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ONCAlert | Upfront Therapy for mRCC

The IMpassion130 Study in Metastatic TNBC

Targeted Oncology
Published Online:5:07 PM, Thu December 27, 2018

Joyce O’Shaughnessy, MD: IMpassion130 is a very important trial in a first-line metastatic triple-negative breast cancer population. Patients were randomized to nab-paclitaxel with placebo versus nab-paclitaxel with atezolizumab. There were 2 different groups of patients: Those who were PD-L1 [programmed death-ligand 1]–positive and those whose breast cancers were PD-L1–negative. What was looked at was the percentage of immune cells that were PD-L1–positive. You had to have a cut point of 1% or more of the immune cells that were PD-L1–positive. The women were randomized to nab-paclitaxel plus or minus atezolizumab. They could not have had a taxane within the last year. The primary endpoints were progression-free survival, both in the overall population—the intent-to-treat as well as the the PD-L1–positive population—as well as overall survival.

In IMpassion130, the primary endpoint of progression-free survival was met in both the intent-to-treat and PD-L1–positive population. In the intent-to-treat population, it was clearly positive statistically, although clinically it was of somewhat limited utility because the real benefits were seen in the PD-L1–positive population. The hazard ratio was 0.62, in favor of the combined treatment with atezolizumab. It went from 5 months median progression-free survival with first-line nab-paclitaxel to 7.5 months with the addition of the atezolizumab, which was statistically significant. Even more important is overall survival. For the intent-to-treat population, there was a 3.5-month improvement in survival, but it was of borderline statistical significance and didn’t quite meet the prespecified threshold for survival.

The protocol said that if the primary survival endpoint was not statistically positive, the exploration would occur in the PD-L1–positive population, but without statistical calculation and import. The survival improved by 10 months in the PD-L1–positive population—from 15 months, which is about what you’d expect with nab-paclitaxel alone, up to 25 months—with the combination of atezolizumab. No statistical calculations were done on that, just the numerical exploration. But that was a very impressive result.

The response rates were also higher with the combination of atezolizumab and nab-paclitaxel in the PD-L1 population. The response was 42% with nab-paclitaxel alone, which is actually quite respectable. It went up to 48% with the combination, showing the additive or synergistic effects with this combination. They definitely were better than either one alone. Safety, thankfully, was actually quite good here. I did not see, looking at the data, any particular increase in nab-paclitaxel type of adverse effects with the addition of the atezolizumab. With regard to immune-related toxicities that we get concerned about, there was a bit more hypothyroidism with the atezolizumab. Of course, that’s very easily managed. There weren’t a lot of other adverse effects, such as hepatitis, pneumonitis, or other serious immune-related toxicities. They just really didn’t occur.

This was a really good first step—combining nab-paclitaxel with atezolizumab. We have a clear proof of concept that chemotherapy with checkpoint inhibitors is going to be more efficacious in the PD-L1 population than chemotherapy alone. Now, of course, we’re very interested in improving upon that. We’re interested in a platinum-based regimen. We await the results of a KEYNOTE trial with gemcitabine, carboplatin, with or without pembrolizumab. We’ll also see pembrolizumab in combination with taxanes as well. But also, of course, checkpoint inhibitors in combination with targeted therapies.

Transcript edited for clarity.

Joyce O’Shaughnessy, MD: IMpassion130 is a very important trial in a first-line metastatic triple-negative breast cancer population. Patients were randomized to nab-paclitaxel with placebo versus nab-paclitaxel with atezolizumab. There were 2 different groups of patients: Those who were PD-L1 [programmed death-ligand 1]–positive and those whose breast cancers were PD-L1–negative. What was looked at was the percentage of immune cells that were PD-L1–positive. You had to have a cut point of 1% or more of the immune cells that were PD-L1–positive. The women were randomized to nab-paclitaxel plus or minus atezolizumab. They could not have had a taxane within the last year. The primary endpoints were progression-free survival, both in the overall population—the intent-to-treat as well as the the PD-L1–positive population—as well as overall survival.

In IMpassion130, the primary endpoint of progression-free survival was met in both the intent-to-treat and PD-L1–positive population. In the intent-to-treat population, it was clearly positive statistically, although clinically it was of somewhat limited utility because the real benefits were seen in the PD-L1–positive population. The hazard ratio was 0.62, in favor of the combined treatment with atezolizumab. It went from 5 months median progression-free survival with first-line nab-paclitaxel to 7.5 months with the addition of the atezolizumab, which was statistically significant. Even more important is overall survival. For the intent-to-treat population, there was a 3.5-month improvement in survival, but it was of borderline statistical significance and didn’t quite meet the prespecified threshold for survival.

The protocol said that if the primary survival endpoint was not statistically positive, the exploration would occur in the PD-L1–positive population, but without statistical calculation and import. The survival improved by 10 months in the PD-L1–positive population—from 15 months, which is about what you’d expect with nab-paclitaxel alone, up to 25 months—with the combination of atezolizumab. No statistical calculations were done on that, just the numerical exploration. But that was a very impressive result.

The response rates were also higher with the combination of atezolizumab and nab-paclitaxel in the PD-L1 population. The response was 42% with nab-paclitaxel alone, which is actually quite respectable. It went up to 48% with the combination, showing the additive or synergistic effects with this combination. They definitely were better than either one alone. Safety, thankfully, was actually quite good here. I did not see, looking at the data, any particular increase in nab-paclitaxel type of adverse effects with the addition of the atezolizumab. With regard to immune-related toxicities that we get concerned about, there was a bit more hypothyroidism with the atezolizumab. Of course, that’s very easily managed. There weren’t a lot of other adverse effects, such as hepatitis, pneumonitis, or other serious immune-related toxicities. They just really didn’t occur.

This was a really good first step—combining nab-paclitaxel with atezolizumab. We have a clear proof of concept that chemotherapy with checkpoint inhibitors is going to be more efficacious in the PD-L1 population than chemotherapy alone. Now, of course, we’re very interested in improving upon that. We’re interested in a platinum-based regimen. We await the results of a KEYNOTE trial with gemcitabine, carboplatin, with or without pembrolizumab. We’ll also see pembrolizumab in combination with taxanes as well. But also, of course, checkpoint inhibitors in combination with targeted therapies.

Transcript edited for clarity.
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