Category: Precision Oncology

Late Breaking Abstract – 2025 ASCO GI Symposium: Circulating Tumor DNA (ctDNA) as a Predictive Biomarker for Celecoxib Benefit in Stage III Colon Cancer: Insights from CALGB/SWOG 80702

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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.

It is estimated that approximately 30% of patients with Stage II or III CRC and 60-70% of patients after oligometastatic resection experience recurrence. Adjuvant chemotherapy for patients with resected, locally advanced, node-positive (Stage III) colon cancer has been the standard of care since the 1990s. However, not all patients with Stage III disease benefit from adjuvant chemotherapy. In the IDEA trial, the absolute Disease Free Survival benefit of adjuvant chemotherapy for the lowest-risk Stage III group and the highest-risk group was 8% and 20%, respectively, suggesting that a substantial number of patients with low-risk Stage III cancer can safely forgo adjuvant chemotherapy or be considered for treatment de-escalation.

More recent data suggests that platelets may play a role in tumorigenesis as well, through the release of angiogenic and growth factors due to overexpression of Cyclooxygenase 2 (COX-2). Aspirin and COX-2 inhibitors such as Celecoxib have been associated with a reduced risk of colorectal polyps and cancer in observational and randomized studies.

The CALGB/SWOG 80702 is a randomized Phase III trial conducted to determine if the addition of Celecoxib to adjuvant chemotherapy with Fluorouracil, Leucovorin, and Oxaliplatin (FOLFOX) improves Disease-Free Survival (DFS) in patients with Stage III colon cancer. Patients were randomized to receive adjuvant FOLFOX (every 2 weeks) for 3 versus 6 months with or without 3 years of Celecoxib (400 mg orally daily; N=1263) versus placebo; N=1261). In this study, the addition of Celecoxib for 3 years to standard adjuvant chemotherapy did not significantly improve Disease-Free Survival (DFS).

The present analysis evaluated the prognostic and predictive value of circulating tumor DNA (ctDNA) in identifying a subpopulation of patients in the above study, who may potentially benefit from Celecoxib therapy. A subset of 1,011 patients from the CALGB/SWOG 80702 trial with adequate biospecimen availability was included in this analysis. ctDNA status was assessed using a tumor-informed, clinically validated 16-plex multiplex Polymerase Chain Reaction Next-Generation Sequencing (mPCR-NGS) assay (Signatera(TM), Natera, Inc.). Plasma samples were collected post-surgery and before the initiation of adjuvant chemotherapy. Survival outcomes, including DFS and Overall Survival (OS), were analyzed using Kaplan-Meier estimates and Cox proportional hazards models.

Results:

  • Of the 1,011 patients with ctDNA data, 189 (18.7%) tested ctDNA-positive.
  • ctDNA positivity correlated with male sex, advanced T stage, and N2 nodal disease.
  • Patients with detectable ctDNA had significantly worse outcomes:
    • DFS: Hazard Ratio (HR)=6.52; P<0.0001
    • OS: HR=6.28; P<0.0001
  • Three-year DFS rates were:
    • 6% in ctDNA-negative patients
    • 8% in ctDNA-positive patients
  • Celecoxib did not significantly impact DFS in ctDNA-negative patients (HR=0.75; P=0.095, 3-year DFS: 87.7% vs. 85.5%).
  • However, in ctDNA-positive patients, Celecoxib was associated with a notable improvement in DFS (HR=0.59; P=0.004, 3-year DFS: 44.1% vs. 26.6%).
  • OS trends mirrored those observed for DFS:
    • ctDNA-negative group: HR=0.86 (P=0.49) with Celecoxib versus placebo.
    • ctDNA-positive group: HR=0.63 (P=0.028) with Celecoxib versus placebo.
  • Multivariate analysis confirmed a statistically significant benefit of Celecoxib in ctDNA-positive patients.

Conclusion: ctDNA serves as a strong prognostic biomarker for both DFS and OS in Stage III colon cancer. Furthermore, ctDNA positivity appears to predict a significant therapeutic benefit from adjuvant Celecoxib, suggesting its potential role in stratifying patients for COX-2 inhibitor therapy. These findings highlight the utility of ctDNA assessment in guiding adjuvant treatment decisions and optimizing personalized therapeutic strategies in colon cancer.

Clinical Implications:

  • Post-surgical ctDNA testing can help identify patients at elevated risk of recurrence.
  • Celecoxib may offer a survival advantage for ctDNA-positive patients when used alongside standard FOLFOX chemotherapy.
  • Further research is warranted to elucidate the role of ctDNA-guided treatment in personalizing colon cancer therapy.

Prognostic and predictive role of circulating tumor DNA (ctDNA) in stage III colon cancer treated with celecoxib: Findings from CALGB (Alliance)/SWOG 80702. Nowak JA, Shi Q, Twombly T, et al. J Clin Oncol. 2025;43(4):LBA14.

