Category: 3. Business

For patients with ESR1-mutated, hormone receptor (HR)-positive, HER2-low metastatic breast cancer, progression on initial CDK4/6 inhibitor-based therapy presents a key sequencing decision. Claudine Isaacs, MD, professor of medicine and oncology, associate director of Clinical Research, and leader of the Clinical Breast Cancer Program at the Georgetown Lombardi Comprehensive Cancer Center, and the medical director of the Jess and Mildred Fisher Center for Hereditary Cancer and Clinical Genomics Research, moderated a virtual Case-Based Roundtable event for oncologists in Georgia and Virginia. In the event, participants debated whether to use elacestrant (Orserdu) or trastuzumab deruxtecan (T-DXd; Enhertu) in the second-line setting.

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CASE SUMMARY

• A 52-year-old woman with a history of:
  • 2.4-cm, grade 2, node-negative invasive ductal carcinoma (IDC), HR positive, HER2 immunohistochemistry (IHC) 1+, Ki-67 20% of the right breast, 21-gene recurrence score of 27
  • Initial therapy included chemotherapy, radiation therapy, and 5 years of adjuvant anastrozole
• Three years after completing anastrozole, she reported new lower back and hip pain during a routine office visit.
  • Laboratory results: alanine and aspartate aminotransferase normal, elevated alkaline phosphatase, normal bilirubin, mild anemia
  • Imaging: multiple masses (largest 2 cm) in right lobe of liver and sclerotic lesions in multiple vertebrae and bilateral iliac crests
  • Liver biopsy: carcinoma consistent with breast primary; estrogen receptor 90%, progesterone receptor 60%, HER2 IHC 1+
  • ECOG performance status: 1
• Treatment: letrozole (Femara) plus ribociclib (Kisqali) with denosumab
  • Good clinical response with reduction in size of liver masses
  • One dose reduction to 400 mg of ribociclib due to neutropenia

Sixteen months after starting therapy

• Follow-up imaging for response assessment showed new liver lesions and 1 new sclerotic lesion in T12 suspicious for malignancy
  • Mild abdominal pain
  • Laboratory results: mildly elevated transaminases, about 2 times the upper limit normal
• Circulating tumor DNA analysis confirmed an ESR1 mutation; no evidence of PIK3CA/AKT1/PTEN mutations

DISCUSSION QUESTION

What is the rationale for your selection of treatment in this patient?

Claudine Isaacs, MD: For this patient who’s progressed after more than 12 months with an ESR1 mutation and HER2-low disease with no mutation or alteration in the PI3 kinase AKT pathway, would you choose elacestrant, T-DXd, everolimus and endocrine therapy, fulvestrant and abemaciclib [Verzenio], other chemotherapy, or something else?

Soren Caffey, MD: My option is elacestrant, if I’m getting the case correctly with the ESR1 mutation and at the time of progression, more than 12 months on first line therapy. I don’t know what others’ thoughts might be.

Walid L. Shaib, MD: I thought the same. Patients who were exposed to elacestrant who had longer time on the CDK4/6 inhibitor had better progression-free survival [PFS], as opposed to the overall population that was discussed in the paper.¹ I will try to use the T-DXd maybe later on, at the time of progression.

Cesar Santa-Maria, MD, MSCI: I think elacestrant is a very reasonable option. Another option to consider is fulvestrant and abemaciclib. I’m not terribly impressed by the net improvement and PFS of either. But I’ve certainly seen some patients do well with that CDK4/6 inhibitor after CDK4/6 inhibitor approach, so I think that’s reasonable. You get a little more toxicity with it, though.

Rao Moravineni, MD: I’m not impressed with elacestrant as well…. I thought there would be much more benefit, however, [with the patient] being more than 3 years out of therapy…I would do elacestrant first.

Nagender Mankan, MD: I was leaning towards T-DXd, then elacestrant. I’ve never had a similar scenario, but I have had other patients with good response to T-DXd, even for 1+ IHC. I have very few patients with ESR1, much more within HER2 1+ IHC.

Isaacs: When you’re thinking about sequencing then in somebody like that, would you reach for T-DXd first or would you reach for elacestrant, or some other endocrine therapy at this point? Is there something in this patient that’s making you think about T-DXd first or at some point?

Mankan: I don’t know the data to compare the 2, but T-DXd response rate was more than the ESR1-based response rate [with elacstrant]….^1,2 I don’t know how that plays a role, but my heart is [leaning] towards T-DXd.

