Targeted Therapy Innovator Foresees New Paradigms in Breast Cancer

Nearly 35 years ago, when Debu Tripathy, MD, was a fellow at the University of California, San Francisco, he became involved with a translational project that would help shape his career and cement his passion for research. “I joined a project to turn off this new oncogene that had been discovered recently called HER2. My job in the lab was to turn it off using antisense DNA. As a control, I needed to have a good antibody that worked against HER2-positive breast cancer cells. Genentech was right down the road from us. I knew some of the [investigators] there, and they gave me this antibody that is now Herceptin [trastuzumab],” he recalled.

Tripathy continued to study trastuzumab from the initial early phases¹ through the latestage trials that ultimately led to the monoclonal antibody’s approval. It proved to be a golden opportunity. “I was a fellow going on to become junior faculty when I got to be 1 of the 3 physicians who presented the data to the FDA when Herceptin got approved in 1998. That was a really special accomplishment for me,” he said.

Today, Tripathy is a professor and chair of the Department of Breast Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston. His role in the development of trastuzumab, which introduced a new era in the treatment of HER2-positive breast cancer,² marks an early milestone in a career packed with diverse research projects. Over the years, Tripathy has continued to pursue novel drug targets and treatments along with developing models of patient-centered care and assessing complementary therapies.

He also has become a leader in the breast oncology community. In March 2022, Tripathy will again serve as a cochair of the 39th Annual Miami Breast Cancer Conference^®, a role he has filled since 2012. Physicians’ Education Resource^® (PER^®), LLC, is hosting the conference Thursday, March 3, through Sunday, March 6, as a live and virtual meeting in Miami Beach, Florida. The hybrid conference will feature a broad range of sessions, tumor board panels, multidisciplinary meet-the-expert sessions, poster talks, and debates.

Tripathy finds the impact that research can have on his patients’ lives especially meaningful. He recounted the story of a patient he saw early in his career when trastuzumab was still in its infancy. The patient had advanced metastatic breast cancer with significant liver involvement, and she barely met the inclusion criteria for the trastuzumab study. At first, she had a tough time with the treatment and became more ill, but she eventually improved and then kept improving to the point that Tripathy was able to clear her to go on a vacation.

“She sent me this amazing picture of her scuba diving in Belize. And just a couple of months before that, she was so ill that I didn’t think she would even qualify for the study. To see someone who was so ill such a short time ago be able to send me a picture from vacation was a really special moment for me,” he said.

Balancing Research and Care

Tripathy developed a passion for science and medicine at a very early age by observing his father, who was an investigator and a physician.

“When I was young, between 8 and 10 years old, I used to go to the lab with my father and help wash the glassware and do other simple tasks. I was just fascinated with all the experiments. And I also got to accompany him on house calls when he thought it was safe for me to go. So I sort of got to see the whole picture at a young age,” Tripathy told OncLive^® in a recent interview.

Like his father, he has been able to structure his time so that he can engage in research activities as well as care for his patients in a way that allows him to maintain a personal touch. “I didn’t want to be trapped in just the cold science part or have a super busy clinician type of experience either,” he said.

Today, he says he has the best of both worlds, maintaining 1 or 2 clinic days and then spending the remainder of his time on research, teaching, and administration. This balance has enabled him to get to know his patients and keep in tune with their needs while also participating in the cutting-edge research that is expanding their treatment options and helping move the field forward.

Trastuzumab was among the first targeted therapies approved for cancer therapy. Tripathy has continued identifying and studying new drug targets that will personalize care. In 2014, he became the global principal investigator of the phase 3 MONALEESA-7 trial (NCT02278120) assessing ribociclib (Kisqali), an orally bioavail-able, selective CDK 4/6 inhibitor, as first-line therapy for premenopausal and perimenopausal patients with advanced hormone receptor–positive, HER2-negative breast cancer. Four years later, Tripathy and colleagues reported a progression-free survival (PFS) improvement in patients with the addition of ribociclib to endocrine therapy.³

“We were really excited when those data came out because we had broken the survival barrier that really hadn’t been crossed in hormone receptor–positive breast cancer. Being part of that story was very exciting,” he said.

