Author: RR

Advancing Prostate Cancer Treatment: The Efficacy of Primary Partial-Gland Cryoablation

RR

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated by the American Cancer Society that in the United States, about 313,780 new cases of prostate cancer will be diagnosed in 2025 and 35,770 men will die of the disease. The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced prostate cancer and is the first treatment intervention.

Prostate cancer treatment has traditionally revolved around whole-gland procedures, primarily radical prostatectomy, which, while effective in cancer eradication, is often associated with significant adverse effects, including urinary incontinence, erectile dysfunction, and the absence of semen. However, advancements in focal therapy, particularly Primary Partial-Gland CryoAblation (PPGCA), present a promising alternative that mitigates these consequences while maintaining efficacy. Primary Partial-Gland Cryoablation is a minimally invasive treatment for prostate cancer that involves the focal application of ultra‐cold temperature that destroys only the cancerous part of the prostate gland by freezing and thawing the cancerous cells.

The introduction of multiparametric Magnetic Resonance Imaging (mpMRI) has significantly improved our ability to determine the size, location, and aggressiveness of prostate cancer, enabling better candidate selection for focal therapy.

To rigorously assess the effectiveness of PPGCA, a study conducted at NYU Langone Health between May 2017 and March 2024, enrolled 313 men diagnosed with intermediate-risk prostate cancer, with no out-of-field Gleason grade group 2 or more, gross extracapsular extension, or extreme apical disease on pre-treatment mpMRI. Of these, 91 patients were followed for at least five years to evaluate the long-term efficacy of PPGCA. An intensive follow-up regimen was implemented. Patients underwent PSA testing every six months and received mpMRIs at 6-12, 24, 42, and 60 months post-treatment. Initially, protocol biopsies were conducted at 6-12 and 24 months; however, these were discontinued after interim analysis revealed a low incidence of clinically significant Prostate Cancer (csPCa) recurrence, defined as Gleason grade group 2 or more disease. The Primary end point was Freedom-from-failure, defined as no prostate cancer-specific mortality, metastatic disease, or whole-gland salvage treatment.

Key Findings

Among the 91 patients monitored for at least five years:

  • Clinically significant Prostate Cancer (csPCa) was detected in 33 (10.5%) patients.
  • The freedom-from-recurrence rates at five years were:
    • In-field csPCa: 86%
    • Out-of-field csPCa: 85%
    • Overall csPCa: 70%
  • The overall freedom-from-failure rate at five years was 89%.
  • No patient succumbed to prostate cancer during the study period.
  • One patient (1%) developed metastatic disease.
  • 15 patients (16.5%) underwent whole-gland salvage treatment.
  • 15 patients (16.5%) received salvage focal therapy.
  • Patient compliance with the five-year surveillance protocol was exceptionally high, with only three patients (3.3%) deviating from scheduled monitoring.

Clinical Implications and Future Directions
The researchers emphasized that intermediate-risk patients were selected because, under conventional treatment paradigms, they would have been recommended for immediate whole-gland removal. The study suggests that 80% of men diagnosed with intermediate-risk prostate cancer may opt for focal cryotherapy over prostatectomy if given the choice, based on the effectiveness of treatment and reduced side effects.

The authors highlighted the comprehensive nature of this research, marking it as the largest prospective study of intermediate-risk prostate cancer treated with PPGCA. They reiterated the importance of rigorous follow-up and high patient compliance in ensuring accurate outcome assessment. As the study cohort matures, researchers aim to expand their evaluations to include lower-risk patients, who may not qualify for active surveillance but could benefit from less invasive alternatives to whole-gland treatment.

In conclusion, the current study demonstrated that PPGCA can effectively prevent cancer recurrence while avoiding the significant functional side effects of whole-gland removal. This study underscores the efficacy and feasibility of PPGCA as a viable alternative to prostatectomy, demonstrating very encouraging intermediate-term oncological outcomes. The high compliance rate with a rigorous surveillance protocol reinforces the potential of focal therapy in preserving quality of life while maintaining robust cancer control. Future research will focus on refining patient selection criteria and further validating long-term oncological and functional outcomes.

Five-year Oncologic Outcomes Following Primary Partial Gland Cryo-ablation Prospective Cohort Study of Men With Intermediate-risk Prostate Cancer. Lepor H, Rapoport E, Tafa M, et al. Urology. 2025 Feb;196:189-195. 

Breakthroughs in Targeted Therapy for Low-Grade Serous Ovarian Carcinoma

RR

Written by: Dr. Charles K Anderson, MD
Sponsored by Verastem

Low-grade serous ovarian carcinoma (LGSOC) is a rare and molecularly distinct ovarian cancer accounting for <10% of new epithelial ovarian cancers.1,2 Recently, significant progress has been made with new therapy options currently in the developmental phase. LGSOC commonly presents at advanced stages, with over 70% of patients experiencing relapse.3  There is an indication of slower tumor progression, leading to an extended overall survival (OS) of around 97 months, in contrast to the 72 months typically seen in high-grade serous ovarian carcinoma (HGSOC) cases.4 LGSOC patients tend to have a longer median progression-free survival (PFS) of 97 months, whereas HGSOC patients usually experience 35 months before progression.4 While LGSOC tends to progress slowly, the relatively young age of patients at diagnosis and their resistance to traditional cytotoxic therapy indicate that the majority will ultimately succumb to the disease.3,5,6 

Primary treatment for newly diagnosed patients typically involves primary debulking surgery (PDS) if feasible. The historical standard-of-care (SOC) treatment options include cytotoxic platinum and taxane based regiments often combined with bevacizumab or primary endocrine targeted therapy (ET) with aromatase inhibitors, selective estrogen receptor modulators (SERMs) or selective estrogen receptor degraders (SERDs). In a study of 58 patients with recurrent LGSOC who were treated with a total of 108 cytotoxic regimens, a response rate of only 3.7% was observed with other combined data showing a response rate of 0-13%.3,5,6,7

Promising advancements in targeted therapies such as MEK inhibitors and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors with concurrent endocrine therapy, have exhibited potential in treating LGSOC with improved response rates. LGSOC tumors frequently exhibit activating mutations in the mitogen-activated protein kinase (MAPK) pathway and lack TP53 mutations.8 Given that over 60% of LGSOC tumors carry RAS/RAF mutations, multiple phase 2/3 trials have explored the clinical effectiveness of mitogen-activated protein kinase kinase (MEK) inhibitors in patients with recurrent or persistent LGSOC. Response rates of 26% and 16% were observed with trametinib and binimetinib, respectively, but with discontinuation rates of 36% and 31% due to toxicity.2,7

It has been realized that focal adhesion kinase (FAK) activation in the development of resistance to MEK inhibitors, the phase II trial RAMP201 assessed the effectiveness of avutometinib, a dual RAF/MEK inhibitor, administered alone and in combination with defactinib, a FAK inhibitor, for the treatment of recurrent LGSOC. This trial also included stratification by KRAS mutation status.3 In May of 2023, at the American Society of Clinical Oncology, the findings from the RAMP201 trial were unveiled, indicating an objective response rate (ORR) of 45% and tumor shrinkage in 86% of assessable patients who received the combination therapy of avutometinib and defactinib. The phase 3 confirmatory trial, RAMP 301, will evaluate the effectiveness of avutometinib and defactinib compared to SOC chemotherapy or hormone therapy options. These trials indicate that MAPK pathway inhibitors hold promise in offering clinical advantages to individuals with LGSOC.

