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New Insights in Breast Cancer: Independent Conference Coverage of SABCS 2020

Sara Hurvitz, MD, FACP
Joyce O'Shaughnessy, MD
Released: February 19, 2021

Advances in the Treatment of Metastatic TNBC

KEYNOTE-355: Study Design

Joyce O’Shaughnessy, MD:
At SABCS 2020, Rugo and colleagues[53] presented additional analyses of the phase III KEYNOTE‑355 trial, with the findings simultaneously published in The Lancet.[54] KEYNOTE-355 enrolled adults with previously untreated TNBC that was metastatic or locally recurrent and inoperable and randomized them to receive pembrolizumab plus a chemotherapy regimen selected by the investigator vs placebo with chemotherapy. The chemotherapy options were nab-paclitaxel, paclitaxel, and gemcitabine plus carboplatin.

In November 2020, supportive data from KEYNOTE-355 led to the FDA approval of pembrolizumab plus chemotherapy for treatment of patients with locally recurrent unresectable or metastatic TNBC expressing PD-L1.[55,56] PD-L1 expression was defined as a combined positive score (CPS) ≥ 10 determined by the FDA-approved PD-L1 IHC 22C3 pharmDx assay. The approved chemotherapy regimens are nab-paclitaxel, paclitaxel, and gemcitabine plus carboplatin. This approval was based on a significant improvement in PFS in patients with PD-L1 CPS ≥ 10 who received pembrolizumab plus chemotherapy vs placebo plus chemotherapy (median PFS: 9.7 vs 5.6 months, respectively; HR: 0.65; 95% CI: 0.49-0.86; P = .0012).[54,56] There was a trend toward improvement in PFS among those with PD-L1 CPS ≥ 1, but this was not statistically significant.

The current analysis focused on PFS and key secondary endpoints (eg, response and safety) in subgroups defined by which of the 3 chemotherapy regimens they received in KEYNOTE-355.[53]

KEYNOTE-355: PFS by Chemotherapy Regimen Across Subgroups

Joyce O’Shaughnessy, MD:
Shown here are the PFS results in 3 key trial populations stratified by chemotherapy regimen.[53,54] The left graph depicts the forest plot for patients with PD-L1 CPS ≥ 10, and we can see that the point estimates for each of the 3 chemotherapy regimens favor treatment with pembrolizumab plus chemotherapy vs placebo plus chemotherapy. This is particularly pronounced in the subgroups who received nab‑paclitaxel (HR: 0.57; 95% CI: 0.34-0.95) and paclitaxel (HR: 0.33; 95% CI: 0.14-0.76). The results are less impressive in those who received gemcitabine plus carboplatin (HR: 0.77; 95% CI: 0.53-1.11).

The lesser benefit with gemcitabine plus carboplatin is likely due to the trial permitting patients to enroll even if they had a shorter than 12 month disease free interval after completing adjuvant or neoadjuvant chemotherapy. These high-risk patients preferentially received gemcitabine plus carboplatin because of their rapid recurrence after an adjuvant or neoadjuvant taxane, making this a particularly challenging group to treat. Thus, it was still encouraging to see a point estimate favoring the pembrolizumab arm in those who received gemcitabine plus carboplatin, even though the CI did overlap 1.0.

These positive results for each of the 3 chemotherapy regimens led to the FDA approving treatment with pembrolizumab plus the physician’s choice of nab-paclitaxel, paclitaxel, or gemcitabine plus carboplatin.[55]

KEYNOTE-355: ORR by Chemotherapy Regimen Across Subgroups

Joyce O’Shaughnessy, MD:
Moving on to response data, we will continue to focus on those with PD-L1 CPS ≥ 10 because that is the population covered in the FDA approval.[53,55] As shown in the left graph, the ORR in the overall population with PD-L1 CPS ≥ 10 was impressive, increasing from 39.8% in those treated with placebo plus chemotherapy to 53.2% with pembrolizumab plus chemotherapy. Consistent with the PFS data, the response results were most impressive in those treated with nab-paclitaxel or paclitaxel, although there was still some numerical increase in ORR in the gemcitabine plus carboplatin subgroup. Again, I think this is because the patients who were chosen to receive gemcitabine plus carboplatin were more likely to have had a disease free interval of less than 12 months after adjuvant or neoadjuvant chemotherapy.

KEYNOTE-355: Duration of Response by Subgroup

Joyce O’Shaughnessy, MD:
The duration of response curves are also quite impressive.[53] Looking at the left graph, which depicts patients with PD-L1 CPS ≥ 10, we see a median duration of response of 19.3 months with pembrolizumab plus chemotherapy vs 7.3 months with placebo plus chemotherapy. It is very unusual to see durable disease control in patients with TNBC.

KEYNOTE-355: Clinical Implications

Joyce O’Shaughnessy, MD:
An important clinical implication of KEYNOTE‑355 is that we have a choice among chemotherapy regimens for our patients because the FDA label is broad.[55] Thus, we can individualize the chemotherapy to the patient and know that we can achieve durable responses and improve PFS. That being said, we should bear in mind that these analyses by chemotherapy regimen were not powered or designed to test for statistical significance.

