Cancer treatment is undergoing a reformation because of novel therapeutics that provide dramatic responses, including complete radiographic or pathologic remission. However, minimal residual disease (MRD) is often retained, resulting in relapse. Early evidence indicates that iterative detection, profiling, and targeting of MRD could improve outcomes and even lead to a cure.

Complete remission (CR) generally requires more than 99% reduction in tumor burden, and remaining tumor cells have been referred to as MRD. Treating a patient when only MRD is present is preferable to waiting for clinical relapse because the smaller number of tumor cells in MRD increases the chance of eradication of all tumor cells and is associated with a lower likelihood of the following cancer-promoting factors: resistance due to clonal complexity, microenvironment remodeling, reprogramming of infiltrative hematopoietic cells, and development of chemoprotective niches. As a result, certain drugs may have greater efficacy against MRD than against the same cancer at the time of relapse. Additionally, patients may tolerate drugs better when only MRD is present.

Tailoring consolidation therapy based on MRD load is already standard practice for the treatment of children with acute lymphoblastic leukemia (ALL). If such a patient tests positive for MRD (exceeding a defined threshold), this can suggest a change in doses but does not yet guide the selection of therapies targeted specifically at eradicating MRD. Looking ahead, precise targeting of MRD through genetic, transcriptional, functional, and other predictive biomarkers is the next step toward improving outcomes for patients.

“MRD results correlate with PFS [progression-free survival], so it is prognostic for how patients do with finite-duration treatment. [Patients] get a course of treatment, they [achieve] remission, and [when] they come off treatment, their MRD status clearly correlates with PFS and overall survival [OS]. [This has] given us a prognostic tool for outcomes for our patients with fixed-duration treatment,” 

, professor, section chief of chronic lymphocytic leukemia (CLL) and executive medical director at The University of Texas MD Anderson Cancer Center, stated in an interview with 

MRD assessment does have limitations, such as reliance on measuring disease within bone marrow without taking into account the bone marrow microenvironment, lack of uniform bone marrow involvement, and the possibility of extramedullary disease.

 The clearest limitation is the need to perform a bone marrow aspirate for MRD assessment. This has led to interest in liquid biopsy or analyzing circulating cell-free tumor DNA (ctDNA) in the peripheral blood for MRD. However, using optimal methodologies for bone marrow to test on peripheral blood may result in lower sensitivity.

 In a multiple myeloma (MM) study, approximately 40% of patients with MRD-positive bone marrow were deemed MRD negative when ctDNA was assessed with a deep sequencing technique designed for bone marrow samples.4 Because of this, other ctDNA assays are under development, including targeted mutation detection and low-pass whole-genome sequencing.

The clinical application of MRD testing is variable. There are no prospective, randomized data to guide treatment decisions. Recent studies incorporating the use of MRD hope to shed more light on how MRD can help guide therapeutic decisions, and several studies were presented at the recent 2021 American Society of Hematology (ASH) Annual Meeting.

A recent study incorporating MRD by nextgeneration sequencing with the combination of daratumumab (Darzalex), carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (Dara-KRd) revealed MRD response–adapted consolidation therapy leads to the highest rate of MRD negativity reported in patients with newly diagnosed MM (NDMM). A total of 123 patients with NDMM were enrolled in the phase 2 MASTER trial (NCT03224507), 53 (43%) patients had no high-risk cytogenetic abnormalities (HRCAs), 46 (37%) had 1, and 24 (20%) had 2 or more HRCAs. Patients received 4 cycles of Dara-KRd as induction therapy, autologous hematopoietic cell transplantation (AHCT), and 0, 4, or 8 cycles of Dara-KRd as consolidation therapy, according to MRD status. The primary end point was MRD negativity below 10-5, and patients continued therapy until 2 consecutive MRD assessments of less than 10-5, at which point patients entered treatment-free observation (TFO) and MRD surveillance.

At a median follow-up of 25.1 months, disease was trackable by MRD in 118 (95.9%) patients, with 4 (3.2%) remaining on protocol treatment, 20 (16.3%) on maintenance lenalidomide, and 84 (71.2%) reaching confirmed MRD negativity and entering treatment-free MRD surveillance. The depth of response improved with each phase of therapy, and similar responses were observed in patients with 0, 1, or 2 or more HRCA abnormalities assessed post-AHCT and with MRD-guided consolidation. Overall, 80% reached MRD negativity at 10-5 and 66% achieved MRD levels below 10-6 by the consolidation phase. Rates of MRD negativity below 10-5 were similar per HRCAs. Best response post MRD-adapted consolidation was CR or stringent CR (sCR) in 86% of patients. The 2-year PFS rate was 87% and the OS rate was 94%. Cumulative incidence of MRD resurgence or International Myeloma Working Group progression 12 months after cessation of therapy was 4%, 0%, and 27% for patients with 0, 1, or 2 or more HRCA abnormalities, respectively. This strategy suggests MRD surveillance could be an alternative to indefinite maintenance, although patients with ultra-high–risk MM will likely need novel consolidative strategies.

