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Cedric Pobel, MD, is a medical oncologist, PhD student, Institut de Cancérologie, Gustave Roussy, Paris, France.

Cedric Pobel, MD, covers the PEACE-1 trial of radiotherapy, standard of care, and abiraterone in low-volume metastatic castration-sensitive prostate cancer.


Findings From the PEACE-1 Trial in mCRPC

Cedric Pobel, MD, discusses the design and objectives of the phase 3 PEACE-1 trial for patients with de novo metastatic castration-sensitive prostate cancer. 

Behind the Design of the PEACE-1 Trial in mCSPC

ASH 2024 Preview for Community Oncologists: The Show and After Show

The American Society of Hematology (ASH) Annual Meeting and Exposition aims to educate oncology providers across an array of hematologic malignancies, with a focus on novel agents, drugs across the FDA pipeline, and more.

, co-hosts Kristie L. Kahl and Andrew Svonavec offer a glimpse at some of the presentations guaranteed to spark one’s curiosity, spur debate, and enhance the field even further. Some key highlights include:

 Continued advancements in CAR T-cell therapy are expected to revolutionize the treatment of hematologic malignancies.

 Bispecific antibodies, such as Epcoritamab (Epkinly), offer a novel approach to target multiple antigens on cancer cells.

 The assessment of MRD is becoming increasingly important in predicting treatment response and overall survival.

Advances in Acute Lymphoblastic Leukemia (ALL)

Blinatumomab (Blincyto) in pediatric ALL:

 The addition of blinatumomab to chemotherapy has shown promise in improving disease-free survival in high-risk pediatric ALL. This combination therapy may offer a more effective treatment option for young patients.

Acalabrutinib (Calquence) in mantle cell lymphoma (MCL):

 The FDA is set to review the approval of acalabrutinib with bendamustine or rituximab (Rituxan) for previously untreated MCL, based on data from the phase 3 ECHO trial (NCT02972840).

Asciminib (Scemblix) in chronic phase chronic myelogenous leukemia (CML-CP):

 The FDA recently granted accelerated approval to asciminib for newly diagnosed CML-CP. This tyrosine kinase inhibitor has shown favorable safety and tolerability profiles.

 isn't just about data, as the duo also offers food recommendations, tourist attractions and fun activities to partake in, as well as interesting facts about San Diego.

This is just a taste of the wealth of information and inspiration waiting at the 2024 ASH Annual Meeting. Check back for future meeting previews with 

Targeted Oncology co-hosts Kristie L. Kahl and Andrew Svonavec highlight abstracts for community oncologists to look out for at the upcoming ASH Annual Meeting in San Diego, with some additional tidbits to round out the main event.

News

The biologics license application (BLA) of the subcutaneous formulation of nivolumab (Opdivo) coformulated with human hyaluronidase (rHuPH20) has been accepted by the FDA.

Findings from the CheckMate -67T (NCT04810078) support this BLA of subcutaneous nivolumab as the trial met its coprimary pharmacokinetic end points and key secondary end point of overall response rate (ORR) vs intravenous (IV) nivolumab in clear cell renal cell carcinoma.

The FDA has set a Prescription Drug User Fee Act (PDUFA) goal date for December 29, 2024.

The FDA has accepted the BLA of the subcutaneous formulation of nivolumab coformulated with rHuPH20, also known as subcutaneous nivolumab, for all previously approved adult solid tumor indications of nivolumab as a monotherapy, monotherapy maintenance following completion of the combination therapy with nivolumab plus ipilimumab (Yervoy), or in combination with chemotherapy or cabozantinib (Cabometyx).

Results from the phase 3 CheckMate -67T trial of subcutaneous nivolumab support this application. In the trial, experts sought to evaluate subcutaneous nivolumab vs its intravenous (IV) formulation.

 Here, the subcutaneous form demonstrated noninferior pharmacokinetics and efficacy, as well as consistent safety compared with the IV formulation of nivolumab among patients with advanced or metastatic clear cell renal cell carcinoma (ccRCC) who have received prior systemic therapy.

