Durvalumab and oleclumab boost for SBRT plus chemo in ER+/HER2- breast cancer

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Published: 16 Sep 2024
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Dr Alex De Caluwe - Institut Jules Bordet, Brussels, Belgium

Dr De Caluwe talks to ecancer at ESMO 2024 about data he presented from the three armed Neo-CheckRay phase II trial evaluating neoadjuvant chemotherapy with stereotactic body radiation therapy (SBRT) alone, or with durvalumab, or with durvalumab and oleclumab for early-stage, high risk ER+/HER2- breast cancer.

His team speculated that combining SBRT with a PD-L1 inhibitor and an adenosine-targeting agent (oleclumab, anti-CD73) could potentiate anti-tumour immunity and response to neoadjuvant chemotherapy in high-risk early-stage luminal breast cancer.

The study found that the addition of durvalumab +/- oleclumab numerically increases pathological complete response and residual cancer burden 0/1 rates compared to neoadjuvant chemotherapy combined with SBRT alone.

Durvalumab and oleclumab boost for SBRT plus chemo in ER+/HER2- breast cancer

Dr Alex De Caluwe - Institut Jules Bordet, Brussels, Belgium

The Neo-CheckRay trial was presented at ESMO 2024. This is a trial in luminal B breast cancer of early stage and that is of high risk in MammaPrint high risk patients.  We investigated if we could use radiation therapy to make these cold tumours hotter in the hope to increase the response to immunotherapy. It is a randomised trial with three arms where the control arm received chemotherapy with radiation therapy only targeting the primary breast cancer in three fractions. In the second arm we also added durvalumab and in the third arm we also added oleclumab.

The hypothesis of the trial is that this new way of doing radiation therapy would synergise with durvalumab and oleclumab and increase response at surgery. So the primary endpoint of the trial was the rate of RCB 0 or 1 and the rate of pathological complete response. The trial revealed a high rate of RCB 0 or 1 in all arms, also in the control arms. Because of this, the primary endpoint was not met. However, the RCB 0 or 1 rate in the experimental arms was higher than expected. For pCR we see a doubling of PCR rate in the immunotherapy combined with radiation therapy arms.

Interestingly, in the PD-L1 subgroup, so the colder cancers, we see a very big difference when radiation therapy is combined with durvalumab. So the main hypothesis of the trial is indeed that we could make these colder tumours hotter and responsive for immunotherapy and we think this might be the first step towards proving this. However, it’s a phase II trial; current practice will not change but it paves the way forward to future trials to examine this novel concept.

The radiation therapy technique we used was to exclusively target the primary breast cancer. We actively spared the lymph nodes, also in case of involved lymph nodes. So the response in the lymph nodes, because most of the patients in this trial were node positive, so the response in the lymph nodes is a marker of the systemic response, not of the direct radiation effect. This also reflects our hypothesis that we’re looking for synergy between durvalumab and radiation therapy to induce a systemic immune response.

What sort of toxicities were found?

This trial was a novel combination of radiation therapy with immunotherapy. So before starting the phase II trial we did a safety run-in in six patients where we could not identify toxicity signals. So we went ahead with the phase II trial. After randomising 135 patients we did see an increase in grade 3 and 4 adverse events in the immunotherapy arms, so this is definitely something we have to look into. However, it seems that the toxicity is not coming from the radiation therapy. For the radiation therapy itself we didn’t identify any grade 3 or grade 4 side effects and only very few grade 1 side effects.

What are the next steps?

In terms of future developments, the next step will be to do a larger trial to further test this hypothesis and also to look further than pathological complete response but also event free survival or other markers to prove benefit for the patients.