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Although trastuzumab (Herceptin)-based regimens remain the standard treatment for patients with early-stage HER2-positive breast cancer, unanswered clinical questions surround the use of other agents in the neoadjuvant and adjuvant settings. With several options on the table, risk-adapted approaches to therapy have paved the way for personalized medicine and the opportunity to move away from therapies with higher toxicity profiles, such as anthracyclines.

“The debates that are going on are what’s the appropriate chemotherapy backbone and do you need an anthracycline, for example?” Lisa A. Carey, MD, said during a recent 

. “What’s the extent to which we need all those drugs, and can we rationally optimize therapy even for patients at higher clinical risk?”

A panel of breast cancer experts examined neoadjuvant and adjuvant systemic therapy approaches for patients with HER2-positive early-stage breast cancer. They also unpacked key updates to clinical trial data and shared how these affect their decision-making.

Reexamining Neoadjuvant Standards of Care

“We’re treating the majority of patients with HER2-positive breast cancer in the neoadjuvant setting. They’re getting their chemotherapy and anti-HER2 targeting preoperatively, for the most part, and then [postoperative] HER2 targeting is predicated on extent of disease that’s found at surgery,” Carey said, noting this approach has shown several benefits. “You can create more lobectomy candidates and can reduce the need for axillary dissection.”

It also enables oncologists to see how responsive a patient’s tumor is to their neoadjuvant regimen, enabling better tailoring of postoperative adjuvant treatment. For example, in the KATHERINE trial (NCT01772472), adjuvant ado-trastuzumab emtansine (Kadcyla; T-DM1) was associated with better outcomes than trastuzumab alone in patients who had residual invasive disease after completing neoadjuvant therapy.

A key ongoing question for patients with HER2-positive disease is which neoadjuvant regimen is best. In the preoperative setting, Carey said she typically uses TCH (docetaxel [Taxotere], carboplatin, trastuzumab), adding pertuzumab (Perjeta) for patients with node-positive disease, but not for those with node-negative disease, per the APHINITY trial (NCT01358877) data. Six-year follow-up data showed patients who were node-positive continued to derive a benefit from the addition of pertuzumab, demonstrating a 4.5% absolute improvement in invasive disease–free survival, regardless of their hormone receptor status.

“I shifted a little while ago more toward TCHP [docetaxel, trastuzumab, pertuzumab, carboplatin], although I do find that it’s a difficult regimen,” Claudine Isaacs, MD, said. “From a symptom-control perspective, it’s one of the toughest regimens we give.”

Overall, the participants agreed that they no longer use anthracyclines as they once did. “The TRAIN-2 data were further evidence for us that the anthracyclines really didn’t add much,” Isaacs said. The phase 3 TRAIN-2 study (NCT01996267) looked at chemotherapy with or without anthracyclines in the presence of dual HER2-blockade for HER2-positive breast from anthracyclines, which should be the ultimate goal. Claudine Isaacs, MD cancer.

 Three-year follow-up showed an estimated event-free survival of 92.7% for the anthracycline cohort versus 93.6% in the nonanthracycline cohort, with 3-year overall survival (OS) estimates of 97.7% and 98.2%, respectively. Two patients in the anthracycline cohort developed acute leukemia. These findings confirmed the results of the primary outcome analysis, which was that anthracyclines do not improve treatment efficacy and are associated with clinically relevant toxicity.

Despite these data, Vijayakrishna Gadi, MD, PhD, noted that some patients in his practice who are HER2-positive still receive anthracyclines. “For patients who have substantial burden of disease— maybe somebody who has not been [screened] but walks in with a big mass—I frequently start with the taxane portion, and then I’m on the fence a little on the anthracycline, [but] most of those patients still end up [receiving] the anthracycline in my practice,” he said. “There [are] always going to be patients whose circumstances are different, where you think you need to escalate in that direction and offer more with an anthracycline or what have you,” he explained.

Moderator Joyce A. O’Shaughnessy, MD, added that part of the concern about relying on TRAIN-2 data regarding the role of anthracyclines is that it is a relatively small trial with fewer than 500 patients. Nevertheless, she said, the data are still encouraging because they show it is possible to move away from anthracyclines, which should be the ultimate goal.

Identifying and Treating Patients at High Risk of Recurrence After Neoadjuvant Therapy

“In my mind, the fundamental thing that defines risk after receiving neoadjuvant therapy is what the residual disease burden looks like. If there’s significant disease, particularly in nodes, that would be very worrisome, as it would be if there’s a significant amount of disease in the breast,” William J. Gradishar, MD, said. He also noted that anyone who progresses while on neoadjuvant therapy would be considered high risk but said this is not something he has frequently observed.

