Dri Healthcare Trust T.DHT.UN

RBC

[retiredcf]

December 11, 2024

DRI Healthcare Trust
Highlights from the San Antonio Breast Cancer Symposium

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Sentiment: Neutral

Our view: We are attending the SABCS in San Antonio this week, where LLY presented the Phase 3 data from the EMBER-3 trial for its oral SERD, imlunestrant, a potential competitor to Orserdu (elacestrant). Orserdu is the largest contributor (~28%) to our estimated gross NAV for DRI. As such, we are closely monitoring the upcoming competition for Orserdu. In patients with an ESR1 mutation, median PFS was 5.5 months with LLY's imlunestrant vs. 3.8 months with SOC ET [HR=0.62 (95% CI 0.46-0.82)]. In the Phase 3 EMERALD trial for Orserdu, the median PFS was 3.8 months with Menarini's elacestrant vs. 1.9 months with SOC ET [HR=0.55 (95% CI 0.39-0.77)], suggesting Orserdu may have a better efficacy compared to LLY’s imlunestrant. We note that, unlike the EMERALD trial, the EMBER-3 trial did not require previous treatment with a CDK4/6 inhibitor. Additionally, LLY's EMBER-3 trial showed median PFS of 9.4 months for imlunestrant-abemaciclib combination vs. 5.5 months for imlunestrant alone [HR=0.57 (95% CI 0.44-0.73)]. We note that the combination trials for Orserdu are currently ongoing. Our base case outlook on Orserdu accounts for the introduction of competing products into the market. Our peak sales estimate of $510MM in 2025 remains well below the consensus revenue forecasts for competitor drugs that are currently under development, with Visible Alpha consensus forecasts implying these drugs to become blockbuster drugs (>$1B).

EMBER-3 trial results - Monotherapy: In patients with an ESR1 mutation, median PFS was 5.5 months with imlunestrant vs. 3.8 months with SOC ET [HR=0.62 (95% CI 0.46-0.82); p-value<0.001]. In all patients, the median PFS was 5.6 months with imlunestrant vs. 5.5 months with SOC ET [HR=0.87 (95% CI 0.72-1.04); p-value 0.12] and did not reach statistical significance. With the usual caveat of exercising caution when comparing clinical trials, we note that in the Phase3 EMERALD trial for Orserdu (elacestrant), the median PFS was 3.8 months with elacestrant vs. 1.9 months with SOC ET [HR=0.55 (95% CI 0.39-0.77); p-value=0.0005]. In the overall patients, the median PFS was 2.8 months with elacestrant vs. 1.9 months with SOC ET [HR=0.70 (95% CI 0.55-0.88)] and was statistically significant.

Imlunestrant and abemaciclib (CDK4/6i) combination showed significant improvement in PFS vs. monotherapy: Imlunestrant- abemaciclib combination showed significantly improved PFS vs. imlunestrant in all patients, regardless of ESR1 mutation status. Median PFS was 9.4 months for the combination vs. 5.5 months for imlunestrant alone [HR=0.57 (95% CI 0.44-0.73); p-value <0.001]. LLY noted that the PFS benefit of the combination was consistent across subgroups, regardless of ESR1 mutation, or PI3K pathway mutation status, and including patients who had previously received CDK4/6 inhibitor treatment.

Grade 3 or higher adverse events: In the EMBER-3 trial, the incidence of grade 3 or higher adverse events was 17.1% with imlunestrant, 20.7% with standard therapy, and 48.6% with imlunestrant–abemaciclib. In the EMERALD trial for Orserdu, the incidence of grade 3 or higher adverse events was 27.0% vs. 20.5% with SOC therapy.

Takeaways related to Orserdu: Orserdu is currently the sole approved oral selective estrogen receptor degrader (SERD) targeting tumors with ESR1 mutations, which occur in up to 50% of ER+/HER2- advanced or mBC tumors following previous endocrine therapy (ET) in the metastatic setting. Menarini presented real-world progression-free survival (rwPFS) results of Orserdu in adult patients with ER+/HER2-, advanced or metastatic breast cancer (mBC). The analysis of the overall population showed a median rwPFS of 6.8 months. For patients with 1-2 previous lines of ET for mBC, the median rwPFS was 8 months. Additionally, Menarini presented updated results for combination trials that continue to demonstrate promising PFS data and a favorable safety profile, without any new indications of toxicity.