Ibrutinib, Ublituximab, and Umbralisib in CLL 

High overall response rates and durable responses have been observed in patients with CLL treated with time-limited novel agent combinations, but high rates of adverse events occur. Additionally, patients on chronic ibrutinib monotherapy have a risk of developing cumulative toxicity and acquired resistance.

In a recent phase 2 study (NCT04016805), patients with CLL treated with a combination of ibrutinib (a Bruton tyrosine kinase [BTK] inhibitor; Imbruvica), umbralisib (a PI3K inhibitor; Ukoniq), and ublituximab (an anti-CD20 monoclonal antibody) achieved deep remissions and a tailored, time-limited therapy and sustained TFO using an MRD-driven approach. Patients with CLL with detectable MRD were treated with monotherapy ibrutinib, then umbralisib and ublituximab. The open-label study enrolled patients with CLL already taking ibrutinib for a minimum duration of 6 months, with detectable residual CLL in the peripheral blood via MRD assay. Umbralisib and ublituximab were added, and patients were serially monitored for MRD starting on day 1 of cycle 3. Patients entered a period of TFO once undetectable MRD (uMRD) was achieved and confirmed 4 weeks later. If uMRD was not attained, patients completed 24 cycles followed by TFO.

Ublituximab and umbralisib were added for 26 patients receiving ibrutinib. MRD was assessed in 24 patients, with 17 (71%) having uMRD in at least 1 assessment. A total of 16 patients (67%), 15 achieving 2 consecutive uMRD assessments and 1 completing 24 cycles with detectable MRD, entered TFO. A median of 242 days (range, 5-538) of TFO was achieved as of the cutoff date and 73% remain uMRD as of the most recent follow-up. The median time to first uMRD was 7.4 months (95% CI, 4.6-10.2). No patient has progressed or required retreatment per International Workshop on Chronic Lymphocytic Leukemia criteria. In the study, the use of MRD assessment appeared promising in helping reduce continued exposure to medications preventing possible resistance and increased adverse events.

Results from the phase 2 CAPTIVATE trial (NCT02910583) further support the use of MRD for achieving treatment-free remission with fixed-duration treatment. CAPTIVATE evaluated the use of ibrutinib in combination with venetoclax (Venclexta), an oral BCL-2 inhibitor. First-line ibrutinib and venetoclax were evaluated in fixed duration and MRD cohorts. Patients first received 3 cycles of ibrutinib followed by ibrutinib and venetoclax for 12 cycles. Then patients with uMRD for at least 2 assessments spaced at least 3 months apart in both the peripheral blood and bone marrow were randomized 1:1 to receive double-blind treatment with placebo or single-agent ibrutinib. Those not achieving uMRD were randomized 1:1 to receive single-agent ibrutinib or ibrutinib in combination with venetoclax.

After 12 cycles of ibrutinib and venetoclax, 149 patients were randomized; 86 patients with confirmed uMRD were randomized equally to placebo and ibrutinib; 63 patients without confirmed uMRD were randomized to ibrutinib (n = 31) or ibrutinib plus venetoclax (n = 32). Post randomization 2-year disease-free survival rates in patients who achieved confirmed uMRD were 95.3% for patients receiving placebo and 100% for patients receiving ibrutinib (log-rank 

 = .1573). These results were consistent in patients deemed high risk, including those with unmutated IGHV, del(17p)/

 mutation, complex karyotype, and del(11q) without del(17p). In those with not confirmed uMRD, 36-month PFS rates were 96.7% with ibrutinib monotherapy and with ibrutinib plus venetoclax. These results are promising for an all-oral, once-daily, chemotherapy-free regimen and support high efficacy with an MRD-based approach.

“In our program, most of us are thinking about fixed-duration treatment as an avenue to developing curative therapy,” Wierda said. “This is a large, international, multicenter trial [that] demonstrates the feasibility and activity of a combination of targeted therapy and of chemotherapy-free treatment.”

As a surrogate marker for survival, MRD is increasingly employed as an end point in clinical trials because of the improved PFS and OS results associated with MRD negativity. Patients who achieve uMRD at a more stringent threshold (10-6 vs 10-5) have better outcomes (longer PFS).9,10 Questions remain regarding MRD and its relationship to high risks associated with unfavorable cytogenetic abnormalities. Achievement of uMRD by high-risk patients is less frequent than for standard patients, although highrisk patients who achieve uMRD appear to have survival rates similar to those of standard-risk patients.