Breakthroughs in Targeted Therapy for Low-Grade Serous Ovarian Carcinoma

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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 GU Cancers Symposium: Talazoparib Plus Enzalutamide Improves Overall Survival in mCRPC

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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

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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.

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

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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

Late Breaking Abstract – 2025 ASCO GI Symposium: OPDIVO® Plus YERVOY® Superior to OPDIVO® Alone in MSI-H/MMR Deficient Metastatic Colorectal Cancer

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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. Defective MMR can be a sporadic or heritable event. Approximately 65% of the MSI high colon tumors are sporadic and when sporadic, the DNA MMR gene is MLH1. Defective MMR can manifest as a germline mutation occurring in MMR genes including MLH1, MSH2, MSH6 and PMS2. This produces Lynch Syndrome often called Hereditary Nonpolyposis Colorectal Carcinoma – HNPCC, an Autosomal Dominant disorder that is often associated with a high risk for Colorectal and Endometrial carcinoma, as well as several other malignancies including Ovary, Stomach, Small bowel, Hepatobiliary tract, Brain and Skin. MSI is a hallmark of Lynch Syndrome-associated cancers. MSI high tumors tend to have better outcomes and this has been attributed to the abundance of tumor infiltrating lymphocytes in these tumors from increase immunogenicity. These tumors therefore are susceptible to blockade with immune checkpoint inhibitors.

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. Tumors considered MSI-H have deficiency of one or more of the DNA MMR genes. MMR gene deficiency can be detected by ImmunoHistoChemistry (IHC). NCCN Guidelines recommend MMR or MSI testing for all patients with a history of Colon or Rectal cancer. Unlike Colorectal and Endometrial cancer, where MSI-H/dMMR testing is routinely undertaken, the characterization of Lynch Syndrome across heterogeneous MSI-H/dMMR tumors is unknown.

Nivolumab (OPDIVO®) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, whereas Ipilimumab (YERVOY®) is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152). Blocking the Immune checkpoint proteins unleashes the T cells, resulting in T cell proliferation, activation and a therapeutic response. The FDA in 2018, granted accelerated approval to Ipilimumab for use in combination with Nivolumab, based on CheckMate-142, for the treatment of patients with MSI-H or dMMR metastatic CRC, that has progressed following treatment with a Fluoropyrimidine, Oxaliplatin, and Irinotecan. The FDA in July, 2017, granted accelerated approval to single agent Nivolumab for treatment of this same group of patients.

The CheckMate 8HW is an ongoing Phase III, multinational, open-label, randomized trial evaluating Nivolumab plus Ipilimumab as compared with Nivolumab alone or chemotherapy, in patients with MSI-H or dMMR metastatic CRC. In this study, patients with unresectable or mCRC and MSI-H/dMMR status by local testing who had received 0-1 prior line of therapy were randomly assigned in a 2:2:1 ratio to receive either Nivolumab monotherapy (N=353), Nivolumab plus Ipilimumab combination therapy (N=354), or the investigator’s choice of chemotherapy (mFOLFOX6 or FOLFIRI with or without Bevacizumab or Cetuximab (N=132). Patients who had previously received two or more prior lines of therapy for unresectable or metastatic disease were randomly assigned, in a 1:1 ratio, to receive Nivolumab plus Ipilimumab or Nivolumab alone. In the Nivolumab monotherapy arm, patients received Nivolumab 240 mg IV once every two weeks for six doses, followed by 480 mg IV every four weeks. In the Nivolumab plus Ipilimumab arm, patients were given Nivolumab 240 mg IV plus Ipilimumab 1mg/kg IV every three weeks for four doses, followed by Nivolumab 480 mg IV every four weeks. The median patient age was 64 years and tumor location was in the right colon in two thirds of the patients. Treatments continued until disease progression or unacceptable toxicity in all treatment groups or a maximum of 2 years. The dual Primary end points were Progression-Free Survival (PFS) as determined by Blinded Independent Central Review (BICR) comparing Nivolumab plus Ipilimumab to chemotherapy in the first-line therapy setting, and PFS comparing Nivolumab monotherapy to Nivolumab plus Ipilimumab across all lines of therapy, in patients with centrally confirmed MSI-H/dMMR metastatic CRC. At a median follow-up of 31.5 months the results from the prespecified interim analysis (the primary analysis) showed that the PFS outcomes were significantly better with Nivolumab plus Ipilimumab than with chemotherapy (HR=0.21; P<0.001).