The participants agreed that T-DM1 is the standard of care for patients with residual disease after TCHP or AC-THP (doxorubicin, cyclophosphamide, paclitaxel, trastuzumab, pertuzumab). “Most patients do OK with it, so I would try to leverage that benef it that we saw in KATHERINE and confer [it on] whoever has residual disease,” he said.

Gadi said he struggles a bit with treatment decision-making when it comes to patients who are node-positive and achieve a pathologic complete response (pCR). “You look at some of the trials, and you start picking at them a little. There seems to be a suggestion that maybe you should continue the [trastuzumab and pertuzumab]. I have to be honest; I don’t find that data compelling,” he said, noting that he often continues only the trastuzumab and not the pertuzumab in these patients.

“I don’t think we know the right thing to do,” Carey said. She added that if she observed a pCR out of a trastuzumab/pertuzumab–based regimen, her tendency would be to continue the combination. Isaacs agreed. “I tend to continue trastuzumab and pertuzumab, as well, if somebody is tolerating it and there’s no compelling reason to stop it,” she said.

O’Shaughnessy mentioned that the FDA label for pertuzumab is interesting because it indicates that if this agent is used preoperatively, it should be continued for 1 year postoperatively. The label states, “Following surgery, patients should continue to receive [pertuzumab] and trastuzumab or trastuzumab/hyaluronidase-oysk [Herceptin Hylecta] to complete 1 year of treatment (up to 18 cycles).”

 However, she noted that it is still unclear whether this is necessary. “If someone has a pCR, do they really need it?” she asked.

Adjuvant Systemic Therapy: Implications of Data Updates

The participants also discussed recent updates to key adjuvant therapy trials, including APHINITY, ExteNET, and KATHERINE, and shared how these data may affect clinical practice.

Isaacs discussed a subpopulation treatment effect pattern plot (STEPP) analysis of the APHINITY trial, which was presented at the 2020 San Antonio Breast Cancer Symposium Virtual Annual Meeting.

 “What came out was very much in keeping with what we thought, that the group that derived the greatest benefit were the patients who had higher clinical risk,” she said. In the study, patients with HER2-positive, node-positive early-stage breast cancer benefited the most from the addition of adjuvant pertuzumab (as compared with patients with node-negative early-stage breast cancer), with benefit seen irrespective of STEPP subpopulation; however, the largest gains were for patients with lower-risk node-positive disease and those with the highest number of tumor-infiltrating lymphocytes (TILs) (

Table. Select Data from Adjuvant Therapy Trials

Isaacs noted that although the information on TILs is interesting, it is difficult to apply in practice. “We’re not necessarily getting TIL numbers when we’re getting path specimens on patients who are getting core biopsies,” she said. However, even without knowing patients’ TIL status, she noted the data further support current clinical practice regarding the use of adjuvant pertuzumab for patients with HER2-positive, early-stage breast cancer.

Next, Isaacs reviewed the final OS analysis of the randomized phase 3 ExteNET trial (NCT00878709), which included 2840 patients with estrogen receptor (ER)–positive, HER2-positive early breast cancer who were treated with neratinib (Nerlynx) or placebo after neoadjuvant/adjuvant trastuzumab-based therapy.

 “There emerged a survival benefit [with neratinib]—an approximate 2% survival benefit—if you looked at the super-highest risk: the [patients who were] hormone receptor–positive who started within a year of completing their therapy, and the ones who didn’t achieve a pCR,” Isaacs said.

A challenge she noted is knowing where the drug fits in during the era of T-DM1 and pertuzumab. “In the really high-risk patients, particularly if they have hormone receptor–positive disease—and we all have some patients who have multiple nodes, 2 or 3 nodes—I do tend to give them neratinib,” she said.

Gadi said he has been using neratinib more frequently recently. “I believe that ER-positive disease is fundamentally different from the kind that’s ER negative. If we don’t address that cross talk, and we don’t do that with T-DM1, I’m still worried about these patients having events down the road,” he explained. He also noted that what makes neratinib appealing to him is its ability to cross the blood-brain barrier. “I know that trials are underpowered for CNS [central nervous system] as a first site of recurrent type event. It’s my suspicion that those are patients who are vulnerable to those events when you have residual disease, have done T-DM1, and have ER-positive disease. I’d like to give them that extra bit of coverage for that, as well as for prevention of those CNS events,” he said. 

The challenge with neratinib, however, is its adverse effect profile, particularly diarrhea, which can make it difficult for patients to tolerate.

 Subsequently, Gradishar said he does not use it a lot, but he agreed that he would use it for patients such as Isaacs described, adding that patients and oncologists both need to be highly motivated for the patient to be able to get through this treatment. Because of this agent’s toxicities, O’Shaughnessy emphasized the importance of escalating it per the findings from the CONTROL trial (NCT02400476), which investigated antidiarrheal strategies in patients with early HER2-positive breast cancer treated with neratinib.

