New Guidelines Move Beyond Chemotherapy for Patients With Triple-Negative Breast Cancer

The shifting landscape of treatment options for patients with triple-negative breast cancer (TNBC) is reflected in the recent updates made to the National Comprehensive Cancer Network’s (NCCN) Clinical Practice Guidelines for breast cancer management.¹ These changes reflect data from the KEYNOTE-522 trial (NCT03036488), IMpassion131 trial (NCT03125902), ASCENT trial (NCT0257445), and the OlympiA trial (NCT02032823).^2-5 Consequently, the NCCN recommendations concerning the manage- ment of patients with TNBC have been updated for various settings, including early, recurrent and unresectable, BRCA1/2-mutated, and high-risk TNBC.

The update involved the use of adjuvant and preoperative therapy recommendations for TNBC. Neoadjuvant systemic therapy can be considered for cT1 N0 TNBC, and the NCCN guideline states a preference for preoperative systemic therapy in treating patients with cT of 2 or greater or cN of 1 or greater TNBC.¹ These recommendations follow the results of the KEYNOTE-522 trial, which found that a greater number of patients with early TNBC had a pathological complete response (pCR) when treated with pembrolizumab (Keytruda) and neoadjuvant chemotherapy when compared with the number of patients who were treated with placebo and neoadjuvant chemotherapy.³

William J. Gradishar, MD, chair of the NCCN Breast Cancer Panel, discussed the trial and the rationale behind the guideline updates with Targeted Therapies in Oncology^TM (TTO). “It’s not just that you got a pCR rate. There were long-term results that came to the patients who got pembrolizumab. There was [approximately] an 8% reduction in the risk of a recurrence if you got pembroli- zumab at 3 years, so it was not only pCR but [also] event-free survival that improved, and most of those events that occurred were met- astatic events,” said Gradishar, who is also the chief of hematology and oncology in the Department of Medicine, the Betsy Bramsen Professor of Breast Oncology, and a professor of medicine (hematology and oncology) at Northwestern University Feinberg School of Medicine in Chicago, Illinois.

“You’re trying to prevent things that will lead to death. By increasing the number of patients who had reduced risk for getting metastatic disease, this translated into improvement in overall outcome, so this has now become standard of care,” Gradishar said. “We consider any patient who has either node-positive disease or at least a lesion that’s approaching 2 cm with triple-negative disease to be a candidate for preoperative chemotherapy with pembrolizumab. What’s unique about this is you don’t need to necessarily know the PD-L1 status. With pembrolizumab, we use the combined score system, not just the PD-L1 greater than 1%, as we did with atezolizumab [Tecen- triq]. We used the PD-L1 assessment only in patients with metastatic disease and the preoperative setting that’s not a requirement.”

Aditya Bardia, MD, MPH, director of breast cancer research and assistant professor at Harvard Medical School in Boston, Massachusetts, discussed the benefit of neoadjuvant therapy in early TNBC with TTO. “Neoadjuvant therapy offers several advantages over adjuvant therapy. Multiple studies have demonstrated that neoadjuvant chemotherapy, preoperative chemotherapy, or primary sys- temic therapy results in similar outcomes as compared with adjuvant chemotherapy for patients with localized breast cancer. In addi- tion, neoadjuvant therapy results in surgical downstaging of tumors, facilitating breast conservation in patients who would other- wise need mastectomy. Finally, neoadjuvant therapy allows monitoring of tumor response and absence of tumor at the time of surgery. pCR is considered a robust surrogate marker for improved disease-free survival and overall survival [OS], particularly in TNBC,” Bardia said. “In patients with localized TNBC, dose-dense doxorubicin-cyclophosphamide and paclitaxel was the standard neoadjuvant chemotherapy backbone up until 2021. With the approval of neoadjuvant pembrolizumab, chemotherapy with immunotherapy is the new standard of care for localized TNBC."

For patients with recurrent/refractory metastatic TNBC (mTNBC), the antibody-drug conjugate sacituzumab govitecan-hziy (Trodelvy) has emerged as a treatment option, following the results of the ASCENT trial. In the trial, patients with mTNBC previously treated with taxanes had longer progression-free survival (PFS) and OS when treated with sacituzumab govitecan, compared with patients treated with single-agent chemotherapy.