MONALEESA-7 included 672 patients in the intention-to-treat (ITT) population and randomly assigned them to receive ribociclib or placebo in addition to endocrine therapy (goserelin plus a nonsteroidal aromatase inhibitor [AI] or tamoxifen).⁴ At 42 months, 70.2% of patients in the ribociclib arm were alive versus 46.0% of patients in the placebo arm, indicating a 29% reduction in the relative risk of death compared with placebo (HR, 0.71; 95% CI, 0.54-0.95; P = .00973). In the subgroup of 495 patients who received an AI, the overall survival (OS) benefit was consistent with that of the overall ITT population (HR for death, 0.70; 95% CI, 0.50-0.98).

In July 2018, based on favorable PFS data from the MONALEESA-7 trial, the FDA expanded ribociclib’s indication for use in combination with an AI as an initial endocrine-based therapy in pre/perimenopausal women with hormone receptor–positive, HER2-negative advanced or metastatic breast cancer.⁵ In March 2017, ribociclib had received its initial FDA approval for use in combination with an AI as an initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor–positive, HER2-negative advanced or metastatic breast cancer, based on data from the MONALEESA-2 study (NCT01958021).⁶ Ribociclib also is approved in combination with fulvestrant (Faslodex) for postmenopausal women or in men with hormone receptor–positive, HER2-negative advanced or metastatic breast cancer as initial endocrine-based therapy or following disease progression on endocrine therapy.⁷

Looking forward, Tripathy sees several areas of the breast cancer treatment landscape on the cusp of change. In a wide-ranging interview with OncologyLive^®, Tripathy discussed key developments that may set the stage for new directions in care.

Finding Targets, Adapting Therapy

The cancer treatment paradigm has traditionally been based on killing as many cancer cells as possible. Although this approach is curative for some patients, others develop resistance mechanisms that eventually stop once-beneficial treatments from working, often leaving them in a treatment void.

“Just like rivers continue to flow downward under the force of gravity and form the landscape, we know that tumors do that, too, under selective pressure—just like gravity, they find a path. They are in continual evolution, and we have increasingly better tools to discern what new mutations are being acquired, to understand how that cancer is surviving,” Tripathy said. He explained that an evolving concept in cancer medicine is to use the information gleaned from new technologies, such as liquid biopsies, to adapt patients’ treatments in real time so that they stay ahead of their tumors’ evolving resistance mechanisms. He believes a proactive, rather than a reactive, approach will become the new treatment paradigm.

“If we can understand the mechanisms of resistance and be able to monitor patients in real time, then we will be able to turn many cases of cancer into chronic diseases. Hopefully, [they will be] chronic conditions that allow patients to experience a generally good quality of life,” he said.

To adapt a patient’s treatment requires an understanding of the nature of that patient’s tumor profile, including whether they have any beneficial, harmful, or neutral mutations so that therapies targeting potentially actionable mutations can be identified and used for treatment planning. Recently, mutations in the ESR1 gene, which encodes for an estrogen receptor (ER), have been found to be a common cause of acquired resistance to endocrine therapy in patients with metastatic ER-positive breast cancer. This discovery spurred the development of novel therapies to target these mutations, including potent selective ER degraders (SERDs) or modulators (SERMs) such as lasofoxifene, which Tripathy is studying. The SERD elacestrant was shown be more effective than the current standard, fulvestrant, especially in cases with ESR1 mutations, in findings of the EMERALD trial (NCT03778931) presented at the 2021 San Antonio Breast Cancer Symposium (SABCS 2021).⁸

Lasofoxifene is being investigated in combination with the CDK4/6 inhibitor abemaciclib (Verzenio) in the phase 2 ELAINEII trial (NCT04432454) in patients with advanced or metastatic ER-positive, HER2-negative breast cancer whose tumors harbor an ESR1 mutation. The trial completed enrollment in June 2021, and initial data are expected in the first half of 2022.⁹

Tripathy noted that the National Cancer Institute (NCI) Molecular Analysis for Therapy Choice (MATCH) Screening Trial (NCT02465060) is providing significant assistance in advancing adaptive therapy. It is one of the first trials to match patients with cancer to a treatment based on genetic changes in their tumors rather than their cancer type. NCI-MATCH plans to enroll more than 6000 patients with advanced refractory solid tumors, lymphomas, or myelomas who have progressed on standard treatment and harbor certain genetic changes into 1 of more than 35 subprotocol studies, with most arms planning to enroll approximately 35 patients.¹⁰ Ten substudies in NCI-MATCH are currently open for enrollment.