 In the study, both preemptive prophylaxis and dose escalation reduced the rate, severity, and duration of grade 3 diarrhea compared with the levels observed in ExteNET, but dose escalation was particularly promising, with only 3% of patients on this strategy discontinuing treatment due to diarrhea.

“In the CONTROL trial, they escalated relatively quickly. I was surprised...It was the most effective,” Carey said. She said when she has a patient whose cancer is very high risk, she sometimes uses neratinib. “I’ve been happier with the option of dose escalation,” she said.

Data from the KATHERINE trial showed that among patients with HER2-positive early breast cancer who had residual invasive disease after completion of neoadjuvant therapy, the risk of recurrence of invasive breast cancer or death was 50% lower with adjuvant T-DM1 than with trastuzumab alone.

 “I was really impressed by the KATHERINE data. [The data] showed this really big 3-year, invasive disease–free survival benefit for the patients who didn’t achieve a pCR [in the neoadjuvant setting]. It’s approximately an 11% absolute benefit,” Isaacs said.

Recently, exploratory analyses evaluating the relationship between invasive disease–free survival and biomarkers potentially related to response showed that 

 mutation status did not influence outcomes with trastuzumab or T-DM1, and that T-DM1 benefit was not affected by any of the biomarkers assessed; however, HER2 and PD-L1 expression levels correlated with outcomes in the trastuzumab arm.

Based on the KATHERINE data, the American Society of Clinical Oncology recently updated its guidelines on the selection of optimal adjuvant chemotherapy and targeted therapy for early breast cancer.

 It now strongly recommends that patients with HER2-positive breast cancer with pathologic invasive residual disease at surgery after standard preoperative chemo-therapy and HER2-targeted therapy be offered 14 cycles of adjuvant trastuzumab emtansine, unless there is disease recurrence or unmanageable toxicity. The guidelines note that clinicians may offer any of the available and approved formulations of trastuzumab, including trastuzumab, trastuzumab and hyaluronidase-oysk, and available biosimilars.

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Chan A, Moy B, Mansi J, et al; ExteNET Study Group. Final efficacy results of neratinib in HER2-positive hormone receptor-positive early-stage breast cancer from the phase III ExteNET trial. 

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Articles

Although trastuzumab-based regimens remain the standard treatment for patients with early-stage HER2-positive breast cancer, unanswered clinical questions surround the use of other agents in the neoadjuvant and adjuvant settings. 

Experts Take a Fresh Look at Strategies for Early-Stage HER2+ Breast Cancer

Although endocrine therapies have revolutionized the treatment of breast cancers driven by the estrogen receptor (ER), the development of resistance remains a major challenge that limits long-term remission with currently available drugs. Now there is a growing trend toward developing more potent endocrine therapies with the potential to address this challenge. 

Data highlighted at conferences in the last year showcased the significant potential of oral selective ER downregulators (SERDs) being developed for heavily pretreated ER-positive breast cancers, including those that harbor 

 mutations, a common mechanism of resistance. 

Treatment frontrunners include Sanofi’s amcenestrant (SAR439859), Genentech’s giredestrant (GDC-9545), and AstraZeneca’s AZD9833, with all 3 companies betting on their drug’s success in recently initiated phase 3 clinical trials. Meanwhile, other pharmaceutical companies are investing in new drug designs, such as Connecticut-based Arvinas’ first-in-class proteolysis-targeting chimera (PROTAC)based drug, ARV-471 (

Table. ER-Targeting Therapies in Development for ER-positive, HER2-negative Breast Cancer

Nearly 80% of breast cancers express the ER, making it the most significant driver of this tumor type. In patients with ER-positive breast cancer, endocrine therapy has been the gold standard for decades, beginning with the approval of tamoxifen in the 1970s. Tamoxifen is a selective ER modulator (SERM), a class of agents that act as either ER agonists or antagonists, depending on the tissue. Tamoxifen competes with estrogen for binding to the ER and blocks estrogen-dependent gene transcription and the resulting cellular outcomes.

Tamoxifen remains a recommended treatment option for patients with ER-positive breast cancer and has been joined by the FDA-approved SERMs toremifene (Fareston) and raloxifene (Evista).

 These drugs are often mistakenly referred to as antiestrogens; however, their mechanism of action is much more complex. They can elicit a spectrum of effects, from mimicking estrogen to almost purely antiestrogenic activity.

The mechanisms behind these processes are thought to be related to the SERMs’ interfering with the ER’s ability to recruit coregulatory proteins upon activation. The balance between the activating and repressive coregulatory proteins present within a specific cell may therefore dictate the outcome of SERM activity.

Regardless of the underlying biology, these varying events have important implications. Because of tamoxifen’s estrogenic activity in certain tissues, serious adverse effects (AEs) are associated with the drug’s long-term use.

