The “holy grail” of triple-negative breast cancer therapy has been effective incorporation of drugs to improve outcomes in the early nonmetastatic setting. Although outcomes have improved with better chemotherapy drugs and schedules, triple-negative breast cancer still carries the worst prognosis of all breast cancer subtypes. Of particular interest is the discovery of effective nonchemotherapy drugs.
“Practically speaking..., it is reasonable to consider a backbone of adjuvant pembrolizumab to be the standard at this point.”— Lisa A. Carey, MD, ScM, FASCO
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The recently published KEYNOTE-522 trial,1 summarized in this issue of The ASCO Post, demonstrated an improvement in event-free survival with the addition of the immune checkpoint inhibitor pembrolizumab to chemotherapy. We now for the first time have a nonchemotherapy component of curative-intent treatment of early triple-negative breast cancer that clearly improves outcomes.
Closer Look at KEYNOTE-522
In KEYNOTE-522, nearly 1,200 patients with untreated stage II to III triple-negative breast cancer were treated with neoadjuvant therapy including four cytotoxic agents—paclitaxel plus carboplatin followed by doxorubicin (or epirubicin) plus cyclophosphamide—with the addition of either the immune checkpoint inhibitor pembrolizumab or placebo. The immune checkpoint inhibitor (or placebo) was continued in the adjuvant setting according to the treatment arm regardless of treatment response. The trial had two primary endpoints—improvement in pathologic complete response and improvement in event-free survival.
The pathologic complete response endpoint has been previously reported and was recently updated with the final cleaned data from all participants (which can be reviewed at http://www.fda.gov/media/145654); they reveal a modest but significant improvement in pathologic complete response from 56% with chemotherapy alone to 63% with the addition of pembrolizumab during the chemotherapy phase. Pathologic complete response is a meaningful endpoint; earlier analyses suggest that the impact of the immune checkpoint inhibitor was greatest among patients with node-positive breast cancer in whom additional tumor eradication may facilitate breast conservation and avoidance of axillary node dissection.
With the additional data presented at a 2021 European Society for Medical Oncology (ESMO) Virtual Plenary and published in The New England Journal of Medicine,1 we now know that pembrolizumab given during the neoadjuvant chemotherapy phase and continued postoperatively to a total of 1 year also improves 3-year event-free survival by more than 7% (from 77%–84%), a substantial and highly significant improvement. Unlike the metastatic setting, in which immune checkpoint inhibitor benefit is restricted to PD-L1–positive tumors and/or microenvironment, the benefit in untreated stage II to III triple-negative breast cancer appears unrelated to PD-L1 status, although it should be noted that most early triple-negative breast cancer is PD-L1–positive. There were no clinical subsets that did not appear positively impacted by pembrolizumab.
Toxicity was greater in the immune checkpoint inhibitor–treated arm, with 28% of patients discontinuing at least one drug compared with 14% in the chemotherapy-alone arm. Serious treatment-related adverse events were greater in the immune checkpoint inhibitor–treated arm (34% vs 20%), mostly occurring during the neoadjuvant phase. Immune-related adverse events were common with the immune checkpoint inhibitor, seen in 33% overall (vs 11% in the placebo arm), with grade ≥ 3 events in 13% (vs 1%), and they led to drug discontinuation in 11% (vs 3%). These adverse events included fever, thyroid disorders, diarrhea/colitis, rash, adrenal insufficiency, hypophysitis, pneumonitis, and hepatitis. There were four treatment-related deaths in the immune checkpoint inhibitor arm (vs one in the placebo arm), with two of them due to immune-related adverse events.
For Those in Pathologic Complete Response: Is the Adjuvant Phase Beneficial?
A prespecified exploratory analysis by pathologic complete response status revealed that patients with pathologic complete response did well in both arms, with a 3-year event-free survival of 92.5% with chemotherapy alone and 94.4% with chemotherapy plus pembrolizumab. It should again be noted that approximately 7% more patients achieved pathologic complete response with the addition of pembrolizumab—but these findings do call into question the value of the adjuvant phase in those who achieved pathologic complete response.
This question is highlighted by the results of GeparNuevo, a small (n = 174) triple-negative breast cancer neoadjuvant trial randomizing the addition of durvalumab to chemotherapy for a similar neoadjuvant duration but without the adjuvant phase. This trial had pathologic complete response as the primary endpoint, and survival endpoints were secondary.
