TROPiCS-02 evaluated the novel Trop-2 antibody drug conjugate, sacituzumab govitecan, compared
to chemotherapy of physician’s choice in patients who had heavily pre-treated hormone receptor
positive HER2 negative breast cancer. Just a brief review of the patients and the eligibility, patients
had to have received a CDK4/6 inhibitor and taxane in any setting, one line of endocrine therapy for
metastatic disease and at least two, but not more than four, lines of chemotherapy for metastatic
disease. The median number of lines of chemotherapy was three; the median time from diagnosis of
metastatic disease to a randomisation was four years. 95% of patients had visceral metastases and
about 40% of patients had received CDK4/6 inhibitors for more than a year. So this was a very heavily
pre-treated and uniformly pre-treated patient population.

We showed at ASCO 2022 and published recently in The Journal of Clinical Oncology that
progression free survival was significantly increased with sacituzumab compared to chemotherapy of
physician’s choice. About 48% of patients received eribulin as their chemotherapy and then it was
divided up between the other three agents, vinorelbine, gemcitabine and capecitabine, the smallest
number receiving capecitabine. Most of the patients had received prior capecitabine and you couldn’t
receive the same drug again.

The progression free survival was designed by blinded independent central review, was powered for a
hazard ratio of 0.7. We reached a hazard ratio of 0.66 which was highly statistically significant. But the
median difference was about 1.5 months which had some people concerned because it was so small.
But actually what we saw was in the first two months there was a big drop off that was similar
between the two arms. So you get these patients who are really late in chemotherapy treatment for
metastatic disease, hormone receptor positive disease, and they just have resistance to everything.
So in that situation Kaplan-Meier is not quite as useful and the medians aren’t representative. So we
did landmark analyses and at six, nine and twelve months there were more patients alive and free
from progression who received sacituzumab compared to those who received chemotherapy of
physician’s choice. Notably, at one year three times as many patients were alive and free from
progression with sacituzumab.

At that first analysis we saw no new safety signals. The most common toxicity is neutropenia,
although there wasn’t an increase in febrile neutropenia compared to TPC, treatment of physician’s
choice. Then diarrhoea is the next most common toxicity. My experience, and those of investigators
who have used the agent frequently, is that we can manage this toxicity very easily in a
straightforward way if you’re aware of it up front by giving growth factors in the right setting, anti-
diarrhoeal agents and dose reducing and dose holding when appropriate, dose-reducing working very
well for people who have sensitivity to the irinotecan metabolite SN-38 and develop diarrhoea. Again,
still not as common as we had thought in the beginning in terms of toxicity. The earlier we treat
patients, we’ve seen with triple negative disease based on the approval for triple negative breast
cancer sacituzumab, the less of that toxicity we see relatively.

So at ESMO 2022 we updated the overall survival. There was a statistical hierarchical design which is
very popular now. So you have to have significance in each prior endpoint to evaluate the next one.
So primary endpoint PFS showed statistical significance, at the first analysis we could look at OS,
overall survival. But we didn’t have enough events, it wasn’t mature. We saw a numeric improvement
but not significant. Now at this second interim overall survival and the last formal overall survival
analysis, we saw a statistically significant improvement in overall survival with a hazard ratio of 0.79,
highly statistically significant, and a median improvement of 3.2 months, going from 11.2 to 14.4
months. But also at one year a substantially greater number of patients were alive who received
sacituzumab compared to those who received treatment of physician’s choice.

So that was really encouraging and it allowed us to look at statistical significance, again using this
hierarchical design, for overall response, duration of response, clinical benefit rate, all of which were
improved with sacituzumab, and also health related quality of life. We saw in that setting as well that
there was a delay in deterioration of global health status quality of life and a delay in deterioration in
terms of fatigue.

So this was all very encouraging data and solidifies the importance of sacituzumab govitecan in
heavily pre-treated patients with hormone receptor positive metastatic breast cancer.