 Avutometinib and Defactinib Mechanism of Action

  • Avutometinib is a first-in-class oral RAF/MEK clamp that potently inhibits MEK while also blocking the compensatory reactivation of MEK by upstream RAF1,4
  • Defactinib is a selective inhibitor of FAK, a key adaptive resistance mechanism to the RAS/MAPK pathway9,10,11
  • Phase 1 FRAME study (NCT03875820) demonstrated activity of avutometinib + defactinib study -led to FDA Breakthrough Therapy Designation and rationale for the phase 2 ENGOT-ov60/GOG-3052/RAMP 201 (NCT04625270) study12,13

Summary: RAMP 201: Registration-Directed Phase 2 Trial of Avutometinib ± Defactinib in Patients with Recurrent LGSOC

  • Patient selection: Recurrent LGSOC, prior platinum chemotherapy, measurable disease (RECIST v1.1), prior MEK inhibitor allowed
  • Primary Endpoint: ORR- In KRAS mt patients and all patients (KRAS mt & wt)
  • A go forward regimen was identified with 3 sub-part study with selection phase, expansion phase, expansion combination phase
  • Eventual combination dosing chosen was: Avutometinib 3.2 mg PO BIW and Defactinib 200 mg PO BID
    • ORR: 31% overall; 44% in KRAS mt and 17% in KRAS wt
    • Median DOR: 31 months overall
    • Median PFS: 12.9 months overall; 22.0 months in KRAS mt and 12.8 months in KRAS wt
  • Safety profile: toxicity was acceptable as most adverse events were grade 1 and 2. Adverse events were managed primarily with dose interruptions and reductions with only a 10% discontinuation rate of for adverse events
  • These data support the potential for avutometinib + defactinib as a new standard of care for recurrent LGSOC, regardless of KRAS status

 In conclusion, I am impressed with the results of RAMP 201 trial showing efficacy and tolerability much higher than historical controls comparing traditional cytotoxic therapy, endocrine therapy combinations and other MEK inhibitors.  I am optimistic and excited to see the results of the ongoing RAMP 301 trial (https://clinicaltrials.gov/study/NCT06072781).

References:

  1. Lito, P., et al. (2014). Cancer Cell, 25(5), 697-710.
  2. Gershenson, D. M., Miller, A., Brady, W. E., Paul, J., Carty, K., Rodgers, W., Millan, D., Coleman, R. L., Moore, K. N., Banerjee, S., Connolly, K., Secord, A. A., O’Malley, D. M., Dorigo, O., Gaillard, S., Gabra, H., Slomovitz, B., Hanjani, P., Farley, J., & Churchman, M. (2022). Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): An international, randomised, open-label, multicentre, phase 2/3 trial. The Lancet, 399(10324), 541–553. https://doi.org/10.1016/S0140-6736(21)02175-9Zwimpfer, T. A., Tal, O., Geissler, F., Coelho, R., Rimmer, N., Jacob, F., & Heinzelmann-Schwarz, V. (2023). Low grade serous ovarian cancer – A rare disease with increasing therapeutic options. Cancer Treatment Reviews, 112, 102497. https://doi.org/10.1016/j.ctrv.2022.102497
  3. Gonzalez-Del Pino, G. L., et al. (2021). Proceedings of the National Academy of Sciences of the United States of America, 118(36), e2107207118.
  4. Gershenson, D. M., Sun, C. C., Bodurka, D., Coleman, R. L., Lu, K. H., Sood, A. K., Deavers, M., Malpica, A. L., & Kavanagh, J. J. (2009). Recurrent low-grade serous ovarian carcinoma is relatively chemoresistant. Gynecologic Oncology, 114(1), 48–52. https://doi.org/10.1016/j.ygyno.2009.03.001
  5. Gockley, A., Melamed, A., Bregar, A. J., Clemmer, J. T., Birrer, M., Schorge, J. O., del Carmen, M. G., & Rauh-Hain, J. A. (2017). Outcomes of women with high-grade and low-grade advanced-stage serous epithelial ovarian cancer. Obstetrics & Gynecology, 129(3), 439–447. https://doi.org/10.1097/AOG.0000000000001867
  6. Monk, B. J., et al. (2020). Journal of Clinical Oncology, 38(32), 3753–3762..
  7. Manning-Geist, B. L., et al. (2024). Clinical Advances in Hematology & Oncology, 22(5), 205–226.
  8. Vang, R., Shih, I. M., & Kurman, R. J. (2009). Ovarian low-grade and high-grade serous carcinoma: pathogenesis, clinicopathologic and molecular biologic features, and diagnostic problems. Advances in Anatomic Pathology, 16(5), 267-282. https://doi.org/10.1097/PAP.0b013e3181b4fffa.
  9. Dawson, J. C., et al. (2021). Nature Reviews Cancer, 21, 313–324
  10. Shinde, R., et al. (2020). Cancer Research, 80(Suppl 16), CT143.
  11. Kang, Y., et al. (2013). Journal of the National Cancer Institute, 105(19), 1485–1495
  12. Banerjee, S., et al. (2021). Annals of Oncology, 32(Suppl 5), S7.
  13. Verastem Oncology. (2021, May 24). Press release: Verastem Oncology receives breakthrough therapy designation for VS-6766 with defactinib in recurrent low-grade serous ovarian cancer. Retrieved September 28, 2023, from https://investor.verastem.com/node/12421/pdf.

 

Late Breaking Abstract – 2025 ASCO GI Symposium: Personalized Neoantigen Vaccine in Metastatic Colorectal Cancer

RR

SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 154,270 new cases of CRC will be diagnosed in the United States in 2025 and about 52,900 patients will die of the disease. The lifetime risk of developing CRC is about 1 in 23.

The majority of CRC cases (about 75 %) are sporadic whereas the remaining 25 % of the patients have a family history of the disease. Only 5-6 % of patients with CRC with a family history background are due to inherited mutations in major CRC genes, while the rest are the result of accumulation of both genetic mutations and epigenetic modifications of several genes. Colorectal Cancer is a heterogeneous disease classified by its genetics, and even though the diagnosis of Colorectal Cancer in the US is dropping among people 65 years and older, the incidence has been rising in the younger age groups, with 12% of Colorectal Cancer cases diagnosed in people under age 50.

The DNA MisMatchRepair (MMR) system is responsible for molecular surveillance and works as an editing tool that identifies errors within the microsatellite regions of DNA and removes them. Defective MMR system leads to MSI (Micro Satellite Instability) and hypermutation, with the expression of tumor-specific neoantigens at the surface of cancer cells, triggering an enhanced antitumor immune response. MSI is therefore a hallmark of defective/deficient DNA MisMatchRepair (dMMR) system and occurs in 15% of all colorectal cancers. MSI testing is performed using a PCR or NGS based assay and MSI-High refers to instability at 2 or more of the 5 mononucleotide repeat markers and MSI-Low refers to instability at 1 of the 5 markers. Patients are considered Micro Satellite Stable (MSS) if no instability occurs. MSI-L and MSS are grouped together because MSI-L tumors are uncommon and behave similar to MSS tumors.

Checkpoint inhibitors have revolutionized cancer treatment. They are however not as effective in patients with “cold tumors” (MSS), as these tumors effectively hide themselves from the immune system and do not trigger an immune response following treatment with checkpoint inhibitors.

GRANITE is a personalized neoantigen immunotherapy designed to trigger a strong T-cell immune response against a patient’s tumor. A biopsy of the tumor is performed to identify unique mutations (neoantigens) present in the tumor of patients. An AI platform, EDGE, developed and designed by Gritstone Bio is able to identify critical T-cell vaccine targets, and predict which neoantigens are most likely to be recognized by the immune system of patients. The system has an 80% accuracy rate in selecting the top 20 most immunogenic neoantigens, most likely to generate an immune response in a given patient. The selected neoantigens are incorporated into a chimpanzee adenovirus-based primer vaccine and a Self-Amplifying mRNA (SAM) booster vaccine to train the immune system that leads to an induction of both cytotoxic T-lymphocyte and memory T-cell dependent immune responses, that specifically target and destroy the patients cancer cells that express these neoantigens. This vaccine (GRANITE) is administered via intramuscular injection alongside immune checkpoint inhibitors. Thus GRANITE primes the immune system to recognize and attack these tumors. This vaccine is customized for each patient based on the unique mutations of their tumor. In essence, GRANITE helps make the “cold tumors” visible to the immune system, potentially improving patient outcomes.

GRANITE immunotherapy regimen was evaluated in combination with Nivolumab and Ipilimumab, and compared to the combination of Nivolumab and Ipilimumab alone in a Phase1/2 involving patients with advanced metastatic solid tumors. This study demonstrated robust T-cell activation against targeted neoantigens with no dose-limiting toxicities, and over 50% of patients had a reduction in their circulating tumor DNA (ctDNA) and improved Overall Survival (Palmer CD, et al. Nature 2022).