The researchers herein reported the first results from the other dual Primary endpoint of PFS for Nivolumab plus Ipilimumab versus Nivolumab monotherapy across all lines of therapy in patients with centrally confirmed MSI-H/dMMR metastatic CRC. Of all the randomized patients 296 in the Nivolumab plus Ipilimumab group and 286 in the Nivolumab monotherapy group had centrally confirmed MSI-H/dMMR status. With a median follow-up of 47.0 months, Nivolumab plus Ipilimumab demonstrated clinically meaningful and statistically significant improvement in PFS by BICR versus Nivolumab monotherapy, with a median PFS Not Reached (NR) in the Nivolumab plus Ipilimumab group, compared to 39.3 months for those on Nivolumab monotherapy (HR=0.62; P= 0.0003). The PFS rates at 12, 24, and 36 months were higher in the Nivolumab plus Ipilimumab group at 76%, 71%, 68% versus 63%, 56%, 51% for Nivolumab monotherapy.

The Objective Response Rate (ORR) was significantly higher with Nivolumab plus Ipilimumab at 71%, compared to 58% with Nivolumab alone (P=0.0011). No new safety concerns were identified

It was concluded that the CheckMate 8HW study met its dual Primary endpoints, with Nivolumab plus Ipilimumab demonstrating a statistically significant and clinically meaningful improvement in PFS compared to Nivolumab monotherapy across all lines of therapy in MSI-H/dMMR metastatic CRC. Moreover, Nivolumab plus Ipilimumab was associated with higher ORR, confirming its potential as a new standard of care for patients with MSI-H/dMMR metastatic CRC. The CheckMate 8HW study is a pivotal contribution to the treatment landscape of MSI-H/dMMR metastatic Colorectal cancer, providing compelling evidence for the use of Nivolumab plus Ipilimumab in the first-line and beyond.

First results of nivolumab (NIVO) plus ipilimumab (IPI) vs NIVO monotherapy for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) from CheckMate 8HW. Andre T, Elez E, Lenz H-J, et al. J Clin Oncol 43, 2025 (suppl 4; abstr LBA143)

SIGNATERA® ctDNA Assay Can Guide Therapy in Early Stage Colorectal Cancer

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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.

It is estimated that approximately 30% of patients with Stage II or III CRC and 60-70% of patients after oligometastatic resection experience recurrence. Adjuvant chemotherapy for patients with resected, locally advanced, node-positive (Stage III) colon cancer has been the standard of care since the 1990s. However, not all patients with Stage III disease benefit from adjuvant chemotherapy. In the IDEA trial, the absolute Disease Free Survival benefit of adjuvant chemotherapy for the lowest-risk Stage III group and the highest-risk group was 8% and 20%, respectively, suggesting that a substantial number of patients with low-risk Stage III cancer can safely forgo adjuvant chemotherapy or be considered for treatment de-escalation. Even though 80% of patients with Stage II colon cancer are cured with surgery alone, adjuvant chemotherapy is recommended for patients who have Stage II colon cancer with high-risk clinicopathological features, including tumor penetration of the serosa (T4 disease). However, the benefit of adjuvant chemotherapy for patients with Stage II disease remains unclear, with less than 5% of patients benefiting from adjuvant chemotherapy. There is therefore an unmet need for more precise markers to predict risk of recurrence after surgery for resectable colon cancer, other than clinicopathological risk factors, and thus avoid exposure to unnecessary chemotherapy.

Circulating Tumor DNA (ctDNA) refers to DNA molecules that circulate in the bloodstream after cell apoptosis or necrosis, and can be detected in the cell-free component of peripheral blood samples (Liquid Biopsy) in almost all patients with advanced solid tumors including advanced CRC. ctDNA is a valuable biomarker and is directly evaluated for evidence of Minimal Residual Disease and allows early detection of relapse. Several studies have shown that detectable ctDNA following curative intent surgery for early stage cancers, including those with Stage II colon cancer, is associated with a very high risk of recurrence (more than 80%) without further adjuvant therapy. It has remained unclear whether adjuvant treatment is beneficial for these ctDNA-positive patients who are at high risk for recurrence.

The BESPOKE CRC trial is a multicenter, prospective, observational study, designed to evaluate the role of Natera’s SIGNATERA® assay in informing adjuvant chemotherapy decisions for patients with surgically resected pathologic Stage II and III Colorectal Cancer (CRC). SIGNATERA® test is a personalized, tumor-informed ctDNA (circulating tumor DNA) assay for tracking 16 tumor-specific mutations in the blood for Minimal Residual Disease (MRD) determination and molecular monitoring. This study aimed to assess whether ctDNA could improve the decision-making process for adjuvant chemotherapy, thereby influencing the course of treatment and ultimately, patient outcomes.