In one study, time to progression (TTP) was similar for uMRD patients regardless of fluorescence in situ hybridization (FISH) status, whereas FISH status still impacted TTP for MRDpositive patients (median TTP, 15 months for standard-risk patients vs 12 months for highrisk patients; 

The use of MRD status to decide between autologous stem cell transplant treatment (ASCT) or nontransplant-based treatment is one area of interest. ASCT provides a PFS advantage for many patients, although inconsistent OS results have been reported. In the IFM 2009 trial (NCT01191060) evaluating the addition of ASCT to treatment with bortezomib (Velcade), lenalidomide, and dexamethasone (VRd) in patients with NDMM, MRD status had a greater effect on outcome (PFS) than did treatment group. MRD-negative patients did better than MRD-positive ones.9 Data from several recent studies evaluating Dara-KRd and ASCT indicate patients who are able to achieve MRD negativity with induction therapy may not need ASCT.

The need for maintenance therapy in MRD-negative patients after induction therapy and ASCT is also of interest. In one trial, best PFS rates for patients with MM was associated with lenalidomide maintenance despite MRD-negative status.

The current data are insufficient to recommend that patients who achieve uMRD either before or during maintenance should forego or discontinue maintenance therapy, respectively. Ongoing clinical trials, such as EMN17Perseus (NCT03710603) and SWOG S1803 (NCT04071457), hope to address this question.

The predictive value of MRD status for relapse is another area of interest. MRD-negative patients can become MRD positive over time. One study indicated MRD reappearance from previous uMRD occurred 9 months before clinical relapse,

 although 30% of MRD-positive patients in the same study did not experience relapse.

These data encourage further trials evaluating serial monitoring of MRD and its potential for relapse prediction.

MRD-positive status indicating a need for treatment change is another question.11 A recent phase 1/2 study (NCT02937571) for patients with NDMM used an MRD-guided approach to therapy. Patients received cycles of KRd. Patients who achieved MRD-negative status received 2 cycles from conversion time, then ceased further therapy, whereas patients not achieving MRD-negative status continued a full 12 cycles of therapy. An average of 8 cycles (range 2-12) was needed to achieve MRD-negative status. PFS was similar between MRD-negative and MRD-positive groups, but follow-up was short overall and lack of consistency in post trial therapies was a concern. MRD-negative status was achieved by 5 of 7 high-risk patients but durability was only observed in 2.

The MRD response–adapted approach produced 36-month PFS rates at 77% (95% CI, 60%-97%) for combined dosing cohorts. Median PFS was not reached, and approximately 85% remained in CR/sCR and/or MRD negative at the post-12–month MRD follow-up. Further studies are needed to validate the MRD response–adapted approach and sustainability for clinical practice.

Wierda said there are 2 main strategies for targeted therapy: One is continuous treatment with a maintenance therapy, and the other is a fixed-duration or finite-duration treatment to achieve deep remission with undetectable MRD status.

"We need to develop strategies and clinical trials that utilize MRD status to direct treatment. That may be directing treatment in terms of duration or switching treatment if we have not achieved an MRD undetectable status at a time point we feel is necessary. Moving forward, I look forward to using MRD to direct therapy in our patients with CLL, and ultimately, as a tool to help develop curative therapies for our patients,” he said.

1. Luskin MR, Murakami MA, Manalis SR, Weinstock DM. Targeting minimal residual disease: a path to cure? Nat Rev Cancer. 2018;18(4):255-263. doi:10.1038/nrc.2017.125 

2. Yee AJ, Raje N. Minimal residual disease in multiple myeloma: why, when, where. Hematology Am Soc Hematol Educ Program. 2021;2021(1):37-45. doi:10.1182/hematology.2021000230 

3. Sanoja-Flores L, Flores-Montero J, Puig N, et al. Blood monitoring of circulating tumor plasma cells by next generation flow in multiple myeloma after therapy. Blood. 2019;134(24):2218-2222. doi:10.1182/ blood.2019002610 

4. Mazzotti C, Buisson L, Maheo S, et al. Myeloma MRD by deep sequencing from circulating tumor DNA does not correlate with results obtained in the bone marrow. Blood Adv. 2018;2(21):2811-2813. doi:10.1182/bloodadvances.2018025197 

5. Costa LJ, Chhabra S, Callander NS, et al. Daratumumab, carfilzomib, lenalidomide and dexamethasone (Dara-KRd), autologous transplantation and MRD response-adapted consolidation and treatment cessation. final primary endpoint analysis of the Master trial. Presented at: American Society of Hematology Annual Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract 481. https://bit.ly/3KhRkAD 

6. Costa LJ, Chhabra S, Medvedova E, et al. Daratumumab, carfilzomib, lenalidomide, and dexamethasone with minimal residual disease response-adapted therapy in newly diagnosed multiple myeloma. J Clin Oncol. doi:10.1200/JCO.21.01935 

7. Roeker LE, Leslie LA, Soumerai JD, et al. A phase 2 study evaluating the addition of ublituximab and umbralisib (U2) to ibrutinib in patients with chronic lymphocytic leukemia (CLL): a minimal residual disease (MRD)-driven, time-limited approach. Presented at: American Society of Hematology Annual Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract 395. https://bit.ly/3qkhqL1

