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Highlights From the 2021 SABCS Symposium
  • CME

Joyce O'Shaughnessy, MD
Sara Tolaney, MD, MPH
Released: February 25, 2022

Key Studies in Triple-Negative Breast Cancer

KEYNOTE-522: Neoadjuvant Pembrolizumab Plus CT Followed by Adjuvant Pembrolizumab in TNBC

Joyce O’Shaughnessy, MD:
Switching now to TNBC, at SABCS 2021, updated findings from the important KEYNOTE‑522 trial were presented. Earlier results from this trial were practice changing. Now all our stage II/III TNBC patients receive 4 chemotherapy (CT) agents preoperatively, regardless of the PD‑L1 status of their breast cancer.

The randomized, double-blind phase III trial enrolled 1174 newly diagnosed adults with TNBC in 2 arms: neoadjuvant pembrolizumab plus CT followed by adjuvant pembrolizumab, or neoadjuvant placebo plus CT followed by placebo. With a median 3-year follow-up, there was an approximately 7% absolute improvement in event‑free survival (EFS), as well as an improvement in pathologic complete response. The improvement in EFS was statistically significant and led to FDA approval.9,10

KEYNOTE-522: EFS Sensitivity Analyses

Joyce O’Shaughnessy, MD:
At SABCS 2021, we saw a series of prespecified sensitivity and subgroup analyses on the KEYNOTE-552 data set to evaluate the consistency of the primary EFS data.11

Cases were regrouped for the sensitivity analysis based on predetermined adjustments to the definition of EFS used in the primary analysis, for example, excluding patients who had positive surgical margins when they were previously included. The results of these new analyses were then compared with the primary analyses. The results showed that taking out some of these smaller subsets did not make any difference on the EFS results, confirming their reliability.


KEYNOTE-522: Adverse Events

Joyce O’Shaughnessy, MD:
Adverse events (AEs) seen in this analysis were consistent with those reported in known studies with pembrolizumab and chemotherapy. No new safety concerns were identified.

KEYNOTE-522: Conclusions

Joyce O’Shaughnessy, MD:
In summary, the use of pembrolizumab plus CT in the neoadjuvant setting and then alone as adjuvant treatment resulted in meaningful improvement in 36-month EFS. This finding was statistically significant (84.5% with pembrolizumab vs 76.8% with placebo; HR: 0.63) and supports the use of this regimen as a standard treatment for patients with high-risk, early-stage TNBC.

What is most important about these data at the 3-year timepoint is that all patient groups included had clinically meaningful results and benefited substantially from the treatment. This was true for both stage II and stage III disease as well as for patients who were node negative or node positive. Furthermore, the results were observed at the 3‑year follow-up mark, which, for early TNBC, is noteworthy.

Except for patients with serious comorbidities or serious autoimmune disorders, I would offer this treatment to any Stage II or III patient. However, a small percentage of serious, permanent long‑term toxicities are associated with immunotherapy, and we always have to discuss these with our patients. Nonetheless, there are some patients who will be left with very serious long‑term autoimmune disorders, etc. How do you translate these data, Dr. Tolaney, into your practice?

Sara Tolaney, MD, MPH:
I agree that these data are very important. The benefits are remarkable even in the stage II and node-negative patients. It makes the clinical decision-making that much harder because you see a substantial benefit even in patients who have lower‑risk disease. This changes the risk–benefit ratio for these patients. I think that anyone with stage II/III disease with TNBC should discuss adding pembrolizumab to their CT in the preoperative setting. The benefits are reasonable, but you always have to monitor for potential toxicities, for example, checking cortisol and adrenal sufficiency before surgery.

KEYNOTE-355: First-line Pembrolizumab Plus CT vs Placebo Plus CT in TNBC: PD-L1 CPS Subgroup Analysis

Sara Tolaney, MD, MPH:
Survival and subgroup analyses for the phase III KEYNOTE-355 trial of pembrolizumab plus CT vs placebo plus CT in the first‑line metastatic setting for patients with TNBC were presented at SABCS 2021.12 An improvement in PFS with the addition of pembrolizumab (vs placebo) for patients who were PD‑L1 positive (CPS ≥10) was previously reported.13 Then the survival data were reported showing an important improvement in OS from approximately 16-23 months in the CPS ≥10 group.14 These findings supported the full FDA approval for pembrolizumab in the first‑line setting for the PD‑L1–positive subgroup.

KEYNOTE-355: OS by PD-L1 CPS Subgroup

Sara Tolaney, MD, MPH:
This study analyzed data from KEYNOTE-355 to address the question of whether a CPS ≥10 is the optimal CPS cutoff for treating patients with pembrolizumab in this population? The authors examined OS and PFS by subgroups defined by CPS scores of <1, 1‑9, 10‑19, and ≥20.

KEYNOTE-355: OS in Additional PD-L1 CPS Subgroups

Sara Tolaney, MD, MPH:
We already knew that there is no OS benefit for patients with CPS <10, and this was confirmed in this analysis. But what about for higher cutoff values? The OS benefit seen in the CPS 10-19 subgroup is similar to that seen in the CPS ≥20 subgroup with similar HRs. This suggests that a CPS cutoff of ≥10 is appropriate to see a benefit. We have not seen the data broken down this way, and these findings show that it was not just the very high CPS scores that were driving this benefit. There is significant OS improvement in the CPS 10‑19 group, as well.