Ming Chi, MD: I personally would prefer the elacestrant over T-DXd in this situation, only because it’s a slow progression and it seems like the newer lesions are not a high disease burden. Otherwise, after a year or so, if the disease progression is dramatic, I’d probably want to jump to T-DXd, because I am not comfortable with elacestrant in that situation.

Isaacs: The thing that we’re always grappling with and trying to figure out the best thing to do in this country, where we have access to so many different agents, is the best way to sequence them. I think we would all agree that with a patient like this with an ESR1 mutation and HER2-low disease, we have lots of options. I personally would reach for elacestrant first in this patient, because she has an ESR1 mutation and because she’s had an appropriate and good response to endocrine therapy plus a CDK4/6 inhibitor, and T-DXd would certainly be in the next line or a further down line of therapy for this patient, given the data that are out there on T-DXd and its activity.²

Register today to join a Case-Based Roundtable near you.

_{DISCLOSURES: Isaacs previously reported consulting role for Arvinas, AstraZeneca, Genentech, Novartis, Pfizer, Gilead Sciences, Merck, and Seattle Genetics, and receiving royalties from Wolters Kluwer (UptoDate), and McGraw-Hill (Goodman and Gillman).}

_{Santa-Maria previously reported a consulting or advisory role for Polyphor, Genomic Health, Halozyme, Bristol Myers Squibb, Athenex, Seattle Genetics, Merck, and Pfizer.}

_References:

_{1. Bidard FC, Kaklamani VG, Neven P, et al. Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: Results from the randomized phase III EMERALD trial. J Clin Oncol. 2022;40(28):3246-3256. doi:10.1200/JCO.22.00338}

_{2. Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690}

The firm has moved into levels 16 and 17 of 33 Alfred St today, occupying 2,600 square metres of office space – an increase of 1,850 square metres from its previous home at 1 Macquarie Place. 

The heritage-listed building – Sydney’s first skyscraper – has been refurbished to suit the needs of modern businesses and to improve sustainability. The Pinsent Masons fitout was designed by leading architecture firm Bates Smart and constructed by national fitout and construction services specialist Shape, who also designed and constructed the fitout of the firm’s Melbourne office at 101 Collins Street in 2023.

Partner and Head of Sydney, Sadie Andrew, said the move to 33 Alfred St was an important development for Pinsent Masons.

’33 Alfred Street is an iconic address in Sydney, and we are incredibly excited to be calling it our home,’ Sadie said.

‘Our new office will provide us with the space and flexibility to efficiently collaborate with each other, our colleagues across our multinational network and our clients. It will also aligns with our sustainability goals, as 33 Alfred Street is targeting 5.5-Star NABERS Energy and 6-Star Green Star Office As Built v3 ratings.’

Partner and Head of Australia, Matthew Croagh, said the move was an investment in the future of the firm in Australia.

‘We are proud of what we have achieved so far in our 10 years in Australia, but we are very much just scratching the surface,’ Matthew said.

‘We have launched new practice teams in Australia over the past three years and enhanced the way we develop our people. This expansion has demanded better facilities for our people to thrive. The move into 33 Alfred Street is another sign of the investment we are willing to make to make to ensure the success of the firm and the clients with which we work.’

Oct 6 (Reuters) – MapLight Therapeutics, a clinical-stage biotech backed by Novo Holdings, said on Monday it is targeting a valuation of up to $704.3 million in its U.S. initial public offering, amid a rebound in investor appetite for new issues.

The Redwood City, California-based firm plans to raise $250.8 million by offering 14.8 million shares priced at $17 apiece. The stock is expected to trade on the Nasdaq under the ticker symbol “MPLT.”

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U.S. IPO activity has picked up in recent months, reversing a slowdown from earlier in the year — when trade-policy uncertainty curbed momentum — as recent listings have attracted strong investor demand.

MapLight is developing drugs for central nervous system disorders, especially schizophrenia and Alzheimer’s disease psychosis, autism spectrum disorder and Parkinson’s disease.

The company reported a net loss of $52.2 million for the six months ended June 30, compared with a net loss of $37.3 million a year earlier.

In July, MapLight raised about $372.5 million in a funding round co-led by Forbion and Life Sciences at Goldman Sachs Alternatives.

Morgan Stanley, Jefferies, Leerink Partners and Stifel are the underwriters for the offering.

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This article first appeared on GuruFocus.

Oct 6 – Nvidia (NASDAQ:NVDA) may not be done surprising Wall Street. Despite a strong year-to-date rally near 40%, Melius Research analyst Ben Reitzes believes the chipmaker’s momentum can continue, lifting its shares another 45% to $275. He argues that predictions of a slowdown in AI growth overlook the sheer scale of spending underway across the tech industry.

