$AZN #Enhertu Wins #ASCO22 Outshines Modest $GILD Trodelvy TROPiCS-02 Data

Enhertu ASCO data presentation received a standing ovation for pivotal DESTINYBreast04
in HER2-low BC, clearly signaling physician enthusiasm for the clinical benefit
in 2L+ setting. HER2-low makes up the majority (60-65%) of HER2- BC, which will further
challenge Trodelvy potential adoption in HR+/HER2- if approved. Trodelvy TROPiCS-02
data in HR+/HER2- BC showed a significant 1.5mo PFS benefit (p=0.0003) and numerical
1.6mo OS benefit (p=0.14) over chemo. While not directly comparable, Enhertu in HR+/
HER2-low had a 4.7mo PFS and 6.4mo OS benefit over chemo, both reaching stat sig.
While Trodelvy approval on TROPiCS-02 data is not a given, as Gilead decides whether
to wait for more mature OS, we believe Enhertu would be preferred in HER2-low patients
over Trodelvy, which also puts TNBC revenues at risk, given majority of these patients are
HER2-low. Separately, partial clinical holds on Magro MM and DLBCL studies were lifted,
enabling all Magro trials to resume.
• Trodelvy 1.5mo PFS benefit in HR+/HER2-. Detailed TROPiCS-02 data at ASCO
showed a 5.5mo mPFS for Trodelvy versus 4.0mo for chemo, representing a 1.5mo PFS
improvement (HR=0.66, p=0.0003). The small PFS difference, while significant, draws
concern around clinical meaningfulness, particularly given a trend toward OS benefit
that was only nominally better than PFS. We believe TROPiCS-02 enrollment of highly
refractory patients led to the low mPFS, which is reflected in large number of patients
rapidly progressing within the first 2 months. While PFS curves widen after 6 months,
we expect physicians will make treatment decisions on Trodelvy's 1.5mo mPFS benefit
if approved before OS matures.
• Numerical 1.6mo OS benefit may not improve much. First planned interim OS
analysis showed 13.9mo mOS for Trodelvy versus 12.3mo for chemo, reflecting a
numerical 1.6mo OS benefit (HR=0.84, p=0.14). Gilead may conduct another OS
analysis in 2H22 or wait until early 2024 to avoid spending statistical alpha. We believe
OS can reach stat sig, but may not greatly improve over the 1.6mo difference, given
about 80% of study patients have already passed 12 months on study.
• Enhertu HER2-low data celebrated by docs. HER2-negative (HER2-) is defined by
IHC 0, 1+, or 2+/ISH-, with HER2-low encompassing the two IHC categories with
minimally detectable HER2 (1+ and 2+/ISH-). Enhertu DESTINY-Breast04 data showed
a 4.8mo PFS benefit (9.9 vs. 5.1mo mPFS, HR=0.50, p<0.0001) and 6.6mo OS benefit
(23.4mo vs. 16.8mo mOS, HR=0.64, p=0.001) over chemo in all HER2-low patients.

In the HR+ subgroup, Enhertu showed a similar improvement with
10.1mo mPFS (4.7mo benefit over chemo) and 23.9mo mOS (6.4mo benefit). For HR-, which
defines TNBC and was an exploratory endpoint, Enhertu had an 8.5mo mPFS (2.9mo benefit)
and 18.2mo mOS (9.9mo benefit). In comparison, Trodelvy TNBC ASCENT data showed a
4.8mo mPFS (3.1mo benefit) and 11.8mo mOS (4.9mo benefit)
 Study differences may not matter to physicians. Trodelvy TROPiCS-02 and ASCENT
(TNBC) studies clearly enrolled more severe patients than Enhertu DESTINY-Br04, which
limits Trodelvy's overall benefit. Median prior chemo was 3 for Trodelvy studies compared to 1
for Enhertu study. All TROPiC-02 patients had prior CDK4/6i versus 70% of Enhertu HR+
patients. However, sub-analysis of prior CKD4/6i with Enhertu showed similar benefit (10.0mo
vs. 5.4mo mPFS) as the overall HR+ subgroup. Given physician enthusiasm, we believe
Enhertu will be preferred in HER2-low patients, which represents up to 65% of HR+/HER2-
and TNBC patients, if given a broad label.
 Enhertu's ILD risk surprisingly not limit enthusiasm. Known safety risk of interstitial lung
disease (ILD) for Enhertu did not dampen the clinical benefit for physicians. DESTINY-Br04
reported 12% ILD cases, including 0.8% Grade 5. Trodelvy's lack of ILD in its studies was a
highlighted advantage over deruxtecan (DXd) ADCs, including Enhertu and Daiichi's Trop2
ADC Dato-DXd. Enhertu data suggests that strong efficacy will outweigh the ILD risk,
including fatal cases.
 Remaining holds lifted from Magro studies. The FDA removed the partial hold on the
Phase 2 monotherapy studies in multiple myeloma and DLBCL. While the DLBCL study was
fully enrolled ahead of the hold, the MM study had not begun recruiting. No new safety signals
were identified during the hold and no further modification of the safety language was
implemented. Updated Phase 1b Magro data at ASCO showed comparable response rates to
venetoclax + AZA but lower response rates in 1L TP53m AML (48.6%) versus venetoclax +
AZA (55% in Phase 3).

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