A number of other endocrine therapies have been developed over the years. SERDs antagonize ER activity in a manner similar to that of SERMs, but they have a much higher binding affinity and also induce ER degradation. SERDs are purely antiestrogenic, with none of the agonist effects of SERMs. Currently, fulvestrant (Faslodex) is the only FDA-approved SERD in the breast cancer setting.

Members of a third class of endocrine therapy, aromatase inhibitors (AIs), act indirectly on the ER signaling pathway by inhibiting the activity of the aromatase enzyme involved in the biosynthesis of estrogens from androgens. AIs, which include the steroidal compound exemestane and the nonsteroidal drugs letrozole and anastrozole are recommended treatment options in the adjuvant setting, either as initial adjuvant therapy or following tamoxifen. In the metastatic setting, they are the recommended firstline treatment, demonstrating advantages over tamoxifen.

The benefits of endocrine therapy in ER-positive breast cancer are irrefutable. However, many patients either will have intrinsic resistance or will develop resistance over the course of treatment, which is a major barrier to long-term remission.

A greater understanding of the mechanisms underlying resistance to endocrine therapy has translated into new treatment options designed to tackle resistance. Exploiting cross talk between ER signaling and other intracellular signaling pathways, inhibitors of cyclin-dependent kinases (CDKs) 4/6 and PI3K are now approved by the FDA for the treatment of patients with ER-positive breast cancer.

These drugs are currently approved for use in combination with endocrine therapy (although abemaciclib [Verzenio] also has a monotherapy indication) in the advanced or metastatic setting. Ongoing clinical trials are looking at such combinations in early-stage breast cancer.

 gene, which encodes the main form of ER in the breast, represent another significant mechanism of resistance to currently available endocrine therapies. De novo 

 mutations are found at low frequencies in patients with newly diagnosed disease, but acquired mutations occur in up to 40% of patients who have previously received endocrine therapy.

 Most common are the Y537S and D538G point mutations, accounting for 14% and 36% of somatic 

 mutations promote some level of resistance to all currently available endocrine therapies, fulvestrant appears to be the least affected.

 However, its potency is believed to be limited by its intramuscular route of administration, and an oral SERD could prove more effective and less susceptible to endocrine resistance.

Initial efforts to develop orally bioavailable fulvestrant-like steroidal SERDs were unsuccessful.

 A growing number of nonsteroidal oral SERDs are in clinical development and have demonstrated promising antitumor activity in patients with advanced ER-positive breast cancer, including those with 

Sanofi is developing amcenestrant, which has shown early signs of clinical efficacy in the phase 1/2 AMEERA-1 trial (NCT03284957) in postmenopausal women with heavily pretreated ER-positive, HER2-negative advanced or metastatic breast cancer. AMEERA-1 is evaluating amcenestrant as monotherapy and in combination with other anticancer therapies.

Updated results from the monotherapy cohorts were reported at the 2020 San Antonio Breast Cancer Symposium (SABCS). Pooled data from 62 women included results from those who had received escalating doses from 150 mg to 600 mg once daily in part A (n = 13) and 400 mg once daily during dose expansion (part B; n = 49). All patients had received prior endocrine therapy in the advanced setting, with approximately half having received 3 or more lines.

Among the 59 evaluable patients, the objective response rate (ORR)—all partial responses (PRs)—was 8.5%, and the clinical benefit rate (CBR) was 33.9%. Patients with (n = 30) and without (n = 28) 

 mutations derived similar clinical benefit from amcenestrant (CBR, 36.7% vs 32.1%, respectively). 

Of note, the ORR and CBR were higher in a subset of patients who had not received prior therapy with CDK4/6 inhibitors, mTOR inhibitors, or fulvestrant compared with the overall cohort of patients who generally had been heavily pretreated (ORR, 21.4% vs 8.5%; CBR, 64.3% vs 33.9%). These findings support the development of amcenestrant as first-line therapy, which is being evaluated in the AMEERA-5 trial (NCT04478266). 

Amcenestrant displayed a favorable safety profile, with exclusively grade 1 or 2 treatment-related adverse effects (TRAEs), most commonly hot flush, constipation, arthralgia, decreased appetite, vomiting, diarrhea, nausea, and fatigue. No patients discontinued therapy due to AEs.14

Initial data from a first-in-human phase 1 trial (NCT03332797) of another oral SERD, giredestrant, were presented at SABCS in 2019. They showed encouraging activity in patients with previously treated advanced breast cancer, including those with ESR1-mutant tumors.

 The recommended phase 2 dose identified in this dose-escalation portion of the trial, 100 mg once daily, was then explored in a dose-expansion phase as monotherapy and in combination with palbociclib (Ibrance) in postmenopausal women. Pre- and perimenopausal patients also received a luteinizing hormonereleasing hormone agonist. 