Although pathologic complete response was numerically augmented with the addition of the immune checkpoint inhibitor (44% vs 53%), the more striking finding was reported at the 2021 ASCO Annual Meeting by Dr. Sibylle Loibl,2 in which the 3-year invasive disease–free survival was augmented by 22 weeks of neoadjuvant durvalumab to a similar degree as seen with 1 year of pembrolizumab. Whether the adjuvant immune checkpoint inhibitor is needed in patients with a pathologic complete response will be tested in the upcoming Alliance NCI cooperative group trial (OptimICE-pCR).
Those patients with residual disease carry a substantially worse prognosis; the addition of pembrolizumab appeared also to improve outcomes in this subset, with a 3-year event-free survival that rose from 57% to 67% with pembrolizumab. This illustrates that the impact of immune checkpoint inhibition is not limited to augmenting tumor eradication (pathologic complete response); modifying the tumor microenvironment is beneficial, even in tumors with relative resistance to therapy. It also reminds us that triple-negative breast cancer with residual disease continues to represent an unmet need, with one-third of patients having relapse or another survival event within 3 years of diagnosis.
A Clinical Conundrum
Many clinical challenges remain, particularly in the high-risk residual disease setting. After the publication of the CREATE-X trial,3 treatment guidelines shifted to incorporate 6 months of capecitabine in triple-negative breast cancer with residual disease after chemotherapy. This predated the use of an immune checkpoint inhibitor, and capecitabine was not permitted in the KEYNOTE-522 trial. Similarly, in high-risk triple-negative breast cancer with germline BRCA1 or BRCA2 mutations, the OlympiA trial,4 in which more than 80% of the trial population had triple-negative breast cancer, demonstrated an approximately 9% improvement in 3-year invasive disease–free survival with olaparib vs placebo, similar in scope to the improvement in outcomes with pembrolizumab.
This creates a clinical conundrum, since all these residual disease interventions (capecitabine, olaparib, pembrolizumab) were studied exclusive of the others. Practically speaking, given the poor outcomes in residual disease and that pembrolizumab augments pathologic complete response and outcome regardless of pathologic response to therapy, it is reasonable to consider a backbone of adjuvant pembrolizumab to be the standard at this point.
Regarding what to do in residual disease, there are safety data for both capecitabine and olaparib added to pembrolizumab. In wild-type BRCA1/2, adding capecitabine to pembrolizumab is reasonable, particularly with a high residual disease tumor burden. In the metastatic setting, olaparib outperforms capecitabine in both efficacy and toxicity; for this reason, in germline BRCA1/2 carriers with high-risk residual disease, olaparib added to pembrolizumab can be considered and is preferred over capecitabine. However, we should all be clear that the decision to include other drugs (capecitabine, olaparib) with or after pembrolizumab is currently without clinical data to support it.
It should also be noted that KEYNOTE-522 did not include patients with T1N0 tumors, nor patients with active autoimmune disease requiring treatment (not including hormone replacement—eg, thyroid) in the previous 2 years. These patients should not receive an immune checkpoint inhibitor. The four-drug chemotherapy backbone used in KEYNOTE-522 can be arduous; it is unclear whether a more tailored chemotherapy approach will result in similar outcomes, which should be studied further. With these caveats in mind, the KEYNOTE-522 regimen is the new standard of care for most newly diagnosed patients with triple-negative breast cancer.
Dr. Carey is the Richardson and Marilyn Jacobs Preyer Distinguished Professor in Breast Cancer Research and Deputy Director of Clinical Sciences at the University of North Carolina-Chapel Hill and Lineberger Comprehensive Cancer Center.
DISCLOSURE: Dr. Carey has received institutional research funding from Syndax, Novartis, NanoString Technologies, AbbVie, Seattle Genetics, and Veracyte; has a family member who has a relationship with Falcon Therapeutics; and has uncompensated relationships with Sanofi, Novartis, G1 Therapeutics, Genentech/Roche, GSK, AstraZeneca/Daiichi Sankyo, Aptitude Health, Exact Sciences, and Eisai.
REFERENCES
1. Schmid P, Cortes J, Dent R, et al: Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med 386:556-567, 2022.
2. Loibl S, Schneeweiss A, Bodo Huober J, et al: Durvalumab improves long-term outcome in TNBC. 2021 ASCO Annual Meeting. Abstract 506.
3. Masuda N, Lee SJ, Ohtani S, et al: Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med 376:2147-2159, 2017.
4. Tutt ANJ, Garber JE, Kaufman B, et al: Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer. N Engl J Med 384:2394-2405, 2021.