8. Ghia P, Allan JN, Siddiqi T, et al. First-line treatment with ibrutinib (Ibr) plus venetoclax (Ven) for chronic lymphocytic leukemia (CLL): 2-year post-randomization disease-free survival (DFS) results from the minimal residual disease (MRD) cohort of the phase 2 Captivate study. Presented at: American Society for Hematology Annual Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract 68. https://bit.ly/3GmkR9G 

9. Perrot A, Lauwers-Cances V, Corre J, et al. Minimal residual disease negativity using deep sequencing is a major prognostic factor in multiple myeloma. Blood. 2018;132(23):2456-2464. doi:10.1182/ blood-2018-06-858613 

10. Paiva B, Puig N, Cedena MT, et al. Measurable residual disease by next-generation flow cytometry in multiple myeloma. J Clin Oncol. 2020;38(8):784-792. doi:10.1200/jco.19.01231 

11. Mina R, Oliva S, Boccadoro M. Minimal residual disease in multiple myeloma: state of the art and future perspectives. J Clin Med. 2020;9(7):2142. doi:10.3390/jcm9072142 

12. Oliva S, Gambella M, Gilestro M, et al. Minimal residual disease after transplantation or lenalidomide-based consolidation in myeloma patients: a prospective analysis. Oncotarget. 2017;8(4):5924-5935. doi:10.18632/oncotarget.12641 13. Korde N, Mastey D, Tavitian E, et al. Tailored treatment to MRD response: a phase I/II study for newly diagnosed multiple myeloma patients using high dose twice-weekly carfilzomib (45 and 56mg/m2 ) in combination with lenalidomide and dexamethasone. Am J Hematol. 2021;96(6):E193-E196. doi:10.1002/ajh.26150

Articles

Clinical Articles

Early evidence indicates that iterative detection, profiling, and targeting of minimal residual disease could improve outcomes and even lead to a cure.

Targeting MRD as a Potential Therapy Guide in Hematologic Malignancies

Many patients with hormone receptor-positive/ HER2-negative metastatic breast cancer (mBC) develop resistance during endocrine therapy (ET) or relapse afterward because of various mechanisms, including mutations in ESR1 (estrogen receptor 1, which encodes 1 of the 2 main types of estrogen receptors [ER]; 

). Most tumors remain dependent on ER signaling, and patients with disease progression may be responsive to second- or third-line ET.

Research is ongoing to combat these resistance mechanisms, with new data recently presented by Sara A. Hurvitz, MD, FACP, and other oncologists and investigators during the 2021 San Antonio Breast Cancer Symposium (SABCS), held December 7-10, 2021. Results from several studies are promising and indicate that more effective therapeutic strategies are on the horizon.

“The development of resistance to endocrine-based therapy is the greatest challenge for hormone receptor–positive/HER2-negative breast cancer today,” said Hurvitz, an associate professor at the David Geffen School of Medicine, University of California, Los Angeles (UCLA) and director of the Breast Cancer Clinical Trials Program and Jonsson Comprehensive Cancer Center Clinical Research Unit at the UCLA Medical Center in Santa Monica, in an email with 

“Better therapies [are needed] for breast cancers resistant to endocrine therapy combined with a CDK4/6 inhibitor,” said Rachel M. Layman, MD, associate professor at The University of Texas MD Anderson Cancer Center in Houston, in a separate email with 

™. “Endocrine therapy alone in this patient population has limited efficacy,” Layman added.

A mainstay for the management of hormone receptor-positive/HER2-negative metastatic breast cancer (mBC) is ET, typically with an aromatase inhibitor or fulvestrant (Faslodex) plus a CDK4/6 inhibitor (CDK4/6i).¹ ET targets ER activity and/or estrogen synthesis. CDK4/6i therapies cause cell cycle arrest and decreased expression of the proliferation biomarker Ki67 when used in conjunction with aromatase inhibitors such as anastrozole (Arimidex).²

Elacestrant Improves Outcomes vs Standard of Care 

Elacestrant is considered an oral selective estrogen receptor degrader (SERD) that displays a statistically significant clinical benefit over standard-of-care therapy (SOC) in ER-positive/HER2- negative mBC in the second- or third-line setting, including tumors harboring mESR1, according to results from the phase 3, open-label EMERALD trial (NCT03778931; 

 on page 14). Enrolled patients were postmenopausal with ER-positive/ HER2-negative mBC who had previously received 1 to 2 lines of ET and less than 1 line of chemotherapy and had progression on ET plus CDK4/6i. A total of 477 patients were randomized 1:1 to receive elacestrant (400 mg orally daily) or SOC (investigator’s choice of fulvestrant or an aromatase inhibitor). The 2 primary end points were progression-free survival (PFS), by blinded independent review committee, in patients with tumors harboring mESR1 and in all patients.