Results from the dose-expansion phase were presented at the 2020 American Society of Clinical Oncology meeting. Eighty-eight patients had been enrolled in 2 cohorts (cohort A, giredestrant monotherapy, n = 40; and cohort B, giredestrant plus palbociclib, n = 48). 

The 40 evaluable patients in cohort A had a median progression-free survival (PFS) of 7.8 months (95% CI, 5.3-11.4) and an ORR of 13% (95% CI, 4%-30%). 

Giredestrant monotherapy was well tolerated, with mostly grade 1 or 2 TRAEs and no discontinuations. In cohort B, giredestrant demonstrated a median PFS of 9.3 months (95% CI, 8.9-not evaluable) and an ORR of 33% (95% CI, 20%-49%) among 43 evaluable patients. 

Most AEs also were of grade 1 or 2 severity in the combination arm, with 1 serious AE of grade 3 QT prolongation in a patient with preexisting coronary artery disease.

The phase 3 preservERA Breast Cancer trial of giredestrant in combination with palbociclib in patients with metastatic breast cancer is ongoing (NCT04546009).

AstraZeneca’s AZD9833 has also advanced into phase 3 clinical testing. In the phase 1 SERENA-1 trial (NCT03616587), as of August 2020, a total of 146 patients had received AZD9833 either as monotherapy (n = 98) across dose-escalation and expansion cohorts (parts A and B, respectively) or in combination with palbociclib (n = 48; parts C and D). 

The median number of prior lines of therapy was 3 for patients in the monotherapy parts and 2 for those treated with combination therapy. The ORR and CBR for monotherapy were 10.0% and 35.3%, respectively, and median PFS was 5.4 months. In CDK inhibitor–naïve patients treated with combination therapy, the ORR and CBR were 14.3% and 71.4%, respectively. 

The majority of TRAEs were of grade 1 or 2 severity and most commonly included anemia, fatigue, lymphopenia, nausea, neutropenia, thrombocytopenia, and reduced white blood cell count. The 5 dose-limiting toxicities (3 for monotherapy and 2 for combination therapy) were managed with dose interruption or reduction. There were 2 serious AEs potentially related to AZD9833 in the monotherapy arm. No patients discontinued treatment due to TRAEs.

A number of clinical trials testing AZD9833 are ongoing, including the phase 3 SERENA-4 trial. In this study, investigators are evaluating the combination of AZD9833 and palbociclib in patients with treatment-naïve advanced or metastatic breast cancer (NCT04711252).

Other notable SERDs in development include elacestrant (RAD-1901). Findings from a phase 1 study (NCT02338349) showed that elacestrant monotherapy resulted in an ORR of 19.4% among 31 heavily pretreated patients who received the recommended phase 2 dose of 400 mg once daily. No dose-limiting toxicities occurred and the most common AEs were nausea, increased blood triglycerides, and decreased blood phosphorus.

In September 2020, Radius Health reported that the ongoing phase 3 EMERALD trial (NCT03778931), comparing elacestrant against standard endocrine therapy in patients with previously treated advanced breast cancer, had reached its enrollment goal of 466 patients, including 220 with ESR1 mutations.

Beyond oral SERDs, other novel ER-targeting drug designs have been developed in an effort to overcome endocrine resistance. H3B-6545 is a first-in-class selective ER covalent antagonist (SERCA) being developed by H3 Biomedicines. It binds covalently to a cysteine residue present in both the wild-type and mutant ER and induces an irreversible antagonistic conformation in a manner that is distinct from that of SERMs and SERDs.

As of February 2020, 130 patients had been enrolled in the dose-escalation (100-600 mg once daily) and dose-expansion (450 mg once daily) parts of an ongoing phase 1/2 clinical trial (NCT03250676) of H3B-6545 in pre- or postmenopausal women with previously treated advanced breast cancer. Fifty-eight percent of patients had 

Among 105 evaluable patients, 13 had confirmed PRs, 11 of which were in patients treated with the 450-mg dose. Investigators reported 3 PRs in the 12 patients with the 

 Y537S mutation. In addition, H3B-6545 demonstrated a manageable safety profile.

PROTACs are targeted protein degraders pioneered by Arvinas, a clinical-stage biopharmaceutical company founded by the Yale University investigators who developed the technology.

ARV-471 is a PROTAC in which estradiol, an estrogen hormone, is linked to a small-molecule ubiquitin E3 ligase–binding moiety. This drug is designed to facilitate an interaction between the ER and an E3 ligase complex that will tag the ER for degradation by the ubiquitin-proteasome system.