GRANITE immunotherapy regimen is now being studied as first line metastatic treatment in a randomized Phase 2 trial, among patients with Microsatellite-Stable (MSS) Colorectal cancer patients. GO-010 is an ongoing Phase 2/3, randomized, open-label, multi-center study evaluating the efficacy and safety of GRANITE immunotherapy regimen in combination with Checkpoint Inhibitors (CPIs) as an add-on to Fluoropyrimidine/Bevacizumab as maintenance treatment, following first line therapy with FOLFOX/Bevacizumab, in patients with mCRC. In this study, 104 patients were randomized in a 1:1 ratio, and 67 patients were included in this treated analysis with 39 patients assigned to the GRANITE arm and 28 patients to the control arm. (36 patients withdrew from the study primarily due to early progressive disease or withdrawal of consent, and one patient has yet to begin study treatment). The vaccine manufacturing success rate was 100%. Both treatment groups were well balanced with regards to demographics, clinical characteristics stage, sidedness and presence of liver metastases. Approximately 75% of patients had liver metastases. For the Phase 2 portion of this study, the Primary end point being assessed is molecular response defined as 30% or more decrease from baseline in ctDNA. For the Phase 3 portion of this trial, the Primary end point is Progression Free Survival (PFS). Secondary end points for both Phase 2 and 3 include Adverse Events, Overall Survival (OS), Overall Response Rate (ORR), Duration of Response (DoR) and Clinical Benefit Rate.

Preliminary data from the Phase 2 portion of a Phase 2/3 study showed a positive early trend in PFS for GRANITE immunotherapy patients with a Hazard Ratio (HR) of 0.82 in all patients, HR of 0.52 in high-risk patients1 (more than 90% with liver metastases). The median PFS was 12 months with GRANITE immunotherapy versus 7 months for the control group. Long-term ctDNA responses aligned with positive PFS trend favoring GRANITE immunotherapy patients versus control patients.

In the high-risk group, between first blood draw (time of randomization) and last blood draw (most recent study visit), the ctDNA shifted from high (more than 2% VAF-Variant Allele Frequency) to low (2% or less VAF) in 56% of patients treated with GRANITE immunotherapy versus 22% of control patients. Progressive disease was observed in 44% versus 78% respectively, within this group.

In the low-risk group of patients whose ctDNA was negative after induction chemotherapy, sustained ctDNA negativity was observed in 67% of GRANITE immunotherapy recipients versus 38% in the control patients. Progressive disease was observed in 11% and 38% of these patients, respectively. GRANITE immunotherapy was well tolerated and vast majority of adverse events were Grade1/2 and no patients discontinued study treatment due to an adverse event.

In conclusion, this preliminary Phase 2 results are highly encouraging and suggested that GRANITE immunotherapy demonstrated positive early PFS and long-term ctDNA responses, compared with Fluoropyrimidine/Bevacizumab alone, in front-line metastatic MSS-Colorectal cancer, providing the rationale for a confirmatory Phase 3 trial.

A randomized phase 2 study of an individualized neoantigen-targeting immunotherapy in patients with newly diagnosed metastatic microsatellite stable colorectal cancer (MSS-CRC). Hecht JR, Spira AI, Nguyen AV, et al. J Clin Oncol 43, 2025 (suppl 4; abstr LBA13). DOI 10.1200/JCO.2025.43.4_suppl.LBA13

Survival Benefits with Perioperative IMFINZI® Combined with Neoadjuvant Chemotherapy in Muscle Invasive Bladder Cancer

RR

SUMMARY: The American Cancer Society estimates that in the United States for 2025, about 84,870 new cases of bladder cancer will be diagnosed and approximately 17,420 patients will die of the disease. Bladder cancer is the fourth most common cancer in men, but it is less common in women. Bladder cancer accounts for 90% of urothelial cancers, and urothelial cancer can also be found in the renal pelvis, ureter and urethra. Approximately 12% of urothelial cancer cases at diagnosis are locally advanced or metastatic.

The standard treatment for Cisplatin-eligible patients with Muscle-Invasive Bladder Cancer (MIBC) is neoadjuvant chemotherapy followed by radical cystectomy. However, the high relapse rate and risk of death despite this treatment has prompted further research into optimizing outcomes. Perioperative immunotherapy, particularly with immune checkpoint inhibitors, has shown promise in improving these outcomes. Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions. By inhibiting checkpoint proteins and their ligands, T cells are unleashed, resulting in T cell proliferation, activation and a therapeutic response. It has been noted that PD-L1 is widely expressed in tumor and immune cells of patients with Urothelial Carcinoma. This in turn helps cancer cells to evade detection from the immune system by binding to the PD-1 receptor on cytotoxic T lymphocytes.

Durvalumab (IMFINZI®) is a selective, high-affinity human IgG1 monoclonal antibody directed against PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80. A preceding single-group, Phase 2 trial indicated that perioperative Durvalumab, combined with neoadjuvant Gemcitabine plus Cisplatin chemotherapy followed by radical surgery, was both safe and effective. Building on these findings, the Phase 3 NIAGARA trial aimed to evaluate the efficacy and safety of perioperative Durvalumab combined with neoadjuvant chemotherapy (Gemcitabine plus Cisplatin), followed by radical cystectomy, compared with neoadjuvant chemotherapy alone followed by radical cystectomy, in Cisplatin-eligible MIBC patients.

The NIAGARA trial was an open-label, randomized, multicenter, Phase 3 study, enrolling 1,063 (N=1063) Cisplatin-eligible patients with Muscle Invasive Bladder Cancer (clinical stage cT2–T4aN0/1M0). Patients were randomized in a 1:1 ratio to receive one of two treatment regimens. The experimental arm (Durvalumab group) included neoadjuvant Durvalumab 1500 mg IV alongside Gemcitabine plus Cisplatin every 3 weeks for 4 cycles, followed by radical cystectomy and adjuvant Durvalumab monotherapy 1500 mg IV every 4 weeks for up to 8 cycles (N=533). The comparison arm consisted of neoadjuvant Gemcitabine plus Cisplatin followed by radical cystectomy alone, without the addition of Durvalumab (N=530). Patients were stratified by clinical tumor stage (cT2N0 vs more than cT2N0), renal function (CrCl 60 mL/min or more vs 40 or more to less than 60 mL/min), and PD-L1 status (high vs low/negative). The dual Primary endpoints of the trial were Event-Free Survival (EFS) and pathological Complete Response (pCR), with Overall Survival (OS) as a key Secondary endpoint, as well as Metastasis Free Survival and Disease-Specific Survival. Event-Free Survival was defined as the time from randomization until progression that precluded surgery, failure to undergo surgery, recurrence after cystectomy, or death from any cause.

In the pre-planned interim analysis, the results demonstrated a significant improvement in both EFS and OS in the Durvalumab group compared to the chemotherapy-alone group. At 24 months, the estimated EFS was 67.8% in the Durvalumab group, compared to 59.8% in the comparison group (HR=0.68; P<0.001). Furthermore, the estimated OS at 24 months was 82.2% in the Durvalumab group versus 75.2% in the comparison group (HR for death=0.75; P=0.01). A pathological Complete Response (pCR) as assessed by central pathology review was noted in 37.3% of the patients in the Durvalumab group and in 27.5% of those in the comparison group. Notably, the percentage of patients who underwent radical cystectomy was similar between the two groups, with 88% in the Durvalumab group and 83% in the comparison group, indicating that the addition of Durvalumab did not reduce surgical completion rates.

An exploratory post hoc analysis of EFS and OS in patients with pCR versus those without pCR was also performed in the intent-to-treat population. The researchers herein reported additional outcomes and exploratory analysis results from NIAGARA study.

