Breast Cancer Expert Focuses on Decoding Biomarkers

When a physician-scientist is closely identified with a particular landmark clinical trial, one might expect that study to top a personal list of meaningful accomplishments. For Kevin Kalinsky, MD, MS, director of breast medical oncology at the Winship Cancer Institute of Emory University in Atlanta, Georgia, who is best known for his work on the RxPONDER trial (NCT01272037), it serves as one of a few accomplishments for which he is grateful that have impacted clinical care. The study findings showed that postmenopausal women with low-risk hormone receptor–positive, node-positive, HER2-negative breast cancer who received endocrine therapy do not benefit from adjuvant chemotherapy.¹

Kalinsky also singles out his contributions to the development of sacituzumab govitecan-hziy (Trodelvy), a Trop-2–directed antibody-drug conjugate, calling that work “probably the most meaningful experience I’ve had as a clinical trialist and investigator.” He participated in the early-stage and pivotal trials that led to the agent's initial approval in patients with metastatic triple-negative breast cancer, including the phase 3 ASCENT trial (NCT02574455).^2,3

“What made it so meaningful was seeing in real time that patients who had not had much benefit from other treatments were getting real benefit from this drug that was reasonably well tolerated,” Kalinsky said.

In ASCENT, patients with relapsed or refractory metastatic triple-negative breast cancer were randomly assigned to receive either sacituzumab govitecan or physician’s choice of single-agent chemotherapy (eribulin [Halaven], vinorelbine, capecitabine, or gemcitabine). The median progression-free survival (PFS), the trial’s primary end point, was 5.6 months (95% CI, 4.3-6.3) with sacituzumab govitecan vs 1.7 months (95% CI, 1.5-2.6) in the chemotherapy group (HR, 0.41; 95% CI, 0.32-0.52; P < .001).²

Kalinsky’s response does not surprise Komal Jhaveri, MD, FACP, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York. “He absolutely is best known for RxPONDER, which changed our treatment paradigm for postmenopausal women with 1 to 3 positive nodes with an Oncotype DX score of less than 26,” she said. “But his scientific vigor to bring new treatments to patients and improve outcomes is matched by his passion and drive to deliver optimal care to all patients.”

That passion started early. “What drew many of us into oncology was seeing a loved one cope with cancer when we were young,” Kalinsky said, explaining that his grandfather died from small cell lung cancer when Kalinsky was 6 years old. “One aspect that made a huge impression on me was watching him seek the expertise of a specialist and the importance of that information to guide expectations and treatment options.”

Jane L. Meisel, MD, an associate professor at Winship Cancer Institute, sees that influence on Kalinsky to this day. “He’s been able to take some of the biggest questions that patients ask, turn them into research questions, and get them answered on a much larger level,” she said. “His work has both changed practice and the way we’re able to speak to patients with confidence on these issues.”

Kalinsky brings that dual focus on clinical care and scientific discovery to all his roles at Winship, where he serves as the Louisa and Rand Glenn Family Chair in Breast Cancer Research and director of the Glenn Family Breast Center. As a dedicated trialist, he has worked on increasing patient participation in phase 1 clinical studies. Kalinsky has served as coinvestigator, coprincipal, or primary investigator on research grants worth approximately $2.7 million in federal funding and $1.6 million in private foundation funding.

He also has mentored numerous junior faculty, fellows, and residents. His teaching roles include serving on the steering committee of the 40th Annual Miami Breast Cancer Conference^®. Physicians' Education Resource^®, LLC (PER^®) is hosting the 4-day event (March 2-5, 2023) as an in-person live conference in Miami Beach, Florida.

An Inside Look at RxPONDER

When Kalinsky sat down recently with OncologyLive^® to discuss trends in breast cancer therapeutics and reflect on progress made, RxPONDER seemed like a good place to start. He and his coauthors conceived the trial to try to definitively answer the question of whether the 21-gene Oncotype DX recurrence score (RS) could predict which patients with hormone receptor–positive, HER2-negative breast cancer would benefit from postoperative chemotherapy.

“One of the greatest unmet needs has been to determine who needs chemotherapy and who doesn’t, and we wanted to have patients be able to opt out of treatments that they don’t need,” he said.

RxPONDER grew out of an earlier trial, SWOG-8814 (NCT00929591), which had suggested that the RS could be used to predict which patients with node-positive breast cancer would benefit from having chemotherapy added to their endocrine therapy.⁴ This trial, which Kalinsky describes as “pivotal,” found that women with an RS of less than 18 saw no benefit from the addition of chemotherapy, whereas those with an RS of at least 31 lived longer if they had chemotherapy.