In a December 2020 press release, Arvinas detailed interim findings from a phase 1 clinical trial of ARV-471 (NCT04072952). As of November 2020, 21 patients had completed at least 1 treatment cycle. They were heavily pretreated, with a median of 5 prior lines of therapy. The findings included 1 confirmed PR, 2 unconfirmed PRs, and a CBR of 42%. The most common TRAEs were nausea, arthralgia, fatigue, and decreased appetite; all were grade 1 or 2. A cohort expansion in which ARV-471 is administered in combination with palbociclib is ongoing.

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Baird R, Oliveira M, Ciruelos EM, Patel MR. Updated data from SERENA-1: a phase 1 dose escalation and expansion study of the next generation oral SERD AZD9833 as a monotherapy and in combination with palbociclib, in women with ER-positive, HER2-negative advanced breast cancer. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; virtual. Abstract PS11-05.

Bardia A, Kaklamani V, Wilks S, et al. Phase I study of elacestrant (RAD1901), a novel selective estrogen receptor degrader, in ER-positive, HER2-negative advanced breast cancer. 

. Published online January 29, 2021. doi:10.1200/JCO.20.02272

Radius Health & Menarini Group provide elacestrant update. News release. Radius Health Inc and Menarini Group. September 24, 2020. Accessed February 4, 2021. 

https://www.biospace.com/article/radius-health-and-menarini-group-provide-elacestrant-update/

Puyang X, Furman C, Zheng GZ, et al. Discovery of selective estrogen receptor covalent antagonists for the treatment of ERαWT and ERαMUT breast cancer. 

. 2018;8(9):1176-1193. doi:10.1158/2159-8290.CD-17-1229

Hamilton EP, Wang J, Pluard T, Johnston S, Morikawa A. Phase I/II trial of H3B-6545, a novel selective estrogen receptor covalent antagonist (SERCA), in estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; virtual. Abstract 1142.

ARV-471: an ER-targeting protein degrader for breast cancer. Arvinas. Accessed February 4, 2021. 

https://www.arvinas.com/pipeline-programs/estrogen-receptor

Gao H, Sun X, Rao Y. PROTAC technology: opportunities and challenges. 

. 2020;11(3):237-240. doi:10.1021/acsmedchemlett.9b00597

Arvinas releases interim clinical data further demonstrating the powerful potential of PROTAC protein degraders ARV-471 and ARV-110. News release. Arvinas, Inc. December 14, 2020. Accessed February 4, 2021. 

https://ir.arvinas.com/news-releases/news-release-details/arvinas-releases-interim-clinical-data-further-demonstrating/

Kumar R, Zakharov MN, Khan SH, et al. The dynamic structure of the estrogen receptor. 

. 2011;2011:812540. doi:10.4061/2011/812540

Dhamad AE, Zhou Z, Zhou J, Du Y. Systematic proteomic identification of the heat shock proteins (Hsp) that interact with estrogen receptor alpha (ERα) and biochemical characterization of the ERα-Hsp70 interaction. 

. 2016;11(8):e0160312. doi:10.1371/journal.pone.0160312

Lipovka Y, Konhilas JP. The complex nature of oestrogen signalling in breast cancer: enemy or ally? 

. 2016;36(3):e00352. doi:10.1042/BSR20160017

Although endocrine therapies have revolutionized the treatment of breast cancers driven by the estrogen receptor, the development of resistance remains a major challenge that limits long-term remission with currently available drugs.

A New Crop of ER-Targeting Agents Takes Root 

The combination of navitoclax and ruxolitinib (Jakafi) simultaneously inhibits 2 key mechanisms that promote myelofibrosis (MF), resulting in an improvement in symptom control and positive changes in response biomarkers in patients with high-risk disease, according to Catriona Jamieson, MD, PhD.

The dual regimen demonstrated a reduction in spleen volume and total symptom score (TSS) while improving bone marrow fibrosis, in findings from the phase 2 REFINE study (NCT03222609) presented at the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition held virtually in December 2020. The combination also reduced the expression of driver genes and improved cytokine markers (TABLE).

“This is a very important study. It gives us an idea of why people respond to this combination of ruxolitinib and navitoclax and certainly is encouraging news for the field in terms of being able to predict and prevent unnecessary toxicity,” said Jamieson, deputy director of the University of California, San Diego (UC San Diego) Moores Cancer Center.

Jamieson, who holds the Koman Family Presidential Endowed Chair in Cancer Research at UC San Diego, provided her insights during an 

 program, a video series that features experts delving into key research findings presented at conferences. A hematologist who also focuses on regenerative medicine, Jamieson has participated in navitoclax research.

Improving quality of life is an important goal of therapy for patients with MF, experts say. MF, one of a group of heterogenous myeloproliferative neoplasms (MPNs), results in a heavy constitutional burden of symptoms driven by bone marrow fibrosis and extramedullary hematopoiesis, Jamieson said.