Patients in the Durvalumab group had a 33% reduction in risk of developing distant metastases or death (HR=0.67; P<0.001), and 31% reduction in risk of death from bladder cancer (HR=0.69; P=0.008) versus patients in the comparator group. More patients in the Durvalumab group achieved a pCR at the time of surgery versus the comparator (37% versus 28%) and patients who achieved a pCR had better EFS and OS, compared to those who did not. Patients in the Durvalumab group derived greater EFS and OS benefit versus the comparator group in both pCR group (EFS HR=0.58; OS HR=0.72), reducing the risk of disease progression or death by 42% and the risk of death by 28%, as well as non-pCR group (EFS HR=0.77; OS HR=0.84), reducing the risk of disease progression or death by 23% and risk of death by 16%. The most common immune-related adverse events included hypothyroidism in 10% of patients treated with Durvalumab compared to 1% in the comparator group, and hyperthyroidism in 3% versus 0.8% respectively. All immune mediated adverse events resolved in 41% of affected patients in the Durvalumab group and 44% in the comparator group.

It was concluded that the addition of perioperative Durvalumab to neoadjuvant chemotherapy significantly improved EFS and OS in both pCR and non-pCR groups, compared to chemotherapy alone, without compromising the ability to perform radical cystectomy. Further, perioperative Durvalumab combined with neoadjuvant chemotherapy reduced the risk of developing metastases and death from bladder cancer. These results are practice-changing, marking a major advancement in the treatment of MIBC. The findings support the hypothesis that perioperative immune checkpoint inhibitors, by priming the immune system before surgery and targeting residual micrometastatic disease post-surgery, improve long-term clinical outcomes. Biomarkers like circulating tumor DNA (ctDNA) could be pivotal in guiding treatment decisions, as emerging data suggests that negative ctDNA status post-neoadjuvant therapy correlates with reduced relapse risk.

Additional efficacy and safety outcomes and an exploratory analysis of the impact of pathological complete response (pCR) on long-term outcomes from NIAGARA. Galsky M, Van Der Heijden M, Catto J, et al. J Clin Oncol 43, 2025 (suppl 5; abstr 659). DOI 10.1200/JCO.2025.43.5_suppl.659

Late Breaking Abstract – 2025 ASCO GU Cancers Symposium: Talazoparib Plus Enzalutamide Improves Overall Survival in mCRPC

RR

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 299,010 new cases of prostate cancer will be diagnosed in 2024 and 35,250 men will die of the disease. The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced prostate cancer and is the first treatment intervention.

Androgen Deprivation Therapies have included bilateral orchiectomy or Gonadotropin Releasing Hormone (GnRH) analogues, with or without first generation Androgen Receptor (AR) inhibitors such as Bicalutamide (CASODEX®), Nilutamide (NILANDRON®) and Flutamide (EULEXIN®) or with second-generation Androgen-Receptor Pathway Inhibitors (ARPIs), which include Abiraterone (ZYTIGA®), Enzalutamide (XTANDI®), Apalutamide (ERLEADA®) and Darolutamide (NUBEQA®).

For men diagnosed with metastatic Hormone-Sensitive Prostate Cancer (mHSPC), survival rates have improved with the introduction of Androgen Receptor Pathway Inhibitors (ARPIs) and chemotherapy. These therapeutic advancements, used in conjunction with androgen suppression, have demonstrated survival benefits, though patient outcomes remain highly variable. Approximately 10-20% of patients with advanced Prostate cancer will progress to Castration Resistant Prostate Cancer (CRPC) within five years during ADT, and over 80% of these patients will have metastatic disease at the time of CRPC diagnosis. The estimated mean survival of patients with CRPC is 9-36 months, and there is therefore an unmet need for new effective therapies.

DNA damage is a common occurrence in daily life by UV light, ionizing radiation, replication errors, chemical agents, etc. This can result in single and double strand breaks in the DNA structure which must be repaired for cell survival. The two vital pathways for DNA repair in a normal cell are BRCA1/BRCA2 and PARP. BRCA1 and BRCA2 genes recognize and repair double strand DNA breaks via Homologous Recombination Repair (HRR) pathway. Homologous Recombination is a type of genetic recombination and is a DNA repair pathway utilized by cells to accurately repair DNA double-stranded breaks during the S and G2 phases of the cell cycle, and thereby maintain genomic integrity. Homologous Recombination Deficiency (HRD) is noted following mutation of genes involved in HRR pathway. At least 15 genes are involved in the HRR pathway including BRCA1, BRCA2 and ATM genes. The BRCA1 gene is located on the long (q) arm of chromosome 17 whereas BRCA2 is located on the long arm of chromosome 13. BRCA1 and BRCA2 are tumor suppressor genes and functional BRCA proteins repair damaged DNA, and play an important role in maintaining cellular genetic integrity. They regulate cell growth and prevent abnormal cell division and development of malignancy. Recently published data has shown that deleterious Germline and/or Somatic mutations in BRCA1, BRCA2, ATM, or other Homologous Recombination DNA-repair genes, are present in about 30% of patients with advanced prostate cancer, including metastatic CRPC. Patients with metastatic CRPC harboring BRCA alterations and other HRR gene alterations have poor outcomes, and earlier resistance to commonly used systemic therapies.

The PARP (Poly ADP Ribose Polymerase), family of enzymes include, PARP1and PARP2, and is a related enzymatic pathway that repairs single strand breaks in DNA. In a BRCA mutant, the cancer cell relies solely on PARP pathway for DNA repair to survive. PARP inhibitors trap PARP onto DNA at sites of single-strand breaks, preventing their repair and generating double-strand breaks that cannot be repaired accurately in tumors harboring defects in HRR genes, such as BRCA1 or BRCA2 mutations, and this leads to cumulative DNA damage and tumor cell death. PARP inhibitors have demonstrated significant activity in patients with prostate cancer and HRR gene alterations, with the greatest clinical benefit noted in BRCA1/2 mutation carriers.

Talazoparib (TALZENNA®) is a PARP inhibitor presently approved for HRR Gene-Mutated CRPC and for Germline BRCA- mutated advanced breast cancer.

TALAPRO-2 trial is a multicenter, randomized, double-blind, placebo-controlled Phase 3 study that enrolled 1,035 unique patients with mCRPC (who had not received new life-prolonging systemic treatments after documentation of mCRPC) at sites in the U.S., Canada, Europe, South America, and the Asia-Pacific region. The study included two patient cohorts: Cohort 1 included all comers (N=805, of whom 169 had HRR mutations and 636 did not) and Cohort 2 included those with HRR gene mutations (N=399, including 169 patients from Cohort 1 and 230 enrolled in Cohort 2). A total of 805 patients in Cohort 1 were randomized in a 1:1 ratio to receive either Talazoparib 0.5 mg daily plus Enzalutamide 160 mg daily (N=402) or placebo plus Enzalutamide (N= 403). Randomization was stratified based on HRR gene alteration status and prior Abiraterone or Docetaxel (yes/no) for castration-sensitive prostate cancer. Eligible patients had asymptomatic or mildly symptomatic mCRPC, ECOG PS 1 or less, ongoing Androgen Deprivation Therapy, and no prior life-prolonging therapy for CRPC. All patients underwent tumor tissue testing before enrollment, and approximately 20% were found to have HRR alterations. Specific gene mutations, including BRCA1, BRCA2, ATM, and CDK12, were evenly distributed across treatment arms, with BRCA1 and BRCA2 alterations found in approximately 7% of patients. The Primary endpoint of the study was radiographic Progression-Free Survival (rPFS), and Overall Survival (OS) was a key Secondary endpoint. The researchers had previously reported that TALAPRO-2 trial met its Primary endpoint, showing improved radiographic PFS for Talazoparib plus Enzalutamide compared to placebo plus Enzalutamide as first line treatment in patients with mCRPC unselected for HRR gene alterations (Cohort 1). The final OS data, updated rPFS, and extended safety follow-up in Cohort 1 was reported in this publication

The final OS analysis demonstrated a statistically significant and clinically meaningful improvement in survival for patients treated with Talazoparib plus Enzalutamide compared to Enzalutamide alone. The median OS in the Talazoparib plus Enzalutamide group was 45.8 months versus 37.0 months in the placebo arm, representing a 20% reduction in the risk of death (HR=0.796; P=0.0155). Patients with HRR-deficient tumors had a greater reduction in the risk of death (38%), with a median OS improvement of 14 months (HR=0.622; P=0.0005). The median OS with Talazoparib plus Enzalutamide was 45.1 months and 31.1 months in the placebo plus Enzalutamide group. Patients without HRR mutations still benefited from an approximate 9-month OS gain.