KEYNOTE-355: PFS by PD-L1 CPS Subgroup

Sara Tolaney, MD, MPH:
These are the data for the CPS ≥10, the CPS ≥1, and the ITT population.

KEYNOTE-355: PFS in Additional PD-L1 CPS Subgroups

Sara Tolaney, MD, MPH:
Looking at PFS by subgroup, the benefit is numerically smaller in the CPS 10‑19 group than it is for patients with a CPS score of ≥20. There is almost a 4‑month difference between arms for CPS ≥20, but an approximately 2‑month difference for CPS 10‑19. Although these results are from subgroups and are not statistically significant differences, pembrolizumab still offers an advantage in PFS and an even clearer advantage in OS.

KEYNOTE-355: Adverse Events

Sara Tolaney, MD, MPH:
No new safety signals were identified.

KEYNOTE-355: Conclusions

Sara Tolaney, MD, MPH:
For me, these results confirm that the combination of pembrolizumab plus CT has an acceptable safety profile, and it provides OS and PFS benefits to patients. It confirms that we should be using pembrolizumab for patients with CPS scores ≥10. But I think it brings up the topic of PD‑L1 testing. Dr. O’Shaughnessy, what are you doing at your center regarding testing for PD‑L1? Are you using the 22C3 antibody for everyone, and do you use the CPS ≥10 cutoff?

Joyce O’Shaughnessy, MD:
Reinforcing the CPS cutoff of ≥10 or higher removes any urge to give pembrolizumab to patients whose cancers have either none or lower PD-L1 expression. We do not see any survival improvement with CPS 1-9 scores.

Regarding the use of CPS scores, we still see some SP142 testing. SP142 of 1% is roughly equivalent to CPS ≥10 by 22C3. Unfortunately, you will miss some CPS-positive patients if they show a negative SP142 score. I use the 22C3 antibody as often as possible. If somebody has an SP142 antibody with 1% or higher, I will generally consider that equivalent, so the patient can start therapy posthaste.

Sara Tolaney, MD, MPH:
We order 22C3 but we do not do it in-house as we used to with SP142. Patients come in for consultations with different types of assays, and if they have an SP142 of 1 or higher, I will use it and give them the immunotherapy. This is just one challenge in testing for PD-L1 expression. Another challenge arises when you compare sample sites for testing. The liver samples are almost always negative; lung or lymph node samples are more likely to be positive. So, although there are still challenges to testing, in TNBC, we should focus on the 22C3 assay.

TROPION-PanTumor01: Phase I Study of Datopotamab Deruxtecan in TNBC and Other Metastatic Solid Tumors

Joyce O’Shaughnessy, MD:
The TROPION-PanTumor01 phase I study examined safety, tolerability, and efficacy of datopotamab deruxtecan (Dato-DXd) in patients with TNBC and other solid tumors. This antibody–drug conjugate (ADC) targets TROP2 and carries a deruxtecan payload and is given IV once every 3 weeks. Updated data from the TNBC cohort were presented by Krop and colleagues.15

TROPION-PanTumor01: Baseline Characteristics

Joyce O’Shaughnessy, MD:
Patients had a median of 3 prior regimens in the metastatic setting for TNBC. Note that 30% of the patients had previously been treated with topoisomerase I inhibitor–based ADC, including with sacituzumab govitecan, which also targets TROP2.

TROPION-PanTumor01: Efficacy

Joyce O’Shaughnessy, MD:
The level of activity was really very impressive. The objective response rate (ORR) was 34% among the 44 patients with TNBC. When the patients previously treated with sacituzumab govitecan were removed from the response analysis, the ORR went up to an impressive 52%. Median duration of response was not reached, so most of the patients were still on the study after 6 months, when these data were analyzed.

TROPION-PanTumor01: Safety

Joyce O’Shaughnessy, MD:
The safety profile is somewhat different than that of sacituzumab govitecan. Both agents induce nausea but stomatitis, mostly grade 1/2, is unique to Dato-DXd. Dato-DXd has a low incidence of hematologic toxicity, which distinguishes it from sacituzumab govitecan, and a low incidence of diarrhea. Sacituzumab govitecan also has low levels of diarrhea. 

TROPION-PanTumor01: Conclusions

Joyce O’Shaughnessy, MD:
The Dato-DXd has an impressive level of activity, especially in patients who had no previous ADC therapy. This agent is being examined in the first‑line setting for patients with metastatic TNBC, and we look forward to more data.

Sara Tolaney, MD, MPH:
We are conducting this trial at my institution, and, anecdotally, I have been impressed with the benefits and tolerability I have seen in patients with Dato‑DXd. We have had issues with stomatitis, but not with neutropenia or diarrhea. Administering it every 3 weeks is convenient.

We have seen some Dato-DXd activity post sacituzumab. This is intriguing because they both target the same protein and receptor and have similar topoisomerase 1 inhibitor payloads. They have different linkers and the payloads are not the same, but their mechanism is similar, and yet there is sequential benefit in some cases, although the patient numbers are not large.

I think we are going to hear a lot more about this agent, at least initially, in the TNBC space. I am also eagerly awaiting the results of the hormone receptor–positive trials.

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