These positive data support the addition of pembrolizumab plus chemotherapy to standard of care, although we await the OS results. In current practice, we already have atezolizumab plus nab-paclitaxel, which demonstrated a significant OS advantage in previously untreated, PD-L1–positive TNBC (median OS: 25.0 vs 15.5 months with placebo plus nab-paclitaxel, respectively; HR: 0.62; 95% CI: 0.45-0.86).[57] These positive results led to the FDA approval of atezolizumab plus nab-paclitaxel for treatment of adults with unresectable locally advanced or metastatic TNBC expressing PD-L1, which is defined as PD-L1–stained tumor-infiltrating immune cells of any intensity covering ≥ 1% of the tumor area according to the FDA-approved PD-L1 SP142 assay.[58]

Sara Hurvitz, MD, FACP:
I found the current analysis of KEYNOTE-355 by chemotherapy partner to be interesting. These data indicate that pembrolizumab benefits patients regardless of the chemotherapy partner, but the benefit appears to be greater when combined with a taxane.[53] That being said, I am not discouraged from using gemcitabine plus carboplatin as the partner. Because the chemotherapy partner was not the result of randomization, but rather intentional selection by the investigator, the appearance of less benefit with gemcitabine plus carboplatin may be due to patient characteristics such as previous treatment as Dr. O’Shaughnessy suggests.

Overall, I found these data to be compelling, and I will restrict use of pembrolizumab to those patients with PD-L1 CPS ≥ 10. I certainly consider gemcitabine plus carboplatin to be a reasonable chemotherapy partner for pembrolizumab. This chemotherapy regimen does not cause hair loss and is generally more tolerable for patients, especially those with residual neuropathy from previous taxane treatment.[59] 

Primary Results From IPATunity130 Cohort A: First-line Ipatasertib Plus Paclitaxel for PIK3CA/AKT1/PTEN-Altered Advanced TNBC

Sara Hurvitz, MD, FACP:
There has been a great deal of excitement surrounding the potential use of ipatasertib, an oral AKT inhibitor, in combination with paclitaxel for advanced TNBC.[60] Much of this excitement was generated by promising initial results from the randomized, double-blind phase II LOTUS trial, which reported that PFS was significantly improved with first-line ipatasertib plus paclitaxel vs placebo plus paclitaxel in women with advanced TNBC (median PFS: 6.2 vs 4.9 months, respectively; HR: 0.60; 95% CI: 0.37-0.98; P = .037).

Unfortunately, these positive results were not upheld by the double‑blind phase III IPATunity trial. At SABCS, Dent and colleagues[61] presented primary results from cohort A, which compared first-line ipatasertib plus paclitaxel vs placebo plus paclitaxel in patients with PIK3CA/AKT1/PTEN-altered locally advanced unresectable or metastatic TNBC. This analysis failed to find a PFS benefit with the ipatasertib combination vs the placebo arm (median PFS: 6.1 vs 7.4 months, respectively; HR: 1.02; 95% CI: 0.71-1.45; log-rank P = .9237).

I am sorry to see this negative result as we do still need new, effective therapies for our patients with TNBC.

Joyce O’Shaughnessy, MD:
I agree—this was disappointing. Signaling dysregulation in the PI3K/AKT pathway is quite common in TNBC, with alterations occurring in approximately 30% of patients with this disease.[62] Because AKT activity may inversely correlate with the immunogenicity of breast cancers, combining ipatasertib with an immune checkpoint inhibitor may result in greater antitumor activity.[63] We have seen some excitement around preliminary clinical activity observed with the combination of atezolizumab plus paclitaxel and ipatasertib in TNBC, and this regimen is currently under investigation in a phase III trial (NCT04177108).[64]

Biomarker Analysis of ASCENT: Sacituzumab Govitecan vs Chemotherapy in TNBC

Sara Hurvitz, MD, FACP:
In April 2020, the FDA approved the TROP-2–directed antibody–drug conjugate sacituzumab govitecan for treatment of adults with metastatic TNBC who had received ≥ 2 previous therapies for metastatic disease.[65,66] These results were based on response data from the single-arm IMMU-132-01 trial. Subsequently, the randomized phase III ASCENT trial demonstrated significant improvements in both PFS and OS with sacituzumab govitecan vs single-agent chemotherapy of physician’s choice in this setting.[67] Those data were practice changing and have led to many clinicians using this agent in the setting of advanced TNBC.

As I mentioned, sacituzumab govitecan targets TROP-2, which is highly expressed in TNBC.[68] At SABCS 2020, my colleagues and I[69] presented an exploratory biomarker analysis to evaluate whether the benefits of sacituzumab govitecan were restricted to those patients whose tumors had medium to high expression of TROP-2 and whether benefits with sacituzumab govitecan were different for those with a germline BRCA1/2 mutation.

More than three quarters of patients had medium or high TROP-2 expression as determined by IHC. Patients benefited from sacituzumab govitecan regardless of TROP-2 expression, although patients with low TROP-2 expression tended to have worse PFS and OS overall compared to those with medium or high TROP-2 expression. Finally, BRCA1/2 mutation status did not appear to correlate with benefit from sacituzumab govitecan.

Altogether, these data indicate that we should not use TROP-2 expression or germline BRCA1/2 mutation status to select patients for treatment with sacituzumab govitecan.

Joyce O’Shaughnessy, MD:
It was gratifying to see that even those with lower TROP-2 expression still derived benefit from sacituzumab govitecan vs single‑agent chemotherapy. I agree with Dr. Hurvitz—these data indicate that we do not have to select for patients based on TROP-2 expression.

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