Kathy Miller on IMpassion130: Immunotherapy a New Standard in Breast Cancer? Not Yet

Hi. This is Dr Kathy Miller with Indiana University. I wanted to get right to the details of the IMpassion130 trial,^[1] reported recently at the European Society for Medical Oncology (ESMO) 2018 meeting. You'll recall hearing about that trial by press release a couple of months ago as a positive trial, meeting its primary endpoint. We're now able to look at the details together.

To remind you, this was a large trial of just over 900 patients with metastatic triple-negative breast cancer. Participants could have received adjuvant or neoadjuvant therapy but no previous treatment for metastatic disease. They were randomly assigned to receive nab-paclitaxel (chosen to avoid the need for steroid premedication) with placebo or atezolizumab, one of the PD-L1-targeted agents. Patients were stratified on the basis of their extensive disease, previous chemotherapy, and PD-L1 status. There were defined subsets for the PD-L1-positive patients, which was about 41% of the total subset.

The trial design gets very complicated. There were co-primary endpoints of progression-free survival and overall survival in the entire population, and then separately in the PD-L1-positive group. Now, because of this design, the investigators were required to test those endpoints in the entire study population, and only if that was positive could they then look at the PD-L1-positive group.

So, what did we learn? Progression-free survival was statistically significantly longer in the patients treated with atezolizumab. That was true in the entire population, going from 5.5 to 7.2 months, just under a 2-month improvement. The PD-L1-positive patients had about a 2.5-month improvement in progression-free survival, going from 5 months to 7.5 months. The hazard ratio was 0.8 for the overall group and 0.62 to for the PD-L1-positive group.

Now, the overall survival results are immature. The trial did not reach a significant improvement in overall survival in the entire population; the hazard ratio was 0.84. Thus, they were not able to statistically analyze the PD-L1-positive population. So while the hazard ratio of 0.62 looks a bit better, we don't know whether that's a significant result and we'll need more time to know if it will hold up.

I personally was having a great sense of déjà vu when I saw these results. Let me take you back a decade to the first results of the ECOG 2100 trial looking at bevacizumab in the metastatic setting.^[2] That trial had a better improvement in progression-free survival, with a hazard ratio of 0.498 and a longer absolute improvement in progression-free survival. The early analysis—immature and premature for overall survival—suggested a significant improvement with a hazard ratio of 0.674, but with longer follow-up and more events, it was clear that there was no difference in overall survival.

The authors of IMpassion130 conclude that atezolizumab plus nab-paclitaxel is a new standard of care in the PD-L1-positive subgroup. At this point, I have to say I disagree. What they've reported so far is a very modest improvement in progression-free survival. We honestly don't yet know whether there is an improvement in overall survival. There is an increase in toxicity, but no unusual toxicities. These are the toxicities we've come to know and expect with immune checkpoint agents, but they are not inconsequential. And with only a 2-month improvement in progression-free survival and unknown benefit in overall survival, I can't yet jump to calling this a new standard of care.

I hope I'm wrong. We've been waiting for this day for such a long time, but without knowing overall survival outcomes, I'm going to have to wait. It will be interesting to learn what the rest of the community thinks of these results, and it will be fascinating to see how the US Food and Drug Administration views these results.

I'll be back with you again soon. This is Kathy Miller from Indiana University.