The risk of progression or death was reduced by 30% in all patients receiving elacestrant (HR, 0.697; 95% CI, 0.552-0.88; 

 = .0018) and by 45% in patients with mESR1 (HR, 0.546; 95% CI, 0.387- 0.786; 

 = .0005). The 12-month PFS rate was 22.32% (95% CI, 15.24%-29.4%) with elacestrant vs 9.42% (95% CI, 4.02%-14.81%) with SOC in all patients; the corresponding values in the mESR1 subgroup were 26.7% (95% CI, 16.17%-37.36%) vs 8.19% (95% CI, 1.26%-15.12%). An interim overall survival (OS) analysis demonstrated favorable outcomes for elacestrant compared with SOC, but results of the final OS analysis are not expected until 2023. Treatment-related adverse events (TRAEs) that were common (>10%) for patients treated with elacestrant vs SOC were mostly mild (grade 1 or 2) and included nausea (25.3% vs 8.7%), vomiting (11% vs 2.6%), and fatigue (11% vs 7.9%). Rates of grade 3 or greater AEs were 7.2% vs 3.1% for elacestrant vs SOC, respectively, and AEs leading to discontinuation were uncommon in both groups (6.3% vs 4.4%).

The investigators reported that overall, elacestrant was well tolerated with a predictable and manageable safety profile consistent with other endocrine therapies. These results indicate that elacestrant has the potential to become the new SOC for patients with ER-positive/HER2-negative mBC. A phase 2 trial is planned to determine the impact of combining elacestrant with the CDK4/6 inhibitor abemaciclib (Verzenio) on brain metastases due to ER-positive/HER2-negative breast cancer (NCT04791384).

Neoadjuvant Giredestrant (GDC-9545) Improves Response vs Anastrozole 

Results from an ongoing phase 2 trial (coopERA Breast Cancer, NCT04436744) indicate superior response to giredestrant vs anastrozole for patients with early ER-positive/HER2-negative BC. Giredestrant is a highly potent oral SERD with promising antitumor activity in mBC both as monotherapy and in combination with palbociclib (Ibrance). Patients in the coopERA Breast Cancer trial have measurable cT1c (≥ 1.5 cm)-cT4a-c ER-positive/HER2-negative, untreated, early BC and a baseline Ki67 score of 5% or more. Patients were randomized 1:1 to receive oral anastrozole (1 mg daily) or oral giredestrant (30 mg daily) for 14 days (neoadjuvant window-of-opportunity phase), followed by 16 weeks of the same daily regimen plus 125 mg oral palbociclib on days 1 to 21 of 28-day cycles (4 cycles total; neoadjuvant phase), and then surgery. The primary end point is centrally assessed geometric mean relative Ki67 score change from baseline to week 2, during the window-of-opportunity phase. This change reflects the degree to which an ET suppresses tumor cell proliferation and is a surrogate marker for clinical outcomes. Secondary end points include complete cell cycle arrest (CCCA), defined as a Ki67 score of 2.7% or less at week 2.

Interim analysis results included 83 of the planned 202 patients. The relative reduction in the Ki67 geometric mean at 2 weeks was 80% (95% CI, –85% to –72%) with giredestrant vs 67% (95% CI, –75% to –56%; 

 =.0222) with anastrozole. Patients with baseline Ki67 scores of 20% or higher experienced a greater reduction with giredestrant (83%) vs anastrozole (71%), as did patients with baseline Ki67 scores less than 20% (65% giredestrant vs 24% anastrozole). AEs were less common among patients taking giredestrant (28%) vs anastrozole (38%), with no grade 3 or greater AEs or serious AEs (SAEs) related to giredestrant.

 At the end of the primary analysis, giredestrant had a significantly greater mean Ki67 reduction of 75% (95% CI, –80% to –70%) vs 67% for anastrozole (95% CI, –73% to –59%;

 =.0433). The CCCA rate was 19.6% with giredestrant vs 12.8% with anastrozole (95% CI, –4.25 to 17.97), suggesting that giredestrant was better at suppressing tumor cell proliferation than anastrozole. Results of the final analysis, including overall response rates (ORRs) and combination data with palbociclib, are expected in 2022.

“This is the first clinical trial to report a comparison between an aromatase inhibitor and an oral SERD, and it met its primary end point,” said Hurvitz. “This provides proof-of-concept data, supporting the ongoing larger phase 3 trials of giredestrant in the adjuvant setting [lidERA; NCT04961996] and [in the] metastatic setting [Persevera; NCT04546009], where clinical outcomes, not change in Ki67, will be compared between giredestrant and standard endocrine therapy.”