A PDUFA goal date has been set for December 29, 2024. With this, subcutaneous nivolumab shows promise to become the first and only subcutaneously administered PD-1 inhibitor.

“We believe subcutaneous nivolumab has the potential to make a significant difference in the lives of patients, which is reinforced by the FDA’s acceptance of our application,” said Gina Fusaro, PhD, vice president, global program lead, Bristol Myers Squibb, in a press release.

“[Nivolumab] is a foundational PD-1 inhibitor approved for many different types of cancer, and our continued investment in research that puts patients first remains a priority. If approved by the FDA, the subcutaneous administration of nivolumab would provide patients and their physicians with a new option that delivers the same well-known benefits as IV [nivolumab] but with the improved convenience of an injection administered in 3 to 5 minutes rather than a 30- to 60-minute infusion,” Fusaro continued.

The phase 3, randomized, open-label CheckMate -67T trial is exploring subcutaneous administration of nivolumab coformulated with rHuPH20 vs IV nivolumab for the treatment of patients with advanced or metastatic ccRCC who were previously treated with systemic therapy.

In the study, 495 patients were randomly assigned to receive either subcutaneous nivolumab or IV nivolumab. Enrollment was open to patients with a histological confirmation of ccRCC, advanced RCC not amenable to curative or radiation therapy, metastatic RCC, those who received no more than 2 prior systemic therapies, those with intolerance or progression after last treatment regimen within 6 months of randomization, and those with a Karnofsky performance score ≥ 70 at screening.

Experts assessed the coprimary end points of time-averaged serum concentration over 28 days and trough serum concentration at steady-state of subcutaneous nivolumab vs IV nivolumab. A key secondary end point of the trial was ORR.

The study met its coprimary pharmacokinetic end points and key secondary end point of ORR with subcutaneous nivolumab in this patient population.

 Subcutaneous nivolumab was noninferior in regard to time-averaged nivolumab serum concentration over 28 days and steady-state trough serum concentration vs treatment with IV nivolumab. Additionally, subcutaneous nivolumab also demonstrated a noninferior ORR compared with IV nivolumab.

1. U.S. Food and Drug Administration accepts Bristol Myers Squibb’s application for subcutaneous nivolumab (nivolumab and hyaluronidase). News release. Bristol Myers Squibb. May 6, 2024. Accessed May 6, 2024. 

2. Phase 3 Check-Mate -67T trial of subcutaneous nivolumab (nivolumab and hyaluranisade) meets co-primary end points in advanced or metastatic clear cell renal cell carcinoma. News release. Bristol Myers Squibb. October 19, 2024. Accessed May 6, 2024. 

3. A study of subcutaneous nivolumab versus intravenous nivolumab in participants with previously treated clear cell renal cell carcinoma that is advanced or has spread (CheckMate-67T). ClinicalTrials.gov. Updated October 12, 2023. Accessed May 6, 2024. 

https://www.clinicaltrials.gov/study/NCT04810078

The FDA is considering a subcutaneous nivolumab formulation for various solid tumors based on promising data from the phase 3 CheckMate -67T trial. A target action date has been set for December 29, 2024.

Clinical

FDA Accepts BLA for Subcutaneous Nivolumab Across Various Solid Tumors

Molecular oncology is reshaping how oncologists understand, diagnose, and treat cancer. In contrast to traditional methods, which primarily rely on histopathological examination, molecular oncology delves deeper, identifying the genetic and molecular changes that fuel tumor growth.

By sequencing a patient’s tumor and mapping its unique genetic alterations, clinicians can tailor treatments to the individual, leading to more precise and effective outcomes.

“For many years, cancer was completely defined by what it looked like under the microscope. We still do that, but now we have additional information that we can get by sequencing these tumors and learning what causes them to be the genetic drivers. It can tell us things about how they are going to respond to therapies and it can make them be able to use certain therapies that are targeted to these specific mutations,” explained Alec Kimmelman, MD, PhD, in an interview with 

Molecular profiling has already led to several successes across cancer types, resulting in targeted therapies that are changing the standard of care. In cancers like lung, breast, and colorectal, molecular testing has allowed for more precise identification of mutations and alterations that can be targeted by specific treatments.

