ASCO 2024 commentary: data and therapeutic standouts

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Conference

ASCO 2024 commentary: data and therapeutic standouts

By The Dedham Group and Citeline

Matthew Cunningham, The Dedham Group

Matthew Cunningham, The Dedham Group

This year’s data presented at ASCO only reinforced the importance of patient identification. Countless presentations discussing novel targets such as EGFR, ALK & KRAS emphasized the ever-increasing importance of making sure every patient is tested appropriately. Data from other trials such Enhertu’s DESTINY-BREAST06 will change the way that physicians have been interpreting test results for the past two decades. In addition to novel targets, trials continue to press innovation into earlier lines of therapy and non-metastatic settings with both AZ’s Tagrisso & Novartis’ Kisqali making waves. Ensuring eligible, non-metastatic patients receive appropriate therapy will be critically important and potentially more complex for oncologists than simply ensuring metastatic patients are tested appropriately.

Incredible innovation continues to drive forward progress in across indications, with vaccines, radiotherapies and solid tumor cellular therapies not only representing novel mechanisms of action, but truly novel delivery vehicles. While the progress being driven at sophisticated trials sites is undeniable, the ability for the broader oncology community to adopt these complex therapies will ultimately drive the true impact of the science presented this weekend – Matthew Cunningham, Partner, The Dedham Group

Merck + Moderna Readouts

Aaron McKeon-Fish, The Dedham Group

Aaron McKeon-Fish, The Dedham Group

Immunotherapies continue to be established as a critical component of the standard of care across various tumor types. At ASCO, Keytruda in combination with mRNA-4175, the cancer vaccine co-developed by Merck and Moderna, showed strong efficacy in patients with high-risk melanoma. The combination acts through driving a more robust immune response against tumor cells than a single immunotherapy, such as Keytruda, alone.

However, the concern with cancer vaccines has always been late relapses that could occur, where the efficacy benefit wanes over time. The data presented from the KEYNOTE-942 trial suggests durable efficacy, though, where benefit has largely been sustained as part of the 3-year follow-up. While there is great potential for patients, novel modalities that are individualized for patients like mRNA-4175 can present barriers to adoption and uptake that will be critical to overcome in ensuring the access needed to drive true impact – Aaron McKeon-Fish, Partner, The Dedham Group

AstraZeneca’s Success

Anna Simmons, Citeline

Anna Simmons, Citeline

After a standing ovation at ASCO 2022, which preceded Enhertu’s landmark FDA approval for HER2-low breast cancer, Enhertu does it again in 2024 with the highly anticipated results from DESTINY-Breast06. The magnitude of benefit was not comparable to that seen in the DESTINY-Breast04 trial, but nevertheless, Enhertu led to a statistically significant and clinically meaningful PFS benefit versus chemotherapy, in both HR+/HER2-low and HR+/HER2-ultralow patient cohorts. Importantly, subgroup analysis was very encouraging, with significantly improved PFS following Enhertu treatment in all subgroups, including in those who had received more than three lines of prior endocrine therapy and those who had endocrine resistance. At 12 months, OS data were not mature but were trending towards significant. 

The robust efficacy highlighted in DESTINY-Breast06’s primary analysis will translate into competitive pressure on Gilead’s Trodelvy, which is also seeking a label expansion into the post-endocrine HR+/HER2- setting, and will set a high benchmark. The approval of one or both of these therapies will cause a significant shift away from chemotherapy in the second-line and beyond treatment paradigm of HR+/HER2- metastatic breast cancer.

With interstitial lung disease a key safety risk associated with Enhertu treatment—three patients died on the DESTINY-Breast06 trial because of this severe side effect— prescribing physicians will have to carefully weigh the benefits of Enhertu against its toxicity.  

The accuracy of current IHC testing and whether it will be able to discern between a true HER2-ultra low and HER2 low is now under question, and this may hinder initial Enhertu uptake should the drug receive a label expansion in these populations. Following this success and with the Phase II DAISY trial now assessing Enhertu in HER2 0 patients, the commercial viability for Enhertu is steadily increasing – Anna Simmons, Oncology Analyst I, Citeline

Specific Indications

NSCLC

Unprecedented efficacy for Lorbrena in NSCLC

Neha Anand, Citeline

Neha Anand, Citeline

Lorbrena has shown very promising results in the CROWN study, showing the longest progression-free survival (PFS) ever reported for ALK-positive NSCLC patients. The study revealed that after five years, 60% of those treated with Lorbrena had not experienced disease progression, which is nearly twice the median PFS of 34.8 months observed with Alecensa in the ALEX trial. Lorbrena also appears to be more effective against brain metastases compared to Alecensa.