In the MPN Landmark Survey, patients reported symptoms of a severity of 6 or greater on a 10-point scale for a range of problems including fatigue, depression, headaches, sweating, unintentional weight loss, vision changes, and blood clots. MF also takes a toll on patients’ ability to work, resulting in absenteeism and early retirement.

Ruxolitinib, a JAK1/2 inhibitor approved for patients with primary and secondary MF, is effective in improving splenomegaly and disease-related symptoms. The agent “has little impact on bone marrow fibrosis, and a number of patients are refractory or develop secondary resistance,” noted investigators, in a poster presented at the 25th European Hematology Association Annual Congress in June 2020.

Navitoclax, a small molecule like ruxolitinib, targets members of the BCL-2 family of apoptotic receptors, including BCL-X

, which may prevent fibrosis in the bone marrow. Results from preclinical studies have shown that synergistic activity of JAK2 and BCL-2/ BCL-X

-mutated cells and can help overcome resistance to JAK2-targeted therapy.

Jamieson described the development of MF in the context of the JAK/STAT network. “This pathway is upregulated in the majority of patients with these myeloproliferative neoplasms. In some, it's based on a mutation in JAK2 that prevents the gene from being turned off; in others, a mutation in CALR can also activate JAK/STAT signaling. And in the third group, it's through the MPL mutation, which activates signaling through the thrombopoietin receptor more readily.”

Moreover, patients with MF who harbor high molecular risk (HMR) mutations at diagnosis have worse survival outcomes and are more likely to experience leukemic transformation to more aggressive disease, Jamieson said. “There is a great unmet need for therapies that are effective in myelofibrosis, regardless of disease biology or risk,” she noted.

In the ongoing REFINE study, patients include those with primary or secondary MF with splenomegaly who have had ruxolitinib failure after 12 weeks or more of continuous treatment. Participants receive navitoclax at a starting dose of 50 mg once daily along with ruxolitinib twice daily at their dose at study entry. The navitoclax dose can be increased to a maximum of 300-mg daily, provided the patient’s platelet count is greater than 100 x 109/L.

The primary end point is the percentage of patients who achieve a spleen volume reduction (SVR) of 35% or greater from baseline through week 24. Secondary end points are the percentage of participants reaching a reduction in TSS of 50% or greater through week 24, anemia response, and change in grade of bone marrow fibrosis.

Overall, Jamieson said, the primary objectives of the study are to evaluate whether the presence of HMR mutations or the total number of mutated genes has an impact on clinical outcomes and to discover how the combination therapy affects inflammatory cytokines. Investigators are performing mutational analyses at baseline and week 24, including next-generation sequencing with a 54-gene assay of variant allele frequency (VAF) in peripheral blood samples. Cytokine levels are assessed in plasma samples.

At the ASH meeting, investigators reported data for 34 patients with MF who had received at least 1 dose of navitoclax plus ruxolitinib as of February 28, 2020. The median age of participants was 68 years (range, 42-86), ECOG performance status was 0 or 1, and median duration of prior ruxolitinib therapy was 20 months (range, 4-97). The median spleen volume was 1695 cm3 (range, 465-5047).

In terms of mutations, 79% of participants had a JAK2 mutation and 21% had a CALR alteration. In all, 58% of patients (n = 19) had mutations in HMR genes, most frequently in ASXL1, followed by SRSF2, EZH2, U2AF1, and IDH1. Of those with HMR gene mutations, 42% (n = 8) had 2 or more aberrations (FIGURE).

At week 24, the combination therapy resulted in an SVR reduction of 27% in 34 evaluable patients; a TSS reduction in 30% of 20 participants; and a VAF reduction of 10% or more in the driver genes of JAK2 or CALR in 46% of 26 patients. The therapy also led to bone marrow fibrosis improvements of at least 1 grade at any time in 29% of 34 patients.

Investigators observed treatment-emergent adverse events (TEAEs) in all patients, most commonly thrombocytopenia (88%), diarrhea (68%), and fatigue (62%). They reported TEAEs of grade 3 or greater severity in 85% of patients, most frequently thrombocytopenia (53%), anemia (32%), and pneumonia (12%). “Thrombocytopenia is manageable with dose modification and the pneumonia will require a little bit more investigation,” Jamieson said.

“We’re very excited about the results of this study in terms of reducing the variable allele frequency as well as bone marrow fibrosis grade,” Jamieson said. “The efficacy will really be borne out over time.”

The impact on bone marrow fibrosis was not affected by the presence of total mutations or HMR alterations. At week 24, 4 of 5 patients who reached a molecular response, defined as a reduction of 20% or greater in driver genes, demonstrated evidence of fibrosis reversal of at least 1 grade. “This is a really important finding from this study,” she said.