In patients with BRCA1/2 alterations, the median OS was not reached in the Talazoparib plus Enzalutamide group versus 28.5 months in the placebo plus Enzalutamide group (HR=0.497; P =0.0017). For those with non-BRCA1/2 HRR alterations, the median OS was 42.4 versus 32.6 months (HR=0.727; P=0.0665).

The updated rPFS data continued to favor Talazoparib plus Enzalutamide. The median rPFS was 33.1 months versus 19.5 months in the placebo arm (HR=0.667; P<0.0001). In the HRR-deficient cohort, median rPFS was 30.7 months versus 12.3 months (HR=0.468; P <0 .0001).

No new safety signals emerged with extended follow-up. The most common adverse event was anemia. Grade 3-4 anemia occurred in 49% of the unselected population and 43.4% of the HRR-deficient population. Talazoparib discontinuation due to adverse events was 21.6% in the unselected population and 13.1% in the HRR-deficient cohort. Anemia-related discontinuations were 8.5% in the unselected population and 4.5% in the HRR-deficient group.

It was concluded from this study that Talazoparib plus Enzalutamide significantly improved OS and rPFS compared to Enzalutamide alone in both HRR-deficient and non-deficient populations. The findings support the broad use of this combination as a new standard of care for treatment-naïve patients with mCRPC.

Final overall survival (OS) with talazoparib (TALA) + enzalutamide (ENZA) as first-line treatment in unselected patients with metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 TALAPRO-2 trial. Agarwal N, Azad A, Carles J, et al. J Clin Oncol. 2025,43(suppl 5):LBA141. doi:10.1200/JCO.2024.42.4_suppl.LBA18.

Late Breaking Abstract – 2025 ASCO GI Symposium: Aspirin Reduces Recurrence in Colorectal Cancer Patients with PI3K Pathway Alterations

RR

SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 154,270 new cases of CRC will be diagnosed in the United States in 2025 and about 52,900 patients will die of the disease. The lifetime risk of developing CRC is about 1 in 23. Among patients with Stage II-III CRC, 20-40% will develop metastatic disease.

The majority of CRC cases (about 75 %) are sporadic whereas the remaining 25 % of the patients have a family history of the disease. Only 5-6 % of patients with CRC with a family history background are due to inherited mutations in major CRC genes, while the rest are the result of accumulation of both genetic mutations and epigenetic modifications of several genes. Colorectal Cancer is a heterogeneous disease classified by its genetics, and even though the diagnosis of Colorectal Cancer in the US is dropping among people 65 years and older, the incidence has been rising in the younger age groups, with 12% of Colorectal Cancer cases diagnosed in people under age 50.

Aspirin (AcetylSalicylic Acid) has been studied as a chemopreventive agent for several decades and the temporal relationship between systemic inflammation and cancer has been a topic of ongoing investigation. The US Preventive Services Task Force (USPSTF) found adequate evidence that Aspirin use reduces the incidence of CRC in adults after 5-10 years of use, and recommends initiating low-dose Aspirin use for the primary prevention of CardioVascular Disease (CVD) and CRC, in adults aged 50-69 years, who have a 10% or greater 10-year CVD risk, are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose Aspirin daily for at least 10 years.

Aspirin has been shown to lower the incidence of adenomas and CRC in high-risk patients. Additionally, observational studies suggest that treatment with Aspirin following diagnosis improves Disease-Free Survival (DFS) in unselected populations. Furthermore, retrospective findings indicate that somatic PIK3CA mutations predict treatment response to Aspirin. However this has not been validated in randomized trials.

The ALASCCA trial was designed to find the impact of Aspirin, on the recurrence of CRC with PI3K pathway mutations. The ALASCCA trial is a randomized, double-blind, multicenter, placebo-controlled trial conducted across 33 hospitals in Sweden, Denmark, Finland, and Norway. Researchers screened 3,508 patients diagnosed with Stage II or III colon cancer or Stage I, II, or III rectal cancer and identified 1,103 individuals with PI3K pathway mutations. Participants were categorized into two groups:

• Group A (N=515): Patients with a PIK3CA mutation in exon 9 and/or 20.
• Group B (N=588): Patients with other PI3K mutations, including PIK3CA mutations outside exon 9/20 or mutations in PIK3R1 or PTEN genes.

Of the 626 patients (419 with colon cancer and 207 with rectal cancer) who continued participation in this trial, 157 and 156 patients in Groups A and B respectively, received Aspirin 160 mg daily for 3 years, whereas 157 and 156 patients in each respective group received placebo. The median age was 66 years, 52% of patients were female, and majority of patients were white. Fifty percent of patients with both rectal and colon cancer had received neoadjuvant therapy. The Primary end point was Time to CRC recurrence (TTR). Secondary end points included Disease Free Survival (DFS) in Group A, TTR in Group B, DFS in Group B, and Safety.

The study met its Primary end point and demonstrated that Aspirin use significantly reduced the risk of CRC recurrence. After 3 years of follow up in Group A, patients taking Aspirin had a 51% lower recurrence risk compared to the placebo group (HR=0.49; P=0.044). In Group B, patients taking Aspirin experienced a 58% reduction in recurrence risk versus the placebo group (HR=0.42; P=0.013). Overall, across all groups, Aspirin was associated with a 55% reduced risk of recurrence compared to placebo. There was no statistically significant difference in 3-year DFS rates among those who received Aspirin versus placebo in Group A (88.5% versus 81.4%, respectively; HR=0.61; P =0.091). There was however significantly improved DFS rates in Group B with Aspirin use (89.1% versus 78.7%, respectively; HR=0.51; P=0.17). Severe side effects of daily Aspirin use were rare.

The researchers concluded that this landmark study provides compelling evidence for the role of low-dose Aspirin in reducing colorectal cancer recurrence in patients with PI3K pathway mutations. By integrating precision medicine with a widely available drug, the ALASCCA trial sets the stage for a new standard in colorectal cancer management.

Low-dose aspirin to reduce recurrence rate in colorectal cancer patients with PI3K pathway alterations: 3-year results from a randomized placebo-controlled trial. Martling A, Lindberg J, Myrberg IH, et al. J Clin Oncol. 2025;43(4):LBA125.

Revolutionizing Treatment: Newer Agents and Innovations mCRC Management

RR

Written by: Dr. Jerome Goldschmidt Jr, MD
Sponsored by Takeda

The treatment landscape for metastatic colorectal cancer (mCRC) has seen considerable evolution over the past two decades. Early therapeutic strategies focused on a handful of chemotherapy agents, with incremental progress in survival seen through the addition of targeted therapies like VEGF and EGFR inhibitors. However, while these agents offered modest improvements, they also brought additional toxicity. More recent advancements, particularly in molecular diagnostics, have ushered in a new era of precision medicine, enabling a better understanding of genetic mutations and the tailoring of treatments. This article examines the key advancements in mCRC management, including immunotherapies, targeted therapies, and chemotherapy agents, and how these innovations are transforming the treatment landscape for this complex disease.

For almost two decades mCRC management has revolved around the use of a handful of drugs: 5-fluorouracil (5-FU), leucovorin, oxaliplatin and irinotecan. Additions to the chemotherapy backbones of FOLFOX and FOLFIRI with the VEGF and EGF receptor inhibitors were the first big innovation in the early 2000s. In retrospect, the benefit of adding these targeted agents to the chemotherapy backbone added on average 2-3 months to overall survival with additional toxicity. It took another few years to discover that EGFR blockers were only effective in ~40% of patients with the discovery of mutated KRAS, BRAF and NRAS. To date, biomarkers pointing to the benefit from VEGF inhibition have proven elusive.