Giredestrant Shows Promising Activity in Advanced/Metastatic Breast Cancer 

Results from the phase 1a/b GO39932 study (NCT03332797) show encouraging clinical activity of giredestrant, either as a single agent or in combination with palbociclib, in patients with locally advanced or metastatic breast cancer. Updated results of activity and biomarker analyses were presented at 2021 SABCS. Eligible patients were postmenopausal, had received up to 2 prior therapies, had experienced disease recurrence or progression while on adjuvant ET for at least 24 months, and had exhibited tumor response or stable disease for at least 6 months. One group of patients received monotherapy (30 mg oral giredestrant daily), and another received combination therapy (100 mg giredestrant plus 125 mg palbociclib, administered on a 21-days on/7- days off schedule). Treatment effects on ER signaling and tumor cell proliferation were assessed in paired pre- and on-treatment tumor biopsies using immunohistochemistry to determine biomarker protein levels of ER, progesterone receptor (PgR), and Ki67. To examine ER pathway activity, the gene expression of a predefined set of 38 ER target genes was analyzed using the Illumina TruSeq RNA Access kit. Pre- and on-treatment plasma samples were also examined for 22 mutations across the 

 genes in circulating tumor DNA (ctDNA) using a digital polymerase chain reaction assay.

For patients with measurable disease at baseline, the ORRs in patients with measurable disease at baseline were 27% in the 30 mg giredestrant group (8/30 patients) and 48% in the 100 mg giredestrant plus palbociclib, with or without luteinizing hormone-releasing hormone, combination group (21/44). Clinical benefit rates were 54% (22/41 patients) and 81% (39/48), respectively. Paired biopsy analyses revealed consistent treatment-associated downregulation of ER, PgR, and Ki67 protein levels, as well as of ER pathway activity, regardless of clinical benefit or baseline mESR1. These biomarker results support consistent biological activity of giredestrant and generally consistent decreases in 

 ctDNA levels. Even stronger suppression of ER, PgR, and Ki67 levels was observed with the addition of palbociclib to giredestrant. Of 36 patients with 

 ctDNA mutations detected at baseline, 34 had decreased 

 ctDNA levels at the beginning of cycle 2, and 27 patients’ levels ultimately became undetectable. Early changes in ctDNA levels of 

, but not ESR1, were correlated with response. These GO39932 trial results will encourage further investigation into the use of giredestrant in mBC.

Samuraciclib Shows Promise for Heavily Pretreated Patients 

The CDK7 inhibitor samuraciclib, given in combination with fulvestrant, demonstrated antitumor activity and a tolerable safety profile for patients with advanced ER-positive BC who had progressed on previous CDK4/6i treatments, according to results from a phase 2 modular study (NCT03363893). Samuraciclib is a once-daily, oral, small-molecule, selective inhibitor of CDK7. The trial enrolled a total of 31 patients with confirmed locally advanced or metastatic ER-positive/HER2-negative BC who had prior CDK4/6i treatment, 1 or fewer lines of chemotherapy, and 2 or fewer lines of ET with no previous fulvestrant exposure.

Tumor shrinkage was observed in 72% (18/25) of evaluable patients. Stratification of patients according to TP53 status showed that the 19 patients (76%) with wild-type TP53 displayed a median PFS of 32 weeks compared with 7.9 weeks for the 6 patients with mutant TP53 (HR, 0.17; 95% CI, 0.05-0.53; 

 =.0008). The CBR at 24 weeks was 36% overall, 55% in patients without liver metastases, and 53% in patients with wild-type TP53. Liver metastasis at baseline, a known risk factor for poor prognosis, negatively impacted median PFS, which was not reached in the 17 patients without liver metastasis and was 11.9 weeks in the 14 patients with liver metastasis (HR, 0.16; 95% CI, 0.05-0.59; 

 =.0021). The predictive value of liver metastasis on samuraciclib therapy will be evaluated in future studies. The most common AEs were reversible, low-grade gastrointestinal events, including diarrhea (90%), nausea (81%), vomiting (74%), and fatigue (36%). Grade 3 or higher AEs were uncommon and included diarrhea (19%) and nausea (10%; TABLE 15 ).

Samuraciclib has been granted fast track designation by the FDA for treatment of HR-positive, HER2-negative advanced BC and locally advanced or metastatic triple-negative breast cancer (TNBC).

Datopotamab Deruxtecan Promising for Triple-Negative Breast Cancer 

Datopotamab deruxtecan (Dato-DXd) demonstrated promising antitumor activity with a manageable safety profile in patients with previously treated advanced or metastatic TNBC, according to results from the phase 1 TROPION-PanTumor01 study (NCT03401385). Datopotamab deruxtecan is an antibody-drug conjugate (ADC) consisting of a humanized anti-TROP2 IgG1 monoclonal antibody linked to a topoisomerase I inhibitor. A total of 44 patients were included in the TNBC cohort. Based on dose-escalation studies in the non–small cell lung cancer cohort, a dose of 6 mg/kg intravenously every 3 weeks was recommended; however, 2 patients with TNBC received 8 mg/kg prior to this dose selection.