Findings from various NCI-MATCH substudies have confirmed that targeting genetic changes in tumors, such as mutations, amplifications, and fusions, is an effective strategy and that genomic sequencing in patients with advanced cancers may be beneficial in guiding treatment decision- making.¹¹ “We’re sequencing everyone at MD Anderson with metastatic breast cancer because we may find a rare mutation that’s got a drug approved for it or in clinical trials, regardless of where the tumor originated,” Tripathy said.

NCI-MATCH data have led to plans for other large NCI basket trials such as ComboMATCH, which will test genomically directed combination regimens; MyeloMATCH, which will assign therapy for patients with acute myeloid leukemia and myelodysplastic syndromes based on genetic changes in their cancer cells; and ImmunoMATCH, which will use immune profiling to channel patients to treatments based on tumor mutational burden and γ interferon signature.^11,12 Tripathy expressed excitement about the PI3K/AKT pathway, a signal transduction pathway that was successfully targeted in the NCI-MATCH trial.

The PI3K/AKT pathway is one of the most frequently altered pathways in cancer, including genetic changes such as aberrant signaling, overexpression, sequence variations, and somatic copy number alterations. In the EAY131-Y subprotocol of the NCI-MATCH trial, 35 patients with AKT1 E17K-mutated metastatic tumors of various histologies were treated with capivasertib, an AKT inhibitor, at 480 mg orally twice daily for 4 days on and 3 days off weekly in 28-day cycles until disease progression or unacceptable toxicity. In patients with metastatic breast cancer who continued hormone therapy, capivasertib was reduced to 400 mg.¹³

The most prevalent cancers treated included patients with breast (n = 18) and gynecologic (n = 11) malignancies. The overall response rate across cancer types was 28.6% (95% CI, 15%-46%). One patient with endometrioid endometrial adenocarcinoma achieved a complete response and was still receiving treatment at 35.6 months. Nine patients had partial responses and continued to receive treatment at 28.8 months, which included 7 patients with hormone receptorpositive/ERBB2-negative breast cancer, 1 with uterine leiomyosarcoma, and 1 with oncocytic parotid gland carcinoma.¹³ Several trials are open at MD Anderson that target different components of this critical pathway both for breast and other cancers.

Tripathy expects data for several key trials focused on the AKT pathway to be released in 2022, including a follow-up trial of the EAY131-Y subprotocol with capivasertib. He also anticipates follow-up data from the phase 1/2 FAKTION trial (NCT01992952). The initial FAKTION trial data showed a nearly 6-month PFS improvement when capivasertib vs placebo was added to fulvestrant in women with advanced ER-positive/HER2negative breast cancer (median PFS, 10.3 vs 4.8 months, respectively).¹⁴

Based on these promising initial data, the phase 3 trial CAPItello-291 trial (NCT04305496) is currently recruiting patients. Investigators plan to enroll more than 800 patients with locally advanced or metastatic hormone receptor–positive/HER2-negative breast cancer in the study, which has an estimated primary completion date of May 2022. Additionally, capivasertib is being studied as first-line therapy for women with locally advanced or metastatic triple-negative breast cancer in the randomized, double-blinded, phase 3 CAPItello-290 trial (NCT03997123), where capivasertib vs placebo is being added to paclitaxel. This trial is seeking to enroll more than 900 patients and has an estimated primary completion date of March 2023.

Finding Therapies for Tumors with Low Expression of Targetable Biomarkers

For a tumor to be considered positive for a targetable biomarker, it must express a certain quantity of that biomarker, which is usually set at fairly high levels. It has been discovered, however, that such tumors may still express very low levels of the targetable biomarker, which may render them vulnerable to a treatment targeting that biomarker if a potent enough treatment is found.

This is the story that is now unfolding with HER2-positive breast cancers. Although patients with HER2-positive breast cancers historically have had a lower likelihood of cure and survival, this changed with the advent of HER2-targeted therapies, including trastuzumab. Until recently, however, only patients with strong HER2 expression could be treated with such agents, but Tripathy said that may soon change.