In non–small cell lung cancer (NSCLC), genetic testing has identified mutations in the 

 gene. In patients with these mutations, targeted therapies like erlotinib (Tarceva) and gefitinib (Iressa) have improved survival rates by focusing on the specific genetic cause of the cancer.

“In lung cancer therapy, it is basically part of everyone's cancer treatment pathway to have this baseline testing done when they have advanced disease,” Sarah Kerr, MD, a pathologist at Allina Health, told 

Both erlotinib and gefitinib are FDA-approved as targeted therapies for patients with 

-mutant NSCLC, based on findings from the IPASS (NCT00322452), EURTAC (NCT00446225), and OPTIMAL (NCT00874419) trials.

 mutation testing has become a standard part of the diagnostic pathway for patients with advanced NSCLC.

In breast cancer, molecular profiling has also yielded success with the identification of the HER2 gene. Agents like trastuzumab (Herceptin) now specifically target HER2-positive tumors, offering a precision approach that has transformed breast cancer treatment, particularly for advanced or metastatic cases.

Clinical trials, including HERA (NCT00045032), CLEOPATRA (NCT00567190), and NCCTG N9831 (NCT00004067; NCT00005970),

 have demonstrated significant improvements in overall and progression-free survival for patients with HER2-positive breast cancer. Additionally, newer therapies like pertuzumab (Perjeta) and trastuzumab deruxtecan (Enhertu) have improved outcomes, providing more options for patients.

Other prime examples are imatinib (Gleevec), which offered a new treatment for patients with chronic myeloid leukemia by targeting the 

, and vemurafenib (Zelboraf) for patients with melanoma harboring 

“The key part of developing a molecular program, whether you have that molecular lab in-house or are sending it out to a commercial lab, is having that good process, pre analytically, to have the best specimens so that you can get the most information out of them. That is usually my message to the oncologists out there,” added Kerr in the interview.

Immunotherapy represents another significant achievement in molecular oncology. Checkpoint inhibitors, such as pembrolizumab (Keytruda) and nivolumab (Opdivo), and ipilimumab (Yervoy), block proteins like PD-1 and CTLA-4 that cancer cells use to evade the immune system. These drugs have shown efficacy in melanoma, NSCLC, and renal cell carcinoma.

Another advancement is chimeric antigen receptor (CAR) T-cell therapy, where a patient’s T cells are genetically engineered to recognize and destroy cancer cells.

 CAR T-cell therapies have achieved success in certain blood cancers, including B-cell acute lymphoblastic leukemia and large B-cell lymphoma.

Combining immunotherapies with traditional treatments like chemotherapy and radiation or targeted therapies can also enhance overall treatment effectiveness for patients with cancer. Clinical trials have shown that combining immune checkpoint inhibitors with chemotherapy or radiation can lead to synergistic effects, like with the combination of nivolumab with ipilimumab in treating melanoma.

Next-generation sequencing (NGS) marks another advancement in molecular oncology as it enables comprehensive tumor profiling, allowing clinicians to identify genetic mutations and alterations that are driving cancer growth. Liquid biopsies, which detect 

 from a simple blood draw, represent a non-invasive alternative to traditional biopsies, allowing for real-time monitoring of tumor progression and treatment efficacy.

"Liquid biopsy or ctDNA started with advanced next-generation sequencing-based platforms but has now moved into detecting minimal residual disease. This allows us to spare patients the toxicity of unnecessary treatments and focus on those who need it," explained Pashtoon Kasi, MD, MS, medical director at City of Hope, highlighting the impact of ctDNA on patient care.

This method also enables clinicians to monitor patients over time without the need for frequent, invasive procedures, offering a real-time understanding of how a tumor is evolving and responding to treatment.