Many patients were heavily pretreated, with 68% having received 2 or more prior lines of therapy. The ORR among 38 evaluable patients was 34% (14 patients with confirmed complete [CR] or partial response [PR] and 1 patient with confirmation pending). Stable disease was observed in 17 patients (39%), 2 patients (5%) were not evaluable, and 8 patients (18%) had progressive disease. For patients who had not received prior treatment with a topo I inhibitor– based ADC (n=27), the ORR was 52% at a median follow-up of 8.8 months. This included 13 patients (48%) with confirmed CR or PR, 1 patient (4%) with confirmation pending, 9 patients (33%) with SD, 1 patient (4%) who was not evaluable, and 4 patients (15%) with progressive disease. Treatment-emergent AEs (TEAEs) occurred in 98% of patients, with 45% being grade 3 or higher, and 23% of patients experienced grade 3 or higher TEAEs.

The HER2-negative cohort of TROPION-PanTumor01 is fully enrolled, and data are forthcoming. The phase 1b/2 BEGONIA trial (NCT03742102) is also underway; it is evaluating datopotamab deruxtecan in combination with durvalumab (Imfinzi) as a first-line treatment for patients with metastatic TNBC. The phase 3 TRIOPION-Breast01 trial is evaluating datopotamab deruxtecan in HR-positive/HER2-negative breast cancer, and a phase 3 trial in patients with TNBC is being planned.

Results in Combination With Eribulin Results from the international, phase 3 FORTRESS trial (NCT03786094) indicate that the combination of balixafortide and the microtubule inhibitor eribulin (Halaven) has no advantage over eribulin alone for treating patients with HER2-negative mBC. Balixafortide is a synthetic peptide and a potent selective CXCR4 antagonist. The phase 1 FORTRESS trial (NCT01837095) evaluating balixafortide combined with eribulin in patients with HER2-negative mBC provided promising efficacy and safety data. Patients had HER2-negative, locally advanced or metastatic BC and had received 1 to 4 lines of chemotherapy in the advanced setting. A total of 432 patients were enrolled, 348 of whom were treated in the third-line setting.

Median PFS was not improved by the addition of balixafortide to eribulin (3.5 months vs 4.0 months for eribulin monotherapy; HR, 1.07; 96% CI, 0.81-1.41), nor was interim median OS (11.0 months vs 11.2 months; HR, 1.08; 99.9% CI, 0.66-1.77). Similarities between the arms were also observed in the safety population regarding serious TEAEs (28% vs 26.5%), TEAEs leading to death (6.9% vs 6.4%), and TEAEs of grade 3 or higher (68.3% vs 64.2%).

Gedatolisib Displays Antitumor Activity in First and Late-line Settings

According to results from a phase 1b expansion study (NCT02684032), the addition of gedatolisib to palbociclib and ET (letrozole; Femara) or fulvestrant) in women with ER-positive/HER2-negative mBC provided promising antitumor activity in both first- and later-line settings compared with historical controls. Gedatolisib is a dual inhibitor of PI3K and mTOR. A total of 103 patients were enrolled in one of 4 arms: A) gedatolisib, palbociclib, and letrozole as first-line treatment in CDK4/6inaïve patients (n = 31); B) gedatolisib,palbociclib, and fulvestrant as second-line treatment in CDK4/6i-naïve patients (n=13); C) gedatolisib, palbociclib, and fulvestrant as second- or third-line treatment in patients with prior CDK4/6i therapy (n=32); or D) gedatolisib, palbociclib, and fulvestrant as second- or third-line treatment in patients whose most recent regimen included a CDK4/6i (n = 27).

Results are summarized in TABLE 211. Median PFS was not reached, 31.1 months, 11.9 months, 5.1 months, and 12.9 months in arms A, B, C, and D, respectively. The most common TEAEs (≥ 50%) across all arms were nausea (81.6%), stomatitis (80.6%), fatigue (79.6%), and neutropenia/neutrophil count decrease (79.6%). The most common treatment-emergent SAEs (≥ 2%) were febrile neutropenia (4.9%), acute kidney injury (2.9%), and pyrexia (2.9%).

“The treatment regimen was very effective for metastatic HR-positive/ HER2-negative breast cancer, especially when compared with standard-of-care treatments currently available,” Layman said. “Results also suggest that the treatment may be effective in patients with harder to treat breast cancers, such as those with primary endocrine resistance.” A phase 3 study evaluating gedatolisib in patients with ER-positive/ HER2-negative mBC is planned.

Several therapies presented at 2021 SABCS hold much promise for patients with hormone receptor–positive/HER2-negative BC, and oncologists are eager to see further results in the upcoming year. Hurvitz is keeping a close eye on SERDs and ADCs. “EMERALD data are exciting, and data from ongoing studies evaluating other ER degraders are going to be very interesting. [Further] studies evaluating antibody-drug conjugates in hormone receptor–positive/HER2-negative breast cancer are highly anticipated.”