He noted the development of fam-trastuzumab deruxtecan-nxki (Enhertu), a HER2-directed antibody-drug conjugate currently approved for patients with previously treated unresectable or metastatic breast cancer and for those with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received prior therapy. In the pivotal DESTINY-Breast01 trial (NCT03248492), HER2 positivity was defined as an immunohistochemistry (IHC) 3+ score or a positive result on in situ hybridization (ISH+), with testing conducted on tissue.¹⁵

“That’s probably one of the most potent drugs we have against HER2 cancers. And it turns out that it may also work in HER2-low cancer,” Tripathy said.

At SABCS 2021, investigators presented the results of the phase 2 DAISY study (NCT04132960), which tested trastuzumab deruxtecan in patients with previously treated advanced breast cancer in 3 biomarker-defined cohorts: HER2-overexpressing (HER2 IHC3+ or HER2 IHC2+/ISH+); HER2 low-expressing (IHC1+ or IHC2+/ISH-); and HER2 nonexpressing (IHC0+). Trastuzumab deruxtecan demonstrated a best objective response (BOR) rate of 37.5% in patients with low HER2 expression and 29.7% in patients with no detectable HER2 expression.¹⁶ In contrast, the BOR among patients with HER2 overexpression was 70.6%, which was comparable to the confirmed objective response rate (ORR) of 79.7% reported with trastuzumab deruxtecan as second-line therapy in the phase 3 DESTINYBreast03 study (NCT03529110).¹⁷

The findings in low HER2-expressing tumors from the DAISY study support those previously reported in 2020 in a subgroup analysis of a first-inhuman, phase 1b study (NCT02564900) assessing trastuzumab deruxtecan, which showed an ORR of 37.0% among heavily pretreated patients with HER2 low-expressing advanced or metastatic breast cancers.¹⁸ The finding of a nearly 30% BOR in the DAISY trial among individuals with no detectable HER2 expression, however, has led to some questions, including whether those individuals may have HER2 expression levels below what current assays are able to detect. Another presentation from SABCS 2021 may lend support to that theory.¹⁹ According to an analysis of data from 1400 global laboratories, current standard assays measuring HER2 expression were not able to efficiently differentiate between HER2 expression levels of IHC0 and IHC1+. More studies are under way to understand the distinct biology in HER2-low breast cancers.

Improving Outcomes in Patients with Brain Metastases

The blood-brain barrier has long been difficult to cross. However, some newer agents are able to pass through this barrier and are potent enough to exert their effects on brain metastases, Tripathy said. In patients with HER2-positive breast cancer with brain metastases, one such agent is tucatinib (Tukysa).

In the HER2CLIMB trial (NCT02614794), 612 patients with HER2-positive breast cancer with and without brain metastases were randomized to receive tucatinib or placebo in combination with trastuzumab and capecitabine. Overall, 47.5% (n = 291) of the total population had brain metastases or a history of brain metastases at baseline, according to pivotal findings reported by Rashmi K. Murthy, MD, MBE, of MD Anderson and colleagues.²⁰

The median PFS was 7.8 months for patients who received the regimen containing tucatinib compared with 5.6 months for those who received placebo (HR for disease progression or death, 0.54; 95% CI, 0.42-0.71; P < .001). Findings were similar for patients with brain metastases; the median PFS was 7.6 months with tucatinib vs 5.4 months with placebo (HR, 0.48; 95% CI, 0.34-0.69; P < .001).²⁰ In April 2020, the FDA approved the tucatinib regimen for patients with previously treated advanced unresectable or metastatic HER2-positive breast cancer based on findings from the study.²¹

New data presented at SABCS 2021 from an exploratory analysis of HER2CLIMB results showed that adding tucatinib to trastuzumab and capecitabine in patients with active and stable brain metastases improved the median OS by 9.1 months vs trastuzumab and capecitabine alone (21.6 months vs 12.5 months, respectively; HR, 0.60; 95% CI, 0.44-0.81).²²

Meanwhile, updated data from the DESTINYBreast03 study presented at SABCS 2021 also showed impressive response rates in patients with brain metastases. For participants with stable brain metastases at baseline (n = 82), the median PFS was 15.0 months with trastuzumab deruxtecan compared with 3.0 months with ado-trastuzumab emtansine (Kadcyla; T-DM1), which translated into a 75% reduction in the risk of progression (HR, 0.25; 95% CI, 0.310.45). Additionally, the ORR for patients with stable brain metastases at baseline was 67.4% for patients who received trastuzumab deruxtecan vs 20.5% for those treated with T-DM1.²³

“We’re at the point now where [individuals] with brain metastases can live for many years. Now the next barrier to cross is going to be treating nonHER2-positive brain metastases,” Tripathy said.