“Sacituzumab govitecan is approved now, based on the ASCENT trial,” Gradishar said. “It didn’t matter what the comparator was, meaning [whether] you got gemcitabine or a taxane, every patient who got sacituzumab govitecan did better than those who got chemotherapy. It didn’t matter [whether] you were younger or older. Sacituzumab govitecan targets Trop-2, which is present in the majority of patients with triple-negative disease. It also didn’t matter what level of expression of Trop-2. Whether your tumor was of high-, middle-, or low-expression of Trop-2, patients who got sacituzumab govitecan did better than those patients who got any of the standard chemo- therapies that could have been chosen, so that was clearly a positive trial. The [adverse] effect profile was manageable. We now view this as a treatment option for patients who have received at least 1 prior therapy for mTNBC. It’s not yet viewed as a first-line therapy. If a patient had PD-L1–positive mTNBC, we would try to use an immunotherapy as first-line therapy. Then if they develop disease progression, sacituzumab govitecan could be considered.”⁶

Bardia also said the use of platinum for treating mTNBC hasn’t changed with the other updates for TNBC. “Platinum with/without immunotherapy is one of the recommended first-line regimens for [mTNBC],” he said. However, it remains unclear whether a platinum-based chemotherapy regimen is needed.

“In many of the trials that have looked at either atezolizumab or pembrolizumab in metastatic disease, a platinum has been used,” Gradishar said. “The question becomes: Do you always need a platinum? I don’t think that’s been completely determined at this point. It’s still somewhat of an open question. But just because you have triple-negative disease doesn’t automatically mean you must receive a platinum drug. There’s a diversity...all the data are not going in the same direction on that question. So it’s an active drug, but it’s not an absolute...that you must receive it.”

For patients with high-risk HER2-negative early breast cancer with germline pathogenic or likely pathogenic BRCA1/2 variants, 2 poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors, olaparib (Lynparza), and talazoparib (Talzenna) are adjuvant options. The phase 3 OlympiA trial studied PARP inhibitor olaparib in this patient population and found that, following local treatment and neoadjuvant or adjuvant chemotherapy, adjuvant olaparib was associated with longer invasive or distant disease-free survival when compared with placebo.⁴ However, the NCCN update noted that the patients in the OlympiA trial were not treated with capecitabine, and consequently, no data are available to inform adjuvant therapy selection or therapy sequencing.¹

Talazoparib has been associated with a considerable residual cancer burden rate of 0 as a single-agent neoadjuvant in operable BRCA-positive breast cancer and has shown a PFS benefit as a single-agent in the advanced BRCA1/2-mutated advanced breast cancer setting.^7,8 Olaparib and talazoparib are category 1, preferred agents for patients with germline BRCA1/2-mutated metastatic breast cancer.¹

“The olaparib or talazoparib trials are pretty similar, and they both had the same improvement in outcome [PFS] with enhanced response rate. These drugs could be used in a patient with BRCA1/2 mutations,” Gradishar said. “Some patients also may be candidates for an immunotherapy, as well, so if you had somebody with new mTNBC, you would want to know their BRCA status to determine whether they’d be a candidate for a PARP inhibitor [at some point]. But you may choose to give immunotherapy as first line if they were a candidate, meaning they were BRCA1-positive, because there is an event-free survival that’s quite significant. If they were not PD-L1–positive, in other words, not a candidate for pembrolizumab, you could consider a PARP inhibitor as a first-line therapy. If somebody is PD-L1–positive, I would prob- ably go with immunotherapy, then consider a PARP inhibitor or sacituzumab govitecan.”

When weighing the safety differences between the 2 PARP inhibitors, “the rate of hematologic [adverse] effects was greater with talazoparib than with olaparib,” Gradishar said. “The flip side is [there is greater evidence of] hair loss with olaparib, [and] nau- sea is observed a little more with olaparib— not dramatic differences.... In terms of their efficacy, response rate, [and PFS], they’re pretty similar in terms of the benefits derived. In both cases, the [adverse] effects are manageable. The same is true with sacituzumab govitecan, and there isn’t a shocking potential for severe [adverse] effects. Most patients tolerate it well, [and it’s] the same with immunotherapy. You know there are some predictable potential [adverse] effects with any form of immunotherapy—thyroid disorders, hepatitis, inflammatory processes—that can occur in some patients. But for [most] patients, they do not have or they have only low-grade [adverse effects]. For the more experienced clinicians, most of the [adverse] effects one might encoun- ter are very manageable.”

However, there remains some lack of clarity in treatment selection for patients with high- risk early TNBC or high-risk TNBC with resid- ual disease. “If a patient...had surgery—maybe they got some other form of preoperative therapy and they had residual disease after-ward—we [may] consider pembrolizumab in that setting,” Gradishar said. “But that does not perfectly replicate the [KEYNOTE-522] trial, because pembrolizumab was given both before surgery and after. The other issue that arises is if you have a high-risk patient with residual disease, until pembrolizumab was available in this setting, we would add capecitabine. There are safety data showing you can give capecitabine and pembrolizumab together. Finally, if you had a very high-risk patient with BRCA-positive disease, the question then becomes: Where would you use the PARP inhibitor? Based on the OlympiA trial, there are supportive data to using olaparib in high-risk patients. The question then becomes: Would you give them immunotherapy [and] the PARP inhibitor? Maybe. Again, we don’t have good data to show that’s adding something. These are all open questions we still have to answer.”