This brings us to newer agents which are now interwoven into the tapestry of more modern molecular diagnostics. Molecular diagnostics have changed some of the paradigms in which mCRC patients are treated currently. These agents can be summarized as follows:

Immunotherapies:
Approximately 15% of CRC patients will be classified as having unstable microsatellites. What this means in practical terms are the addition of repeating, multiple CpG islands in the genome of the malignant colonocytes due to inappropriate mismatch repair mechanisms. A little under half of these MSI high patients will have germline mutations in mismatch repair genes like MLH1, MSH2, MSH6 or PMS2 and often present at an earlier age with CRC as part of the “Lynch Syndrome.” More than half of MSI patients will have acquired this genotype through an apparent random methylation of one of these genes which is more common in cells as they senesce. POLE and POLD1 mutations are another family of mutations involving DNA repair that are implicated in the formation of colorectal cancers. These tumors usually have high tumor mutational burden yet are microsatellite stable. The mismatch repair deficient or MSI high colon cancers as well as the POLE and POLD1 mutants are exquisitely sensitive to immune checkpoint inhibitors.1 First line therapies with single agent pembrolizumab and combination ipilimumab/nivolumab are now standard of care.

Targeted therapies:
HER2 directed therapy has long been employed in the more proximal GI tract. HER2 overexpression has been seen in fewer colorectal cancers. Patients will derive benefit with a trastuzumab backbone and the addition of either pertuzumab, tucatinib or lapatinib. The ADC fam-trastuzumab deruxetecan may be employed upon progression.2

The BRAF inhibitor encorafenib and others have long been a staple in the management of melanoma. In CRC, encorafenib is paired with either of the EGFR blockers, panitumumab or cetuximab to extend the usefulness of these antibodies in what would otherwise be a resistant tumor to EGFR blockade.

KRAS G12C is the most commonly mutated form of the KRAS family and has been found to be safely inhibited with two newer agents, sotorasib and adagrasib. Analogous to encorafenib, they must be paired with one of the EGFR blockers approved in mCRC to overcome resistance to these antibodies.

Chemotherapy:
Trifluridine and tipiracil combination by itself or paired with bevacizumab is approved for third line therapy. Modest improvements in overall survival have been seen. It appears to be agnostic in its mechanism of action as it targets DNA synthesis much like its relatives 5FU and capecitabine. Neutropenia appears to be its dose limiting toxicity.

VEGF inhibitors:
Fruquintinib is a novel oral small-molecule tyrosine kinase inhibitor that selectively targets vascular endothelial growth factor receptors (VEGFR-1, -2, and -3). Its mechanism of action involves the inhibition of VEGF-induced phosphorylation of these receptors, which leads to reduced endothelial cell proliferation, migration, and survival, ultimately inhibiting tumor angiogenesis, and promoting tumor cell death. Approved by the FDA on November 8, 2023 for use in adult patients with refractory metastatic colorectal cancer (mCRC), fruquintinib is indicated for those who have previously undergone treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, as well as anti-VEGF and anti-EGFR therapies if RAS wild-type.3

Clinical trials, including FRESCO and FRESCO-2, demonstrated significant improvements in overall survival rates; patients receiving fruquintinib had a median overall survival of 7.4 months compared to 4.8 months for placebo recipients in the FRESCO-2 trial.4 The recommended dosage is 5 mg orally once daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity occurs.5 Common adverse effects include hypertension, palmar-plantar erythrodysesthesia, and proteinuria. This drug represents a critical advancement in the therapeutic landscape for mCRC, particularly in patients who have exhausted other treatment options.

Regorafenib has stood alone for many years as the sole agent in this space. Inhibiting VEGF is the main mechanism of action of this TKI with regards to suppressing colon tumors. It is often used as third line and beyond with only modest benefit. Noteworthy are its significant toxicities at full dose and often requires a ramp up phase to achieve tolerance of the dreaded hand foot syndrome associated with it.

The management of mCRC has made substantial advancements with the introduction of molecular diagnostics and targeted therapies. While the combination of chemotherapy agents and targeted therapies initially provided incremental survival benefits, newer innovations, such as immunotherapies and precision-targeted treatments, are offering more personalized and effective options for patients. However, challenges remain in determining the optimal use of these therapies, managing associated toxicities, and identifying the right biomarkers for treatment selection. As research continues to evolve, the future of mCRC treatment looks increasingly promising, with the potential for even greater advancements in patient outcomes.

Information regarding the studies:
FRESCO – https://jamanetwork.com/journals/jama/fullarticle/2685988
FRESCO2 – https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)00772-9/abstract

References

  1. Ambrosini M, et al. Immune checkpoint inhibitors for POLE or POLD1 proofreading-deficient metastatic colorectal cancer. Ann Oncol. 2023;35(7):643-655.
  2. Strickler JH, Cercek A, Siena S, André T, Ng K, Van Cutsem E, et al. Tucatinib plus trastuzumab for chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer (MOUNTAINEER): a multicentre, open-label, phase 2 study. Lancet Oncol. 2023;24(5):496-508
  3. S. Food and Drug Administration. FDA approves fruquintinib for metastatic colorectal cancer. FDA website. Published November 8, 2023. Accessed January 31, 2025.
  4. Xu RH, Muro K, Morita S, et al. FRESCO-2: A Phase III trial of fruquintinib in patients with refractory metastatic colorectal cancer. Ann Oncol. 2023;34(6):779-787.
  5. Abernero J, et al. Fruquintinib: An oral inhibitor of VEGFR for the treatment of metastatic colorectal cancer. Clin Cancer Res. 2023;29(4):1025-1033.

AI Tool SCORPIO Predicts Overall Survival in Patients Receiving Therapy with Immune Checkpoint Inhibitors

RR

SUMMARY: Immune checkpoint inhibitors (ICIs) have dramatically transformed the management and prognosis of various malignancies. By enhancing the ability of the immune system to identify and destroy cancer cells, ICIs have provided significant improvements in treatment outcomes across a range of tumor types.

Currently, Tumor Mutational Burden (TMB) and PD-L1 expression are the primary biomarkers approved by the FDA for predicting ICI efficacy. While these biomarkers have shown promise, they exhibit limited accuracy and face significant practical limitations, such as the need for sufficient tumor tissue for TMB analysis and the lack of standardized protocols for PD-L1 ImmunoHistoChemistry (IHC). These challenges underscore the need for a predictive model that is more accessible, cost-effective, and applicable across diverse healthcare settings.

Machine learning is a a branch of artificial intelligence that enables algorithms to learn from data, and identify key patterns and make predictions based on available clinical and biological data. SCORPIO is an AI-based model that was developed to address this clinical need, and provides an accurate and scalable tool for predicting patient responses to ICIs.

Study Design: The present study employed a machine learning approach to predict the efficacy of ICIs across a range of cancer types. By using routine blood tests as well as clinical characteristics, and utilizing data from diverse populations and cancer types, SCORPIO aimed to provide a broadly applicable predictive tool that could be used in real-world clinical settings to guide treatment decisions, with the goal of improving precision medicine. SCORPIO was developed and validated using retrospective data from multiple cohorts, including internal data from two major cancer centers (Memorial Sloan Kettering Cancer Center and Mount Sinai Health System, as well as data from 10 global Phase 3 clinical trials.

Participants: This study encompassed a total of 9,745 patients treated with ICIs across 21 different cancer types. The participants came from diverse backgrounds, including varying ethnicities, socioeconomic statuses, comorbidities, and health literacy levels, which added to the robustness of this model and real-world applicability. The study included data from patients at Memorial Sloan Kettering Cancer Center (2,000 patients), Mount Sinai Health System (1,159 patients), and global clinical trials (4,447 patients), representing the largest dataset in cancer immunotherapy to date.

Data Collection Methods: The SCORPIO model was trained using routine blood test results and basic clinical variables such as age, gender, cancer type, and prior treatments. The model was validated across multiple datasets to ensure that it could accurately predict both overall survival (OS) and Clinical Benefits (Response Rate and stable disease) for patients treated with ICIs. This study utilized machine learning algorithms to identify patterns in this data and make predictions about patient outcomes.

Analysis Techniques: Time-dependent Area Under the receiver operating characteristic Curve (AUC) was used to evaluate the predictive accuracy of SCORPIO for OS across different time points (6, 12, 18, 24, and 30 months). The performance of this model was compared to existing FDA-approved biomarkers, including TMB and PD-L1 immunostaining, to assess its superiority in predicting patient outcomes.