Influence of prior treatment outcomes and PIK3CA mutations on clinical investigators (CIs) usage of oral SERDs: According to

a survey of 20 CIs, usage of oral SERDs by clinical investigators (CIs) is influenced by the duration of benefit from prior CDKi/ fulvestrant treatments and the presence of PIK3CA mutations. A shorter duration of benefit and the presence of PIK3CA mutations were found to result in less frequent usage of oral SERDs. For a standard case of a 65-year-old woman with recurrence of bone metastases 18 months after CDKi/fulvestrant, the majority of investigators (19 out of 20) advocated for Orserdu (elacestrant). However, if the benefit from prior CDKi/fulvestrant lasted only 6 months, a minority (4 out of 20) remained in favor of elacestrant. The presence of a PIK3CA mutation divided opinions, leading to a split preference between elacestrant (10 CIs) and capivasertib plus ET (7 CIs). With older patients, such as an 80-year-old, more CIs opted for elacestrant rather than capivasertib/ET. Regarding investigational SERDs such as imlunestrant and camizestrant, CIs in the survey were generally unable to differentiate their efficacy and tolerability from elacestrant based on the available data or considered them similar.

Lack of consensus on second-line treatment selection in relation to biomarker profiles: The results of an April 2024 survey involving 152 US oncologists was presented at SABCS that underscored the significance of biomarker testing in guiding treatment decisions for patients with metastatic HR+/HER2- breast cancer, particularly concerning second-line (2L) treatments. In only 4 of the 12 patient profiles, a majority of the oncologists agreed on the best 2L treatment approach. These profiles stood out because they involved specific biomarker alterations, leading to higher consensus among oncologists. In the remaining 8 patient profiles, there was no strong consensus among the oncologists. This divergence was especially true for patients with only PIK3CA mutations or those with both PIK3CA and ESR1 mutations. For these profiles, the oncologists chose a variety of targeted treatments, indicating that the best therapeutic approach is less clear in these scenarios.

RBC base case outlook on Orserdu - Incorporates competitor products to enter the market: In our base case for Orserdu, we forecast $510MM of peak sales in 2025E after which we forecast sales of the drug to decline 58% to $215MM by 2035 due to heightened competition. Orserdu patents last until January 2038, at which time royalties cease. We noted that our peak sales estimate remains well below the consensus peak revenue forecasts for competitor drugs that are currently under development. Visible Alpha consensus forecasts are implying these drugs to become blockbuster drugs (>$1B).

Other near-term competitor readouts. Vepdegestrant, an investigational, oral, proteolysis-targeting chimeric (PROTAC) protein degrader is being co-developed by Arvinas and Pfizer. The drug is being developed as a potential monotherapy and as part of combination therapy across multiple treatment settings for ER+/HER2- mBC. Arvinas expects to report topline data from the Phase 3 VERITAC-2 monotherapy trial in the 2L+ setting in Q1/25.

Roche’s giredestrant is expected to have a data readout from the persevERA (1L mBC) trial in 2025. persevERA is a Phase 3 study to evaluate the efficacy and safety of giredestrant combined with palbociclib compared with letrozole combined with palbociclib in patients with ER+/HER2- locally advanced (recurrent or progressed) or metastatic breast cancer. The primary outcome measure is progression-free survival (PFS). Roche is also running a Ph2 trial of giredestrant in grade 1 endometrial cancer.

AstraZeneca’s camizestrant is expected to have a data readout from the SERENA-6 trial in 2025. SERENA-6 is a Phase 3 study to assess switching to AZD9833 (camizestrant, oral SERD) + a CDK4/6 inhibitor vs. continuing an aromatase inhibitor (letrozole or anastrozole) + a CDK4/6 Inhibitor in HR+/HER2- mBC patients with detectable ESR1 mutations without disease progression during 1L treatment with an aromatase inhibitor + CDK4/6 inhibitor. The primary outcome measure is progression-free survival (PFS).

Lasofoxifene, a next-generation non-steroidal selective estrogen receptor modulator (SERM) is being developed by Sermonix Pharma (private co.) and is currently in Phase 3 trails. The ELAINE III trial is evaluating lasofoxifene combined with Verzenio (abemaciclib, CDK4/6 inhibitor) compared with fulvestrant combined with Verzenio (abemaciclib, CDK4/6 inhibitor) in locally advanced or metastatic ER+/HER2- breast cancer with an ESR1 mutation.