“What SWOG-8814 demonstrated was that there was a potential role for the RS to determine risk,” he said.

To meet the objective of determining the effect of chemotherapy on invasive disease–free survival (IDFS) and whether the RS influenced that effect, RxPONDER recruited 5083 women (33.2% premenopausal and 66.8% postmenopausal), of which 5018 participated in the trial. Participants with hormone receptor–positive, HER2-negative breast cancer; 1 to 3 positive axillary lymph nodes; and an RS of 25 or less were randomly assigned to endocrine therapy only or to chemotherapy followed by endocrine therapy.¹

In postmenopausal patients, the 5-year IDFS rates were 91.9% with endocrine therapy alone vs 91.3% with chemoendocrine therapy, a difference that was not statistically significant (HR, 1.02; 95% CI, 0.82-1.26; P = .89). In premenopausal patients, the 5-year IDFS rates were 89.0% for women who received endocrine therapy alone vs 93.9% for those on combined chemotherapy and endocrine therapy (HR, 0.60; 95% CI, 0.43-0.83; P = .002).¹

“This is a meaningful outcome for our patients,” Kalinsky said. “We’re now able to save thousands of patients the unnecessary toxicities and adverse effects and costs—both financial and quality of life—associated with chemotherapy.”

Most recently, Kalinsky’s coauthor, Yara Abdou, MD, an assistant professor at the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, presented data from a new analysis of RxPONDER at the 2022 San Antonio Breast Cancer Symposium in December. Abdou was Kalinsky's mentee in the American Society of Clinical Oncology's virtual mentoring program.

The findings showed that non-Hispanic Black patients with hormone receptor–positive, HER2-negative breast cancer were more likely to have worse outcomes than non-Hispanic White, Asian, and Hispanic patients (Figure⁵). The poorer outcomes were observed even with similar RS, Abdou noted.⁵

In a multivariable analysis that accounted for RS, treatment arm, menopausal status, age, and grade, non-Hispanic Black patients had a 37% higher risk of invasive cancer than non-Hispanic White patients. Further data showed that non-Hispanic Black patients had a distant relapse–free survival rate of 90.1% vs 94.7% for non-Hispanic White patients (HR, 1.39; 95% CI, 1.01-1.91; P = .004).⁵

Among RxPONDER’s 4048 evaluable patients, non-Hispanic White patients were the largest group at 70%. The remainder of patients were non-Hispanic Black (6.1%), Hispanic (15.1%), Asian (8.0%), or Native American or Pacific Islanders (0.8%). Recurrence scores were similar across all patient and racial subgroups, but non-Hispanic Black patients were more likely to present with high-grade tumors (18%) vs non-Hispanic White patients (10%).⁵

Abdou’s presentation garnered conversation behind the scenes in San Antonio—and not just because of the findings she shared. “A lot of the younger oncologists were commenting on how Kevin could have chosen to take the podium himself, but he made an explicit effort to mentor and guide a much younger female researcher to both lead that aspect of the trials analysis and then also present the data,” Meisel noted. “He’s so respectful and works hard to lift junior people up, which not every leader does.”

What About Premenopausal Women?

Although RxPONDER clarified clinical decision-making for postmenopausal patients, questions remain regarding premenopausal patients. Younger patients appear to benefit most from chemotherapy, but no one yet knows why that is. A new study, not yet open for accrual, aims to answer this question, Kalinsky said, explaining that ovarian function suppression might hold the key.

NRG Oncology is planning a phase 3 randomized trial, OFSET Chemo (NRGBR009). NRG-BR009 will add ovarian suppression to the familiar equation of endocrine therapy (aromatase inhibitor or tamoxifen) with or without accompanying chemotherapy in the adjuvant setting. The study will seek to recruit nearly 4000 premenopausal patients with hormone receptor–positive, HER2negative breast cancer with pN0 disease with an RS of 16 to 20 plus high clinical risk or an RS of 21 to 25 or with pN1 disease with an RS of 0 to 25. Patients will be stratified by age (> 40 or ≤ 40 years), nodal status (pN0 vs pN1), and RS (0-15 vs 16-25).⁶

“One of the limitations of all the genomic assay studies, including RxPONDER, is that less than 20% of patients underwent ovarian function suppression,” Kalinsky said. “Not all patients can tolerate it so it will be important to look at, in a genomically defined population, what the rate of adherence and tolerability is from ovarian function suppression.”

Revisiting TAILORx

TAILORx (NCT00310180) is another landmark trial that has helped clarify which patients with breast cancer can safely forgo chemotherapy.⁷ Among 9719 evaluable patients with hormone receptor–positive, HER2-negative, node-negative breast cancer, 6711 (69%) had a midrange RS of 11 to 25 and were randomly assigned to receive either chemoendocrine therapy or endocrine therapy alone. The primary outcome of this noninferiority trial was IDFS.