Results: The SCORPIO model demonstrated strong predictive performance in multiple cohorts. In internal testing, SCORPIO achieved median time-dependent AUC values of 0.763 and 0.759 for predicting OS at various time points, significantly outperforming TMB, which achieved AUC values of 0.503 and 0.543. SCORPIO also outperformed TMB for predicting clinical benefit, with AUCs of 0.714 and 0.641, compared to TMB’s 0.546 and 0.573. Additionally, SCORPIO was able to predict clinical outcomes more accurately than PD-L1 IHC. 
External validation using data from 10 global phase 3 clinical trials and a real-world cohort from Mount Sinai Health System further supported the predictive power of SCORPIO. Despite the heterogeneity in the Mount Sinai Health System cohort, performance of SCORPIO remained consistent, demonstrating its potential for broad applicability in different patient populations and healthcare settings. While SCORPIO performed consistently well for Overall Survival prediction, its ability to predict Clinical Benefit varied across cancer types and cohorts, indicating that while the model is reliable for survival prognosis, there may still be challenges in accurately predicting Response Rate or stable disease in some contexts.

Conclusion: The SCORPIO model represents a significant advancement in the field of cancer immunotherapy. By leveraging routine blood tests and basic clinical data, SCORPIO provides a highly accurate and accessible method for predicting patient response to ICIs, surpassing the performance of existing FDA-approved biomarkers like TMB and PD-L1 IHC. Its consistent performance across diverse patient populations and cancer types makes it a promising tool for precision oncology.

This model could revolutionize the way physicians identify patients who are most likely to benefit from ICIs, offering a cost-effective, scalable alternative to current biomarkers that rely on complex genomic and immunologic assays. The widespread use of SCORPIO in clinical practice could improve patient outcomes by guiding more personalized treatment decisions, especially in settings where resources for advanced biomarker testing are limited. Future studies will focus on further refining the model to enhance its ability to predict clinical benefit across all cancer types and patient cohorts.

Prediction of checkpoint inhibitor immunotherapy efficacy for cancer using routine blood tests and clinical data. Yoo, S-K, Fitzgerald CW, Cho BA, et al. Nat Med (2025). https://doi.org/10.1038/s41591-024-03398-5

FDA Approves ADCETRIS® with Lenalidomide and Rituximab for Relapsed and Refractory Diffuse Large B-Cell Lymphoma

RR

SUMMARY: The FDA on February 11, 2025, approved Brentuximab vedotin (ADCETRIS®) in combination with Lenalidomide (REVLIMID®) and a Rituximab product for adult patients with Relapsed or Refractory Large B-Cell Lymphoma (LBCL), including Diffuse Large B-Cell Lymphoma (DLBCL) not otherwise specified (NOS), DLBCL arising from indolent lymphoma, or High-Grade B-Cell Lymphoma (HGBL), after two or more lines of systemic therapy who are ineligible for Autologous hematopoietic Stem Cell Transplantation (auto-HSCT) or CAR T-cell therapy.

The American Cancer Society estimates that in 2025, about 80,350 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 19,390 individuals will die of this disease. Diffuse Large B-Cell Lymphoma (DLBCL) is the most common of the aggressive Non-Hodgkin lymphomas in the United States, and more than 25,000 cases of DLBCL are diagnosed each year in the United States, accounting for more than 25 percent of all lymphoma cases. The incidence has steadily increased 3-4% each year. More than half of patients are 65 or older at the time of diagnosis and the incidence is likely to increase with aging of the American population. The etiology of Diffuse Large B-Cell Lymphoma is unknown. Contributing risk factors include immunosuppression (AIDS, transplantation setting, autoimmune diseases), UltraViolet radiation, pesticides, hair dyes, and diet. DLBCL can develop spontaneously or as a result of Richters transformation of low grade diseases such as Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Follicular Lymphoma, or Marginal Zone Lymphoma.

DLBCL is a neoplasm of large B cells and the most common chromosome abnormality involves alterations of the BCL-6 gene at the 3q27 locus, which is critical for germinal center formation. Two major molecular subtypes of DLBCL arising from different genetic mechanisms have been identified, using Gene Expression Profiling: Germinal Center B-cell-like (GCB) and Activated B-Cell-like (ABC). Patients in the GCB subgroup have a higher 5-year survival rate, independent of clinical IPI (International Prognostic Index) risk score, whereas patients in the ABC subgroup have a significantly worse outcome. Regardless of molecular subtype, R-CHOP regimen (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone), given every 21 days, for 6 cycles, delivered with curative intent, is the current standard of care for patients of all ages, with newly diagnosed DLBCL. Approximately 30-40% of patients experience disease progression or relapse during the first 2 years and attempts to improve on R-CHOP regimen have not been successful. Maintenance treatment strategy following R-CHOP, to better control the disease, delay disease progression and improve long term survival, have included Autologous Stem Cell Transplantation, CAR T-cell therapy, maintenance treatment with agents such as oral protein kinase inhibitor Enzastaurin and Everolimus. Outcomes for transplant-ineligible patients with Relapsed/Refractory DLBCL patients remain poor. There is a critical unmet need for this patient group.

Brentuximab Vedotin (ADCETRIS®) is an Antibody-Drug Conjugate (ADC) that targets CD30, which is a surface antigen, expressed on Reed-Sternberg cells, in patients with Classical Hodgkin lymphoma. This ADC consists of an anti-CD30 monoclonal antibody linked to MonoMethyl Auristatin E (MMAE), an antimicrotubule agent. Upon binding to the CD30 molecule on the cancer cells, MMAE is released into the cancer cell, resulting in cell death. Preclinical data and early phase studies provided the rationale for combining Brentuximab vedotin, Lenalidomide and Rituximab for the treatment of Relapsed/Refractory DLBCL.

ECHELON-3 is an ongoing, global, randomized, double-blind, multicenter Phase III study, designed to evaluate the efficacy and safety of Brentuximab vedotin in combination with Lenalidomide and Rituximab, compared to Lenalidomide and Rituximab plus placebo, in adult patients with Relapsed/Refractory DLBCL, regardless of CD30 expression, who have received two or more prior lines of therapy and were ineligible for or had previously failed Hematopoietic Stem Cell Transplant (HSCT) or Chimeric Antigen Receptor (CAR) T-cell therapy.

In this global study, 230 patients were randomized 1:1 to receive either Brentuximab vedotin plus Lenalidomide and Rituximab (BV+R2) – N=112, with Brentuximab vedotin administered at 1.2 mg/kg IV every 3 weeks, Lenalidomide at 20 mg orally daily, and Rituximab at 375 mg/m² IV every 3 weeks, or Placebo plus Lenalidomide and Rituximab (placebo+R2) – N=118. Placebo for Brentuximab vedotin with Lenalidomide and Rituximab was administered in the same manner. Treatment continued until disease progression or unacceptable toxicity. The median age was 71 years, 56% were male, median prior lines of therapy was 3, 29% had prior CAR T-cell therapy, approximately 15% of patients had prior bispecific antibody exposure, and 68% were CD30 negative with CD30 tumor expression of less than 1%. The Primary endpoint was Overall Survival (OS). Secondary endpoints included Progression-Free Survival (PFS), Objective Response Rate (ORR) and Complete Response (CR) Rate.

At the interim analysis, with a median follow-up of 16.4 months, BV+R2 regimen demonstrated a median OS of 13.8 months compared to 8.5 months with placebo+R2, representing a 37% reduction in the risk of death (HR=0.63; P=0.009). The median PFS was 4.2 months in the BV+R2 arm versus 2.6 months in the placebo+R2 arm (HR=0.53; P<0.001). The ORR was 64% with BV+R2 compared to 42% with placebo+R2 (P=0.001). The CR rate was 40% with BV+R2 versus 19% with placebo+R2. The efficacy benefits of BV+R2 were consistent across key subgroups, including patients with CD30-positive and CD30-negative disease, highlighting the broad applicability of the regimen.
Grade 3 or higher adverse events were more frequent in the BV+R2 arm compared to placebo+R2 (88% versus 77%), and the most common Grade 3 or higher adverse events included neutropenia, anemia and diarrhea. Peripheral Neuropathy was higher with BV+R2 compared to placebo+R2, although generally manageable.