However, Lorbrena’s side effects, which include cognitive and mood issues, could significantly impact the quality of life (QoL) for patients, who are typically young and otherwise healthy. This is a crucial consideration in ALK+ NSCLC treatment,  and its adoption as a first-line treatment may be hindered as a result. In addition, Lorbrena’s efficacy against several single-resistance mutations that often develop with Alecensa use suggests it might be better suited for second-line treatment. Considering the lower QoL and its effectiveness for resistance mutations, doctors might opt to reserve Lorbrena for use after Alecensa treatment fails – Neha Anand, Oncology Analyst II, Citeline

HCC

Camrelizumab and rivoceranib emerge as potential standard of care for HCC

The CARES-310 trial’s groundbreaking overall survival (OS) data indicate that the camrelizumab and rivoceranib duo has the potential to set a new standard of care (SoC) for individuals with unresectable hepatocellular carcinoma (uHCC). This trial is notable for recording the longest median overall survival (mOS) ever seen in a global Phase III trial for uHCC. 

However, it’s important to acknowledge that in May 2024, the FDA returned a complete response letter (CRL) to Jiangsu Hengrui Pharma and Elevar Therapeutics for their applications concerning the PD-1 inhibitor camrelizumab and the VEGFR inhibitor rivoceranib for uHCC treatment. Considering that the CRL did not raise any issues regarding the trial or clinical data, and given the remarkable outcomes reported, it is anticipated that the matters will be addressed in the near future. The duo of camrelizumab and rivoceranib emerges as a strong contender for initial therapy in unresectable HCC, and with the benefit of being among the first on the market, this combination therapy stands a good chance of significant commercial triumph – Neha Anand, Oncology Analyst II, Citeline

Ovarian Cancer

Nkiru Ibeanu, Citeline

Nkiru Ibeanu, Citeline

Despite less-than-optimistic outlooks for numerous Phase III trials investigating the use of anti-PD1 and PD-L1 antibodies, there is still a keen interest in the use of these drugs in ovarian cancer. One research group explored the use of neoadjuvant Keytruda with Lynparza in HRD-positive advanced ovarian cancer, while another looked at the advantage of combining Tecentriq with Avastin (and Cotellic) in platinum-resistant disease regardless of PD-L1 expression, looking to exploit previously reported synergism between the antibodies in other cancers like hepatocellular carcinoma where the combination is already approved. Finally, results were presented from a Phase II trial investigating the use of a combination of Opdivo and Yervoy in ovarian clear cell carcinoma, a rare form of ovarian cancer accounting for about 10% of all cases. The data presented as ASCO 2024 emphasize the continued interest in the potential of checkpoint inhibitors in ovarian cancer and highlight other avenues for their entry into a market where limited inroads have been made so far Nkiru Ibeanu, Oncology Analyst I, Citeline

Bladder Cancer

There is a continued focus on the critical unmet needs of bladder, emphasized by significant interest in treatment options in different areas of need as a theme across ASCO. One such need is for effective bladder-sparing treatments in patients with high-risk non-muscle-invasive bladder cancer (NMIBC). In light of that, positive results from the Phase II CORE-001 were welcome, as the oncolytic adenovirus cretostimogene grenadenorepvec, in combination with the checkpoint inhibitor Keytruda, showed improvement in efficacy and safety over Keytruda alone, the current standard of treatment, essentially paving the way for cretostimogene to become a breakthrough drug in this area of unmet need. The anticipation of further results from ongoing trials like BOND-003 will be much higher following the impressive data shared at ASCO Nkiru Ibeanu, Oncology Analyst I, Citeline

Acute Myeloid Leukemia

Venclexta’s position as a blockbuster drug was highlighted by significant interest in its use and treatment protocols, ranging from modifications to dosing in a retrospective study to investigation in combination with novel therapies in R/R AML. The retrospective study covered the use of “7+7” Venclexta + HMA dosing compared with labelled 28-day dosing cycles in elderly patients across centers in France and the US, finding that there may be scope for shorter Venclexta dosing in patients with unfavorable risk-to-benefit ratios. Additionally, Bio-Path found that a combination of its lead candidate prexigebersen with decitabine and Venclexta showed promising results in patients with R/R AML, for whom Venclexta is not formally approved as a treatment option. There is more to come from Venclexta, as Abbvie seeks to continue the drug’s market expansion beyond higher risk patients Nkiru Ibeanu, Oncology Analyst I, Citeline

Multiple Myeloma

David Dahan, Citeline

David Dahan, Citeline

Following a negative confirmatory Phase III trial in November 2022, Blenrep was withdrawn from the US market. However, in a remarkable comeback, Blenrep has since reported positive results in two additional Phase III trials and is expected to return to the relapsed/refractory multiple myeloma market in 2025. The DREAMM-8 results presented at ASCO confirm Blenrep’s efficacy but also show that protocols have been developed to better manage the troublesome ocular toxicity, such that ocular events can be reversed with dose reductions. While Blenrep, an antibody-drug conjugate, was originally the first BCMA targeted agent approved for multiple myeloma, if approved, it will face competition from other BCMA targeting agents including CAR-Ts (Johnson & Johnson’s Carvykti and Bristol Myers Squibb’s Abecma) and bispecific T-cell engagers (Johnson & Johnson’s Tecvayli and Pfizer’s Elrexfio). Compared to these other agents, Blenrep may be easier for community doctors to prescribe, as the CAR-Ts and bispecifics require hospitalization, as well as treatment in specialty centers able to manage the associated toxicities (cytokine-release syndrome and neurotoxicity) – David Dahan, Senior Oncology Analyst, Citeline