IDFS was very similar in both groups. Five years after treatment, the rate of IDFS among patients with an RS of 11 to 25 was 92.8% in the endocrine-only group and 93.1% for those who also had chemotherapy (HR, 1.08, 95% CI, 0.941.24; P = .26). At 9 years, the IDFS rate in this RS cohort was 83.3% for those who had endocrine therapy alone and 84.3% for those who had both therapies. None of these differences were considered statistically significant.^7,8

Thus, TAILORx was the first trial to prospectively establish that approximately 70% of women with hormone receptor–positive, HER2-negative, lymph node–negative breast cancer can safely skip chemotherapy. The finding applies to women who are older than 50 years at diagnosis with an RS of 11 to 25, any age with an RS of 0 to 10, or 50 years or younger with an RS of 11 to 15.⁸

At the 2022 San Antonio Breast Cancer Symposium, Joseph A. Sparano, MD, deputy director of the Tisch Cancer Institute at Mount Sinai Health System in New York, New York, and TAILORx lead author, presented an additional 3.5 years of recurrence and survival outcomes, for a total median follow-up of 11.0 years.⁹ Importantly, the main study findings remain unchanged: RS continues to be a reliable guide for patients with hormone receptor–positive, HER2-negative disease, Sparano said.¹⁰

Women with an RS of 0 to 25 who had received endocrine therapy alone had very low recurrence rates, at approximately 1% per year during the 12-year event period. However, more late recurrences occurred beyond 5 years than in the first 5 years. Distant recurrence rates remained low, and overall survival rates remained high for women with a score of 0 to 25 when treated with endocrine therapy alone. However, the rates of distant recurrence and IDFS diverged, suggesting the emergence of second primary cancers.¹⁰

Finally, distant recurrence rates remained higher for those with a score above 26 despite adding chemotherapy to endocrine therapy.¹⁰

Other Unmet Needs

The TAILORx updated recurrence data reinforce to Kalinsky the need to be able to prospectively identify patients who are likely to relapse. “One of the most commonly asked questions in clinic is, ‘How do I know this worked? And is there a blood test to tell us whether the cancer might come back?’ ” he said. “The tumor markers we have now are not terribly reliable, but we do have exciting new assays. So the technology is changing rapidly, and we need to figure out how to best use the blood tests.”

According to Kalinsky, exploring circulating markers, such as the use of circulating tumor DNA, may eventually help determine who may be at risk for late recurrence. “What’s going to have the greatest utility?” he mused. “Will it be these bespoke markers for minimal residual disease, meaning that you need the tumor tissue and then you look for specific alterations in the blood based upon what you see in the tissue, or can it be tissue agnostic?”

An RxPONDER substudy that might help answer this and other questions is ongoing. “If patients had not yet had a recurrence and were within 8 years from their randomization, we are collecting blood markers like circulating tumor cells or circulating tumor DNA just to see if we can f ind indicators for late recurrence,” Kalinsky said.

Unraveling the prognostication vs prediction issue is also a major unmet need in breast cancer overall, Kalinsky said. “One thing that’s still unclear is whether the blood-based biomarkers are purely prognostic, meaning simply that those patients who have presence of circulating cells are more likely to do worse. That’s what we’ve seen so far,” he said. “But can biomarkers be predictive? Maybe once we identify them, we could then change therapies to one of the new hormonal therapies, like an oral selective estrogen receptor downregulator, and change the biology of that cancer. That remains an interest as well, but we’re not there yet.”

MAINTAIN Trial

In addition to his interest in new strategies for early breast cancer, Kalinsky is exploring various aspects of metastatic disease. He was the principal investigator on the phase 2 MAINTAIN trial (NCT02632045), which evaluated subsequent therapy for patients with hormone receptor–positive, HER2-negative metastatic breast cancer with disease progression following treatment with endocrine therapy plus a CDK4/6 inhibitor.

