.

Initially, she explains the background of this study. Dr Janjigian then discusses the methodology and rationale of the study.

She concludes, that adding pembrolizumab to trastuzumab and chemotherapy results in a substantial, statistically significant increase in ORR versus trastuzumab and chemotherapy alone as 1L therapy for HER2+ metastatic G/GEJ cancer.

The responses were durable and safety was manageable. This initial data supports pembrolizumab plus trastuzumab and chemotherapy as a potential new treatment option for this population.

ecancer's filming has been kindly supported by Amgen through the ecancer Global Foundation. ecancer is editorially independent and there is no influence over content.

This was a randomised phase III study of pembrolizumab in combination with trastuzumab and chemotherapy. This was a placebo-controlled trial in first line HER2 positive GE junction and gastric adenocarcinoma. By way of background, this trial was designed based on both preclinical data demonstrating synergy for dual PD-1, anti-PD-1 and anti-HER2, blockade in transgenic models of HER2 positive disease showing dramatic tumour regression with combination therapy. We then conducted a phase II study at Memorial Sloan Kettering examining a combination of pembrolizumab with trastuzumab and chemotherapy in the phase II setting and noted a dramatic overall response rate, a near doubling of overall response rate, when you looked at combination dual anti-PD-1 and anti-HER2 blockade. Historically the overall response rate in the first line setting, based on the ToGA study with trastuzumab and chemotherapy, is approximately 47%. We saw 91% overall response rate.

Subsequently there was another phase II study recently presented, coming out of Korea, also demonstrating promising clinical activity. So when we came to phase III what is satisfying to see is that for the first time we saw dramatic responses in the phase III setting once again. This was during the first interim analysis which was a pre-planned analysis based on the initial protocol design. This was the rationale is to study the dual combination in the first line setting and the data is quite promising.

What was the methodology used in this study?

This was a phase III study, placebo controlled. Patients were randomised to receive either standard of care of chemotherapy plus trastuzumab. Tumours were confirmed to be HER2 positive by IHC, so IHC 3+ or IHC 2+ and FISH positive, this was a central confirmation. This was a large global study enrolling patients all over the world and patients were randomised in a placebo-controlled fashion to receive either chemotherapy with trastuzumab and pembrolizumab or chemotherapy with trastuzumab and placebo.

The primary endpoints were dual PFS and OS with a secondary endpoint of overall response rate. The first interim analysis was to look at the improvement in overall response rate and this was a pre-planned interim analysis based on the protocol specified criteria.

What were your findings?

What we found at the interim analysis is that overall response rate for a combination of trastuzumab, pembrolizumab and chemotherapy was dramatically improved. It was 74% overall response rate compared to 51% overall response rate. Furthermore, the treatment was well tolerated, there were no new signals for side effect profile and adverse event profile. There were more immune related adverse events associated with pembrolizumab therapy, as expected, but otherwise this was a very well tolerated regimen, relatively easy to administer and certainly the response rate was dramatically improved. Based on this interim analysis the FDA approved this combination for use in the United States for patients with HER2 positive disease in the first line setting.

How can these results impact the future treatment of gastric cancer?

These results are an important step forward in our understanding of the biology of this disease. We were able to show that you can augment HER2 inhibition with trastuzumab with the use of anti-PD1 therapy. So it’s transformative for patients with HER2 positive disease where we are already using this combination in standard practice and it is practice changing. It raises the bar for HER2 positive disease so going forward, other studies, the future of the field will be transformed where the combination regimens will be compared to this standard regimen.

More importantly, for the field as a whole it highlighted a new approach to treating this disease where combination strategies, and we’ve known that combination strategies are the way to go because this disease is so aggressive and difficult to treat, but for the first time we have demonstrated a synergy between the two agents. Perhaps we can apply the same concepts to other targeted agents and other biomarker selected patients where HER2 is an important validated target. Other targets fell short such as EGFR and MET and perhaps we need to revisit those approaches and those strategies using combination therapies with anti-EGFR and anti-PD-1 therapies and other similarly designed studies.

Is there anything else important that you would like to mention?

It’s important to highlight how quickly this field is evolving. Anti-PD-1 therapy has transformed the field both for HER negative and HER2 positive disease. For HER2 positive disease we have this exciting new option. It highlights how critical it is to know the HER2 status of your patients and to offer them these options. Certainly PD-1 therapy is important in the first line setting but knowing the HER2 status of your patient’s tumour is critical. It suggests that biomarker testing in a routine fashion in all patients will be important to further advance care for our patients. We need to remember to personalise treatment for each patient, even with rare disease subsets such as HER2 positive/MSI high tumours, EBV positive tumours and so on.