In August 2021, the IMpassion131 trial failed to meet its primary end point of PFS in patients with PD-L1–positive TNBC. The trial randomized 651 patients, 45% of whom were PD-L1–positive, to atezolizumab and paclitaxel or placebo and paclitaxel in the first-line setting. The trial found that the investigator-evaluated PFS was not improved for patients with PD-L1–positive TNBC treated with atezolizumab compared with the PFS of patients treated with the control regimen. There was also no difference found between the atezolizumab and control-treated patients with PD-L1–positive TNBC, with respect to the final OS.^2,5 In response, atezolizumab’s manufacturer withdrew its application for the use of atezolizumab with paclitaxel in patients with PD-L1–positive TNBC.⁵

The effects of this withdrawal led to the NCCN’s update, respecting the recommended testing platform for PD-L1. The update recommends the use of the 22C3 antibody test for PD-L1, with the corresponding recommenda- tion for pembrolizumab and chemotherapy in PD-L1–positive TNBC (TABLE9).¹ “We used to have 2 drugs until [approximately] 15 minutes ago. The other one was atezolizumab, then the FDA approval got with- drawn. Each of these drugs has their own platform to assess whether you’re a candi- date. If it would have been atezolizumab, the assay and the machine you [would] use the SP142 antibody, and with pembrolizumab, it’s the 22C3 antibody, and the results are not superimposable....The important point is that, with respect to testing for PD-L1 status, it should be emphasized that you [must] use the assay/instrument that’s appropriate to the drug you’re using,” Gradishar said.

In addition, Bardia noted that “the 22C3 antibody was utilized in the KEYNOTE-355 clinical trial [NCT02819518] that led to approval of first-line pembrolizumab therapy, and thus was recommended as the preferred test for determination of PD-L1 positivity.”¹⁰

Gradishar observed that overall, the changes in TNBC recommendations are encouraging. “Until 3 years ago, all we could say was ‘chemotherapy, chemotherapy, chemotherapy.’ Now at least we’re able to tease out patients from that bigger group who may benefit from very specific strategies, [such as] the PARP inhibitors [and] immunotherapy. And now, we have targeted therapies like sacituzumab govitecan with other drugs that are coming along. The pace of change in this disease is [never fast enough] for patients, but we definitely have more options than we did in the past,” he said.

_REFERENCES:

<sub>1. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 2.2022. Accessed February 8, 2022. https://www.nccn.org/ professionals/physician_gls/pdf/breast.pdf
2. Miles D, Gligorov J, André F, et al; IMpassion131 Investigators. Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unre- sectable locally advanced/metastatic triple-negative breast cancer. Ann Oncol. 2021;32(8):994-1004. doi:10.1016/j.annonc.2021.05.801</sub>

<sub>3. Schmid P, Cortes J, Pusztai L, et al; KEYNOTE-522 Investigators. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020;382(9):810-821. doi:10.1056/NEJMoa1910549
4. Tutt ANJ, Garber JE, Kaufman B, et al; OlympiA Clinical Trial Steering Committee and Investigators. Adjuvant olaparib for pa- tients with BRCA1- or BRCA2-mutated breast cancer. N Engl J Med. 2021;384(25):2394-2405. doi:10.1056/NEJMoa2105215</sub>

_{5. Roche provides update on Tecentriq US indication for PD-L1-posi- tive, metastatic triple-negative breast cancer. News release. Roche. Au- gust 27, 2021. Accessed February 15, 2022. https://bit.ly/3ypzC6K 6. Bardia A, Hurvitz SA, Tolaney SM, et al; ASCENT Clinical Trial Inves- tigators. Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med. 2021;384(16):1529-1541. doi:10.1056/NEJ- Moa2028485}

<sub>7. Litton JK, Rugo HS, Ettl J, et al. Talazoparib in patients with ad- vanced breast cancer and a germline BRCA mutation. N Engl J Med. 2018;379(8):753-763. doi:10.1056/NEJMoa1802905
8. Litton JK, Scoggins ME, Hess KR, et al. Neoadjuvant talazoparib for patients with operable breast cancer with a germline BRCA pathogenic variant. J Clin Oncol. 2020;38(5):388-394. doi:10.1200/JCO.19.01304</sub>

_{9. Telli ML, Gradishar WJ. Updates in HER2-positive and triple-neg- ative breast cancers. JNCCN. 2021;19(5.5):605-609. doi:10.6004/ jnccn.2021.5005}

_{0. Cortes J, Cescon DW, Rugo HS, et al; KEYNOTE-355 Investigators. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or meta- static triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020;396(10265):1817-1828. doi:10.1016/S0140-6736(20)32531-9}