The analyst pointed out that major companies are racing to secure AI infrastructure. OpenAI’s new partnership with Advanced Micro Devices (NASDAQ:AMD), involving six gigawatts of chips and a potential purchase of 160 million AMD shares, underscores how quickly capital is pouring into the sector.

Nvidia, for its part, has committed $100 billion toward OpenAI and signed a $6.3 billion deal with CoreWeave (NASDAQ:CRWV) to lock in computing capacity.

Reitzes sees these moves as strategic, not circular. With AI workloads growing rapidly and data center upgrades continuing, he projects Nvidia could control more than 40% of the AI infrastructure market by 2030. That could translate to roughly $800 billion in potential market share and strong multi-year revenue expansion for the industry’s current leader.

By Christine Ji

Oracle’s massive data-center buildout will require the company to take on new financing strategies – and new risks

Oracle issued $18 billion of debt in September to finance its data-center buildout.

Since Oracle Corp. stunned investors last month with its massive artificial-intelligence pipeline, shares of the company have pulled back from their peak as questions emerge about how the company will afford the massive data-center buildout required for its growth.

Oracle (ORCL) doesn’t yet have the AI infrastructure to fulfill its $455 billion of remaining performance obligations, or the contracted future revenue from signed deals not yet delivered, which is a key concern among investors.

With nearly $6 billion in negative free cash flow over the last four quarters, Oracle is facing questions about how it can afford its AI ambitions. Oracle’s stock was trading at $291.59 on Monday, up 75% year to date but down 16% from its all-time high of $345.72.

Some on Wall Street are optimistic about Oracle’s ability to execute on its contracts. In a note Monday, Mizuho analyst Siti Panigrahi called funding concerns “transitory.” He believes Oracle “can leverage a combination of debt, vendor financing, leasing and creative partnership structures similar to those emerging across the broader AI ecosystem.”

However, Michael Green, portfolio manager and chief strategist at Simplify Asset Management, believes implementing these financing strategies will further push the AI trade into bubble territory. High levels of leverage will create hidden risks that can dramatically worsen if AI demand turns out to be lower than expected, Green told MarketWatch.

Oracle has already been getting “creative” with its financing, according to Baird managing director Ted Mortonson. Last month, the company issued a $18 billion 40-year bond, surprising some on Wall Street with its long duration. Oracle has also increasingly turned to finance leases to fund its data centers in the last year, allowing it to spread out the cost of an asset over its useful life instead of incurring a large upfront cash-flow hit associated with traditional capital expenditures.

Panigrahi also suggested that Oracle could follow a new “blueprint” for the industry by leasing Nvidia Corp.’s (NVDA) graphics processing units instead of purchasing them, referencing a report from The Information about OpenAI’s similar plans.

Also read: Why Oracle’s ‘jumbo’ AI-fueled bond deal is so unusual

While Panigrahi anticipates Oracle’s free cash flow to remain negative in the coming quarters, he sees this trend as “a timing issue rather than a structural concern given the strong visibility from multi-year customer contracts,” pointing out that data centers are monetized “within weeks” once they come online. Panigrahi sees a path for Oracle to cross the trillion-dollar market-capitalization threshold, joining the ranks of infrastructure peers like Microsoft Corp. (MSFT), Amazon.com Inc. (AMZN) and Alphabet Inc. (GOOGL) (GOOG).

However, if demand for AI data centers doesn’t materialize, then Oracle will be on the hook for lease and debt payments that could further eat into its free cash flow, Green pointed out. In this case, these obligations would start hitting Oracle’s balance sheet at a time when the company’s fundamentals are deteriorating from a lack of AI revenue.

The financing questions Oracle faces are hardly unique among the biggest AI players, as more companies add debt to their balance sheets and enter into circular financing agreements.

For example, OpenAI is reportedly considering tapping into debt markets to fund future data-center builds, according to a Reuters report. Additionally, OpenAI’s recent partnership with Advanced Micro Devices Inc. (AMD) gives the company valuable stock warrants that OpenAI could utilize to help pay for more AI hardware.

Panigrahi acknowledged that the prominence of vendor financing could be “inflating valuations” across the AI value chain but said that risk would be mitigated as long as demand from OpenAI, Anthropic, Google, Meta (META) and other model providers remained robust. For Oracle, the stakes are high as it leverages up, and investors will be carefully monitoring its funding plans as it moves forward with its AI buildout.

Representatives from OpenAI and Oracle did not immediately respond to requests for comment.

Read on: AMD’s stock soars toward its best day in 9 years. Here’s why OpenAI wants a stake.

-Christine Ji

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  10-06-25 1704ET
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