He noted that several agents are being examined that may provide benefit to patients with brain metastases without HER2-positive tumors, including sacituzumab govitecan-hziy (Trodelvy). The FDA, which initially approved the drug on an accelerated basis in April 2020, granted regular approval the following year for patients with unresectable locally advanced or metastatic triple-negative breast cancer previously treated with 2 or more prior systemic therapies, at least 1 of which was for metastatic disease.²⁴

The regular approval was based on data from the phase 3 ASCENT trial (NCT02574455), which included patients with and without brain metastases. Among all randomized patients, median PFS in the sacituzumab govitecan plus chemotherapy arm was 4.8 months (95% CI, 4.1-5.8) compared with 1.7 months (95% CI, 1.5-2.5) in those receiving chemotherapy alone (HR, 0.43; 95% CI, 0.35-0.54; P < .0001). Median OS was 11.8 months (95% CI, 10.5-13.8) and 6.9 months (95% CI, 5.9-7.6), respectively (HR, 0.51; 95% CI, 0.41-0.62; P < .0001).²⁴ Studies assessing sacituzumab govitecan in CNS metastases are under way.

Exploring Immunogenicity

Cancer stem cells (CSCs) were discovered in leukemia in the mid-1990s.²⁵ Since their discovery, they have been considered a promising therapeutic target. “Most cells have the capacity to move back into their stem state, and cancer cells do that to escape treatment,” Tripathy explained, adding that this leads to the cancer becoming less immunogenic.

Tripathy is working on a project exploring epithelial-mesenchymal transition (EMT), a complex gene expression program that enables cancer cells to suppress their epithelial features and change into mesenchymal/CSC-like ones, giving the cell mobility and the capacity to migrate from its primary site, which can lead to metastases. Using a proprietary platform called ApoStream that isolates circulating tumor cells (CTCs) for research use, Tripathy and colleagues were able to detect chemotherapy-resistant micrometastatic disease expressing an EMT-like or CSC-like phenotype in the neoadjuvant setting. The presence of EMT-CTCs or CSC-CTCs was not predictive, however, of tumor response to neoadjuvant chemotherapy.²⁶

Focusing on Field of Cancer Energetics

“Cancer cells are highly metabolic and programmed to focus their functions primarily on growth, which requires more energy,” Tripathy said. This understanding has given rise to the field of cancer energetics, which focuses on understanding how cancer cells derive their energy so that their metabolic pathways may become targets for anticancer therapies.

Several important observations have been made in cancer energetics since the 1920s when Otto Warburg, a German physician and Nobel laureate, observed that cancer cells consume more glucose and produce more lactate than normal cells and suggested that cancer cells rely on adenosine triphosphate (ATP) production via the glycolytic pathway to satisfy their energy requirements.^27,28 More recent observations suggest a metabolic symbiosis, with glycolytic and oxidative tumor cells mutually regulating their energy metabolism. Hypoxic cancer cells use glucose for glycolytic metabolism and release lactate. Oxygenated cancer cells then use that lactate as fuel.

“Our bodies also have their own macro level type of energy generation that has a lot to do with our quality of life and whether we gain or lose weight and our energy levels or sleep states. So at that level, understanding the biology of energetics has a whole different meaning,” Tripathy said. At MD Anderson teams are working on both the macro and micro sides of cancer energetics, which is an area of research that he also is actively involved with and one that he sees leading to promising developments in the near future.

Much of the cancer metabolism research is being done in the Gan Laboratory.²⁹ Areas of focus include the role and mechanisms of ferroptosis, an iron-dependent, nonapoptotic form of regulated cell death involving lipid peroxidation, cellular metabolism, tumor suppression, and cancer therapy, as well as cystine metabolism-induced nutrient dependency and its implication in cancer therapy. The hope is that a better understanding of ferroptosis and nutrient dependency will translate into novel efficacious cancer therapies. In June 2021, investigators from the Gan Laboratory published preclinical findings pointing to a possible target, dihydroorotate dehydrogenase (DHODH), with DHODH inhibitors in GPX4low cancers being a potential strategy to inhibit ferroptosis and lead to cancer cell death.³⁰

References

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