In conclusion, the ECHELON-3 study demonstrated that the addition of Brentuximab vedotin to Lenalidomide and Rituximab significantly improved Overall Survival, Progression-Free Survival, and Response Rates in patients with Relapsed/Refractory DLBCL, compared to Lenalidomide and Rituximab alone. This regimen offers a promising new treatment option for patients who have exhausted standard therapies or are ineligible for intensive treatments like CAR-T cell therapy or HSCT. The results underscore the potential of targeted therapies in reshaping the management of DLBCL, providing renewed hope for improved outcomes in this challenging disease setting. As the study continues to follow patients for long-term outcomes, ongoing research will further elucidate the durability of responses and additional safety data, thereby informing future clinical practice guidelines and optimizing patient care strategies.

Brentuximab Vedotin Combination for Relapsed Diffuse Large B-Cell Lymphoma. Bartlett NL, Hahn U, Kim W-S, et al. J Clin Oncol. January 07,2025. https://doi.org/10.1200/JCO-24-02242.

Anthracycline Plus Taxane Based Adjuvant Therapy for High risk Early Stage Breast Cancer

RR

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 316,950 new cases of female breast cancer will be diagnosed in 2025, and about 42,170 women will die of the disease, largely due to metastatic recurrence.

Approximately 50% of all breast cancers are Estrogen Receptor (ER) positive, HER2-negative, axillary node-negative tumors. In the treatment of early-stage breast cancer, particularly in Hormone Receptor-positive (HR-positive) and HER2-negative cases, the standard approach to adjuvant chemotherapy has evolved, with the goal of optimizing patient outcomes while minimizing unnecessary toxicity. Historically, anthracyclines, a class of chemotherapy drugs, were combined with taxanes as part of chemotherapy regimens. However, recent studies have questioned the benefit of adding anthracyclines to treatment, for patients with HR-positive/HER2-negative breast cancer, particularly in those with lower recurrence risk. The addition of anthracyclines has not definitively demonstrated improvements in outcomes like invasive Disease-Free Survival (DFS) for patients with HR-positive/HER2-negative breast cancer who receive taxane-based chemotherapy. Anthracycline-free regimens are typically preferred for lower risk patients, as efficacy is not compromised and there is no heightened risk of long-term side effects, such as leukemia. Yet, a gap exists in the literature regarding the benefit of anthracycline therapy in patients with high-risk profiles, as identified by OncotypeDX assay.

The Oncotype DX breast cancer assay, is a multigene genomic test that analyzes the activity of a group of 21 genes and is able to predict the risk of breast cancer recurrence and likelihood of benefit from systemic chemotherapy following surgery, in women with early-stage breast cancer. Oncotype Dx assay categorizes patients based on Recurrence Scores (RS) into Low risk (0-10), Intermediate risk (11-25), and High risk (26-100) helping clinicians tailor treatment decisions. Despite the widespread clinical use of OncotypeDX, the potential benefits of anthracyclines for patients with high RS scores have not been comprehensively studied.

The Anthracyclines in Early Breast Cancer (ABC) trials demonstrated that the addition of anthracyclines to a taxane-based chemotherapy regimen did not significantly improve invasive DFS for patients with HR-positive breast cancer. As a result, HR-positive/HER2-negative patients with a lower RS or smaller tumors have generally been managed with anthracycline-free regimens.

TAILORx ((Trial Assigning Individualized Options for Treatment) is a Phase III, randomized, prospective, non-inferiority trial in which 10,273 women, 18-75 years of age, with HR-positive, HER2-negative, T1b-T2N0 early-stage axillary node-negative breast cancer were enrolled. Patients had tumors 1.1-5.0 cm in size (or 0.6-1.0 cm and intermediate/high grade). Patients were divided into three groups based on their Recurrence Score (RS). Women with a Low RS of 0-10 received endocrine therapy alone and those with a High RS of 26-100 received endocrine therapy in combination with standard adjuvant chemotherapy which included T-AC (Taxane usually Docetaxel along with anthracycline usually Doxorubicin plus Cyclophosphamide, or TC (Taxane plus Cyclophosphamide, but without an anthracycline). Patient with Intermediate RS of 11-25 (N=6711) were randomly assigned to receive endocrine therapy alone (N=3399) or endocrine therapy and adjuvant chemotherapy (N=3312).TAILORx study concluded that among patients with a Recurrence Score of 11-25, endocrine therapy alone was non-inferior to chemotherapy plus endocrine therapy.

A subset of 2,591 patients, who had a recurrence score between 11 and 100, formed the basis for this analysis. Among them, 437 patients received T-AC, while 2,091 received TC regimen. Outcomes were compared between patients who received T-AC and those who received TC, adjusting for key variables such as age, RS, tumor size, grade, and Estrogen/Progesterone Receptor status. Outcomes were stratified by RS > 31 and < 31.The study population had a median age of 55 years, and median follow up was 7.3 years. The Primary end point of this study was to evaluate Distant Recurrence-Free Interval (DRFI). Other outcomes included Recurrence-Free Survival (RFS) and Overall Survival (OS).

Impact of Recurrence Score
This analysis revealed that the addition of anthracyclines to chemotherapy provided distinct benefits for patients with a high RS, specifically those with an RS of 31 or higher. Among this high risk group, the 5-year Distant Recurrence-Free Interval (DRFI) was significantly improved with T-AC compared to TC (adjusted DRFI rate was 97.5% for T-AC versus 89.4% for TC (adjusted HR=0.27, P=0.01). Similarly, Distant Recurrence-Free Survival (DRFS) was 96.5% for T-AC versus 88.3% for TC (adjusted HR=0.45, P= 0.03), and Recurrence-Free Survival (RFS) was also superior with T-AC. There was a trend towards improved OS at 5 years. For patients with an RS of less than 31, no significant benefit was observed from the addition of anthracyclines. This was particularly true for patients with an RS between 26 and 30, where no clear advantage of T-AC over TC was seen. In these lower-risk patients, both the DRFI and DRFS were similar between the two regimens.
The benefit of T-AC over TC increased further for higher RS values indicating that patients with higher recurrence scores saw more significant benefits from the addition of anthracyclines (HR=0.60 for RS 40 and HR=0.45 for RS 50).

Effect of Tumor Size
The benefit of T-AC in high-risk patients was particularly pronounced in tumors larger than 2 cm. While the primary endpoint of DRFI showed improvement with T-AC when the recurrence score was higher than 31regardless of tumor size, secondary endpoints, including DRFS, were notably enhanced in patients with tumors above the 2 cm size threshold. In contrast, smaller tumors (2 cm or less) did not demonstrate a benefit from the addition of anthracyclines.

Effect in Premenopausal and Postmenopausal Patients
Both premenopausal and postmenopausal patients with high RS showed a benefit from the addition of anthracyclines to chemotherapy. The DRFI advantage was seen in both groups, with statistical significance for premenopausal patients (P=0.032) and a trend toward significance for postmenopausal patients (P=0.028).

Risk of Non-Breast Cancer Deaths
An important consideration when making treatment decisions are the potential risks associated with anthracycline use, especially long-term risks such as leukemia or other non-breast cancer deaths.

In conclusion, the TAILORx analysis suggests that for patients with early stage, HR-positive/HER2-negative breast cancer, OncotypeDX Recurrence Score appears to be a reliable predictor of which patients might benefit from anthracyclines. Patients with a high recurrence score (RS 31 or more) derived significant benefit from the addition of anthracyclines to chemotherapy, especially those with tumors larger than 2 cm. The study was a post-hoc analysis of the TAILORx trial, which was not specifically designed to evaluate the benefit of anthracyclines and must be interpreted with caution pending further validation in prospective trials.

Impact of Anthracyclines in High Genomic Risk Node-Negative HR+/HER2- Breast Cancer. Chen N, et al. Abstract GS3-03. Presented at: San Antonio Breast Cancer Symposium; Dec. 10-13, 2024; San Antonio, TX. Abstract GS3-03