Layman is also watching the developing SERDs closely, along with PROTACs (proteolysis Targeting Chimera). “SERDs and PROTACs are showing promising clinical trial results and may become available as new treatment options. This is great news for patients with hormone receptor–positive, HER2-negative breast cancer.”

1. Bardia A, Neven P, Streich G, et al. Elacestrant, an oral selective estrogen receptor degrader (SERD), vs investigator’s choice of endocrine monotherapy for ER-positive/HER2-negative advanced/metastatic breast cancer (mBC) following progression on prior endocrine and CDK4/6 inhibitor therapy: results ofEMERALD phase 3 trial. presented at: San Antonio Breast Cancer Symposium; December 8, 2021 2021; San Antonio, TX. Session GS2.Accessed January 6, 2022https://bit.ly/33hrpIg

2. Hurvitz S, Quiroga V, Hee Park Y, et al. Neoadjuvant giredestrant (gdc-9545) + palbociclib versus anastrozole + palbociclib in postmenopausal women with estrogen receptor-positive, her2-negative, untreated early breast cancer: primary analysis of the randomized, open-label, phaseII coopERA breast cancer study. Presented at: San Antonio Breast Cancer Symposium; December 10, 2021 2021; San Antonio, TX. Session PD13. https://www.abstractsonline.com/pp8/#!/10462/presentation/594

3. Investor Update. Roche; December 10, 2021, 2021. https://www.roche.com/investors/updates/inv-update-2021-12-10b.htm

4. Turner N, Loi S, Moore H, et al. Activity and biomarker analyses from a phase Ia/b study of giredestrant(GDC-9545; G) with or without palbociclib (palbo) in patients with estrogen receptor-positive, HER2-negative locally advanced/metastatic breast cancer (ER-positive/HER2-negativeLA/mBC). Presented at: San Antonio Breast Cancer Symposium; December 10, 2021 2021; San Antonio, TX. Session PD13. https://www.abstractsonline.com/pp8/#!/10462/presentation/595

5. Coombes C, Howell SJ, Krebs MG, et al. Study of samuraciclib (ct7001), a first-in-class, oral, selective inhibitor of cdk7, in combination with fulvestrant in patients with advanced hormone receptor positive her2 negative breast cancer(HR+BC). Presented at: San Antonio Breast Cancer Symposium; December 9, 2021 2021; San Antonio, TX. Session GS3. https://www.abstractsonline.com/pp8/#!/10462/presentation/2079

6. Pizii W. Samuraciclib plus fulvestrant improves PFS in heavily pretreated HR+ breast cancer. Updated December 10, 2021. Accessed January 4, 2022, 2022. https://www.onclive.com/view/samuraciclib-plus-fulvestrant-improves-pfs-in-heavily-pretreated-hr-breast-cancer

7. 8. Carrick Therapeutics Receives FDA fast track designations for two samuraciclib combinations for the treatment of HR+, HER2-advanced breast cancer and locally advanced or metastatic triple negative breast cancer. August 16, 2021, 2021. https://bit.ly/3JFs9HL

9. Krop I, Juric D, Shimizu T, et al. Datopotamab deruxtecanin advanced/metastatic her2-breast cancer: results from the phase 1 TROPION-PanTumor01 study. Presented at: San Antionio Breast Cancer Symposium; December 7, 2021 2021; San Antonio, TX. Session GS1. https://www.abstractsonline.com/pp8/#!/10462/presentation/2164

10. Writer S. Datopotamab deruxtecan demonstrates highly promising efficacy in advanced or metastatic TNBC. Updated December 7, 2021. Accessed January 4, 2022, 2022. https://www.targetedonc.com/view/datopotamab-deruxtecan-demonstrates-highly-promising-efficacy-in-advanced-or-metastatic-tnbc

11. Kaufman P, Martin M, Mayer I, et al. Balixafortide (a CXCR4 antagonist)+eribulin versus eribulin alone in patients with her2 negative, locally recurrent or metastatic breast cancer: an international, randomized, phase 3 trial (FORTRESS). Presented at: San Antonio Breast Cancer Symposium; December 10, 2021 2021; San Antonio, TX. Session PD13. https://www.abstractsonline.com/pp8/#!/10462/presentation/589

12. Layman R, Wesolowski R, Han H, et al. Phase Ib expansion study of gedatolisib in combination with palbociclib and endocrine therapy in women withER+ metastatic breast cancer. Presented at: San Antonio Breast Cancer Symposium; 2021; San Antonio, TX. Session PD13. https://www.abstractsonline.com/pp8/#!/10462/presentation/590

Research is ongoing to combat key resistance mechanisms, with new data recently presented by Sara A. Hurvitz, MD, FACP, and other oncologists and investigators during the 2021 San Antonio Breast Cancer Symposium.

February 1, 2022 | Targeted Therapies in Oncology

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