"Some institutions pride themselves on not using ctDNA, while others are early adopters. It is important to recognize the value of ctDNA as another tool in our toolbox," Kasi added.

As molecular oncology continues to evolve, several exciting developments are on the horizon. Artificial Intelligence (AI) is beginning to play a key role in analyzing genomic data, enabling faster and more accurate identification of new therapeutic targets. AI is also streamlining the discovery process for new agents, accelerating the development of new therapies tailored to specific genetic mutations.

“AI is a hot topic across everything, from medicine to finance to city planning and everything in between,” 

, medical oncologist at Virginia Cancer Specialists, told Targeted Oncology

. “What I would predict is that as all these massive amounts of data are coming in, patients are getting next-generation sequencing, we are going to find more targets, more mutations, other biomarkers that tell us what treatments may work for what patient but then you also have the added complexity of the sequencing of those treatments, as well as what comorbidities that patients may have.”

New AI tools are emerging to help interpret both germline and somatic mutations in cancer, improving the accuracy of variant annotation. For example, deep learning models like those used in prostate cancer and melanoma detection have shown superior performance over traditional methods.

"Dig" is a deep learning framework that identifies somatic mutations under positive selection, while AlphaMissense predicts pathogenic variants in the proteome, though its oncogenic potential is still under study. AI platforms such as CancerVar also predict the oncogenicity of somatic variants, offering an alternative to curated databases. AI is also advancing cell-of-origin prediction for cancers of unknown primary, which can guide treatment strategies. These predictions use genomics-based algorithms, transcriptomic algorithms, and multi-input molecular approaches.

AI is also being applied in molecular oncology for novel therapies, such as personalized cancer vaccines, where AI is used to identify cancer-specific neoantigens and T-cell receptors. Moreover, deep learning strategies are increasingly influencing clinical trials and immunotherapy approaches in cancer treatment.

“I see that as a space where artificial intelligence is sort of compiling all of those different factors, patient factors, disease factors, etc. and predicting what treatments will be most efficacious for what patient at what time. I think there will be more to come very rapidly over the next several months to years,” said Moorer.

“We believe it’s possible to streamline processes and ensure that we have the right pathways in place to get the right results quickly,” added Kimmelman, chair of radiation oncology and director of the Perlmutter Cancer Center at NYU Langone Health. “AI will help us identify new therapeutic targets, streamline the process of drug discovery, and even predict how a patient will respond to treatment.”

The field is also expanding to include more types of cancer. While some cancers have benefited from molecular profiling, there is a growing focus on rare or difficult-to-treat cancers, where the identification of novel genetic alterations could lead to breakthrough treatments.

“I think we’ve made tremendous advances to where we are now,” Kimmelman said, “but I do agree that we’re going to see some amazing developments in the next 5 to 10 years. Some of these advances will be in speed—the ability to do things right away and get test results immediately. Others will come from the comprehensiveness of the tests we’re developing here, which are far more sensitive to detecting ctDNA.”

While the potential for molecular oncology is immense, there are still significant challenges to address, particularly around accessibility and cost. As the technology advances, the need for broader adoption and insurance coverage remains a key barrier. Additionally, the complexity of cancer’s molecular landscape means that much remains to be discovered, and more work is needed to identify and target additional mutations.

Additionally, the molecular landscape of cancer is complex, meaning there is still much to learn about how different mutations interact and how they can be targeted with therapies. Kimmelman acknowledges that while progress is being made, especially in identifying targetable mutations, there is still much work to be done.

"You cannot expect someone who treats every kind of cancer to be an expert in every molecular alteration and in every cancer, or to know which clinical trials the patient would be eligible for,” said Kimmelman.

“Work with your pathologist, work with the radiologists and pulmonologists, and ask us to make sure you are getting the best specimens,” added Kerr.

Molecular oncology is revolutionizing cancer care by using genetic profiling to tailor personalized treatments, improving efficacy, minimizing adverse events, and paving the way for advanced therapies.

Cedric Pobel, MD

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