Additionally, investigators found a correlation between changes in spleen volume and MF-associated cytokine levels measured from baseline. Levels of 4 cytokines associated with TSS improvement were more moderate for beta-2 microglobulin, tumor necrosis factor receptor 2, tissue inhibitor of metalloproteinases 1, and vascular cell adhesion molecule 1. “It was fairly striking at week 12 and week 24,” Jamieson said. “That may be the pivotal part of this trial—defining new biomarkers of response in addition to showing nice efficacy.”

Overall, Jamieson said, the research advances understanding of MF. “This is a high-risk group of patients that desperately needs newer therapies and I think this team has gotten it right in terms of not just the combination strategy of BCL-X

 inhibition in addition to JAK2 inhibition but also in terms of trying to predict who’s likely to respond.”

In July 2020, AbbVie, the company developing navitoclax, opened the randomized phase 3 TRANSFORM-1 trial (NCT04472598) in patients with primary or secondary MF who have not been previously treated with a JAK2 inhibitor. The trial, which aims to recruit 230 participants, will compare the combination of navitoclax plus ruxolitinib with placebo plus ruxolitinib. The primary end point is an SVR of 35% or greater at week 24.

Pemmaraju N, Garcia JS, Potluri J, et al. The addition of navitoclax to ruxolitinib demonstrates efficacy within different high-risk populations in patients with relapsed/refractory myelofibrosis. Blood. 2021;136(suppl 1):49-50. doi:10.1182/blood-2020-136938

Harrison CN, Koschmieder S, Foltz L, et al. The impact of myeloproliferative neoplasms (MPNs) on patient quality of life and productivity: results from the international MPN Landmark survey. Ann Hematol. 2017;96(10):1653-1665. doi:10.1007/s00277-017-3082-y

Harrison C, Garcia JS, Mesa R, et al. Navitoclax in combination with ruxolitinib in patients with primary or secondary myelofibrosis: a phase 2 study. Presented at: 25th European Hematology Association Annual Congress; June 11-21, 2020. Abstract EP1081. Accessed March 5, 2021. 

Study of oral navitoclax tablet in combination with oral ruxolitinib tablet when compared with oral ruxolitinib tablet to assess change in spleen volume in adult participants with myelofibrosis (TRANSFORM-1). ClinicalTrials.gov. Updated February 26, 2021. Accessed March 5, 2021. 

https://www.clinicaltrials.gov/ct2/show/NCT04472598?term=navitoclax&draw=4&rank=1

The combination of navitoclax and ruxolitinib simultaneously inhibits 2 key mechanisms that promote myelofibrosis, resulting in an improvement in symptom control and positive changes in response biomarkers in patients with high-risk disease.

Navitoclax Shows Early Signs of Clinical Benefit in Myelofibrosis

Even after the most aggressive standard-of-care multimodal treatment strategy—radiation, combining maximal safe resection with temozolomide chemotherapy, and tumor treatment fields

—the median overall survival (OS) for patients with glioblastoma (GBM), the most common adult primary brain tumor, is only 20.9 months. Numerous biological and clinical features affect survival outcomes for patients with GBM tumors; these include 

 mutations, MGMT promoter methylation, 1p/19q chromosomal arm deletions, and the absence of 

 mutations, as well as certain patient characteristics such as age, extent of surgical resection, and performance score. In addition, study results indicate that participation in clinical trials is associated with better response to standard-of-care treatment in this patient population.

However, even patients with GBM who have favorable features eventually experience recurrence and become refractory to treatment.

 Clinical trials play a significant role in the overall management of patients with GBM and, compared with patients with other cancers, a significantly higher number of patients with GBM enroll in clinical trials over the course of their disease.

Because of the highly infiltrative nature of this disease, complete surgical resection is never fully achieved even when “gross total resection” is confirmed by MRI. Further, because of the infiltrative nature of the tumor, radiation therapy is limited in its ability to adequately target the infiltrative disease. Finally, despite the battery of available chemotherapeutic agents, options for patients with GBM are restricted by the inability of most of these agents to cross the blood-brain barrier. Because the current standard-ofcare modalities have significant limitations, there has been a great interest in pursuing immunotherapeutic strategies for GBM.

Because the current standard-of-care modalities have significant limitations, there has been a great interest in pursuing immunotherapeutic strategies for glioblastoma.

Vol. 22/No. 06 | Oncology Live®

Experts Take a Fresh Look at Strategies for Early-Stage HER2+ Breast Cancer

A New Crop of ER-Targeting Agents Takes Root

Navitoclax Shows Early Signs of Clinical Benefit in Myelofibrosis

Surgical Intervention Provides the Foundation for Exploring Immunotherapy in Glioblastoma

Study Tests Guidelines for Monitoring Pancreatic Cysts

The COVID-19 Pandemic Will Have Long-Term Impact on Oncology Practices

Patient Perspective Should Be Part of Assessing Value in Cancer Care

GI Cancer Expert Is Searching for Big Leaps in Care