Patients were randomly assigned to receive ribociclib (Kisqali), a CDK4/6 inhibitor, plus a different endocrine therapy or placebo plus a different endocrine therapy. Participants who previously received an aromatase inhibitor as endocrine therapy received fulvestrant (Faslodex) whereas those who had prior fulvestrant were treated with exemestane. Most participants had previously taken a different CDK4/6 inhibitor— palbociclib (Ibrance).¹¹

MAINTAIN investigators randomly assigned 119 patients to either treatment arm, with median PFS as the primary end point. After a median follow-up of 18.2 months, patients in the ribociclib arm (n = 60) had a median PFS of 5.29 months (95% CI, 3.02-8.12), compared with 2.76 months (95% CI, 2.66-3.25) in the placebo arm, a finding that favored the ribociclib regimen (HR, 0.57; 95% CI, 0.39-0.95; P = .006). At 6 months, the PFS rates were 41.2% and 23.9%, respectively, and at 12 months, they were 24.6% and 7.4%, respectively.¹¹

“CDK4/6 inhibitors have been such a game changer for our patients, so is there a role for just switching the endocrine therapy and continuing the CDK4/6 inhibitor when progression occurs?” Kalinsky asked. “MAINTAIN was the first randomized study to suggest that there was a benefit to doing ribociclib at the time of CDK4/6 inhibitor progression.”

Kalinsky serves as the study principal investigator for postMONARCH (NCT05169567), an ongoing phase 3 trial looking at fulvestrant with or without abemaciclib (Verzenio), a CDK4/6 inhibitor, in a post-CDK4/6 inhibitor population.

Meisel pointed out that many oncologists had been using such strategies even before the MAINTAIN findings were reported at the 2022 American Society of Clinical Oncology Annual Meeting in June. “But Kevin was the first to ask that question in a research setting and then showed a statistically significant benefit to adding ribociclib,” she said. “But every good trial, especially in the metastatic space, answers some questions and then raises others.”

In the case of MAINTAIN, Meisel noted that most study patients had received adjuvant palbociclib in the first line and that all had switched to ribociclib on the study. “So, was it switching to a CDK4/6 inhibitor that mattered, or do you have to switch to that specific CDK4/6 inhibitor?” she said. “Does it matter which CDK4/6 inhibitor you use?”

Although MAINTAIN was a positive trial, it’s also sobering that the results weren’t extremely meaningful clinically, Meisel noted. “The benefit was only a few months," she said, adding that "Kevin is the first to say there’s more work to do.”

References

1. Kalinsky K, Barlow WE, Gralow JR, et al. 21-gene assay to inform chemotherapy benefit in node-positive breast cancer. N Engl J Med. 2021;385(25):2336-2347. doi:10.1056/NEJMoa2108873
2. Bardia A, Hurvitz SA, Tolaney SM, et al; ASCENT Clinical Trial Investigators. Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med. 2021;384(16):1529-1541. doi:10.1056/NEJMoa2028485
3. FDA grants regular approval to sacituzumab govitecan for triple-negative breast cancer. FDA. Updated April 8, 2021. Accessed December 10, 2022. https://bit.ly/3WsEcON
4. Albain KS, Barlow WE, Shak S, et al; Breast Cancer Intergroup of North America. Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial. Lancet Oncol. 2010;11(1):55-65. doi:10.1016/S1470-2045(09)70314-6
5. Abdou Y, Barlow WE, Gralow JR, et al. Race and clinical outcomes in the RxPONDER trial (SWOG S1007): a clinical trial Rx for positive node, endocrine responsive breast cancer. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Accessed December 19, 2022. https://bit.ly/3Vl9CFq
6. Mamounas T. Report from the Breast Cancer Working Group Meeting. Presented at: NRG Oncology Summer Meeting; July 21-23, 2022; Chicago, IL. Accessed December 19, 2022. https://bit.ly/3WA3NVg
7. Sparano JA, Gray RJ, Makower DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018;379(2):111-121. doi:10.1056/NEJMoa1804710
8. TAILORx trial finds most women with early breast cancer do not benefit from chemotherapy. News release. National Cancer Institute. June 3, 2018. Accessed December 20, 2022. https://bit.ly/2J8DowK
9. Sparano JA, Gray RJ, Makower DF, et al; on behalf of the TAILORx Investigators. GS1-05 Trial Assigning Individualized Options for Treatment (TAILORx): an update including 12-year event rates. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Accessed December 20, 2022. https://bit.ly/3GPIlpp
10. The TAILORx trial in over 10,000 women with early breast cancer reaches 12 years of recurrence and survival outcomes. News release. ECOG-ACRIN Cancer Research Group. December 6, 2022. Accessed December 20, 2022. https://bit.ly/3Wo7CNs
11. Kalinsky K, Accordino MK, Chiuzan C, et al. A randomized, phase II trial of fulvestrant or exemestane with or without ribociclib after progression on anti-estrogen therapy plus cyclin-dependent kinase 4/6 inhibition (CDK 4/6i) in patients (pts) with unresectable or hormone receptor–positive (HR+), HER2-negative metastatic breast cancer (MBC): MAINTAIN trial. J Clin Oncol. 2022;40(suppl 17):LBA1004. doi:10.1200/JCO.2022.40.17_suppl.LBA1004