This study included 1780 patients who had undergone surgical resection for Stage II or III CRC. These patients were enrolled in the study and were followed for their ctDNA status at various time points after their resection. The first ctDNA sample was taken for MRD 2 to 6 weeks following surgery (MRD time point). Subsequent samples were collected at 2, 4, and 6 months, and then every 3 months up to 24 months after resection. The surveillance ctDNA collection started at 6 months or later from surgical resection. The treating oncologists were provided with the ctDNA results of their patients and were allowed to base treatment decisions on these findings, within the context of standard-of-care guidelines. After exclusions, 1166 patients remained in the final analysis, 694 patients in the adjuvant chemotherapy cohort and 472 patients in the observation cohort. The median age of the study participants was 61.8 years, majority of the patients were male (56.7%), most patients had stage III CRC (55.7%), 59.5% of patients received adjuvant chemotherapy, while 83.9% of the participants did not experience a recurrence during the study period. The Primary endpoint of this study was to evaluate the impact of ctDNA testing on adjuvant treatment decisions, as well as the rates of asymptomatic CRC recurrences. Secondary endpoints included the MRD clearance rate, survival rates of MRD-negative patients, Overall Survival, and Patient-Reported Outcomes. The median follow-up was 23.9 months

ctDNA and Disease-Free Survival (DFS)
The study found that postoperative ctDNA positivity was a strong predictor of inferior Disease-Free Survival (DFS) in patients with both Stage II and III disease. At the MRD time point (first ctDNA sample 2-6 weeks post surgery), 7.54% of patients with Stage II disease (N= 517) tested positive for MRD versus 28.35% of patients with Stage III disease (N= 649). These findings were crucial for determining which patients might be at higher risk of recurrence.

  • Among Stage II patients, those with positive postoperative ctDNA had a significantly lower 2-year DFS rate of 45.9%, compared to 91.8% in ctDNA-negative patients (HR=11.23; P <0.0001).
  • Among Stage III patients, those with positive ctDNA were also associated with poorer DFS, with a 2-year DFS rate of 35.5% versus 87.4% for ctDNA-negative patients (HR=8.33; P <0.0001).

Further analyses showed that positive ctDNA at the first surveillance time point was linked with an inferior DFS (HR=20.63; P <0.0001). Patients who became positive for ctDNA at any time during surveillance had a 26.4-times higher risk of recurrence compared to those who remained ctDNA-negative.

ctDNA Clearance and Treatment Efficacy
One of the most compelling findings of the study was the correlation between ctDNA clearance during and after adjuvant chemotherapy and improved DFS. Patients whose ctDNA was cleared during treatment had significantly better outcomes:

  • Hazard ratio for DFS at 3 months after chemotherapy: 0.43 (P <.0001)
  • Hazard ratio for DFS at 6 months: 0.31 (P <.0001)

These results suggest that ctDNA clearance could be a powerful marker for assessing the effectiveness of adjuvant chemotherapy, reinforcing its potential as a treatment monitoring tool.

Recurrence Detection and Metastasis-Directed Therapy
The ctDNA test demonstrated high sensitivity in detecting disease recurrence, particularly in the liver, which had the highest sensitivity at 96%. It also showed high sensitivities in detecting recurrences in low-shedding sites like the lung (76%) and peritoneum (79%). Bone and abdominal wall recurrences had a sensitivity of 100%, though the small number of such cases limits the ability to draw firm conclusions.

Of the 188 patients who experienced disease recurrence, 86% had a prior positive ctDNA test. Notably, 30% of those patients received metastasis-directed therapy, with 81% of them undergoing surgical intervention. This emphasizes the potential of serial ctDNA monitoring in improving early detection of recurrences and facilitating more effective interventions, including metastasis-directed therapy, which could provide these patients with a chance for a cure.

Impact of Adjuvant Chemotherapy in MRD-Positive vs MRD-Negative Patients
The study also highlighted the differing effects of adjuvant chemotherapy in MRD-positive versus MRD-negative patients. While MRD-negative patients saw no significant difference in DFS regardless of whether they received chemotherapy or observation, MRD-positive patients showed a clear benefit from adjuvant chemotherapy:

  • 2-year DFS rates for MRD-positive patients was 40.3% with chemotherapy versus 24.7% with observation (HR=0.48; P =0.0008).
  • 2-year DFS rates for MRD-negative patients was 89.7% with chemotherapy versus 89.5% with observation (HR=0.93; P =0.03).

These results underscore the potential of using ctDNA as a tool to help personalize treatment strategies, offering chemotherapy to those who are most likely to benefit (MRD-positive patients) and sparing others from unnecessary treatment.

Summary of Key Findings

  • Tumor-informed ctDNA assays had a significant impact on adjuvant treatment decisions, influencing chemotherapy de-escalation in 16.3% of Stage II/III CRC cases.
  • Postoperative ctDNA positivity correlated with inferior DFS, making it a strong prognostic tool for identifying high-risk patients.
  • ctDNA clearance during and after chemotherapy was associated with improved DFS, highlighting its potential to monitor treatment efficacy.
  • ctDNA assays demonstrated high sensitivity in detecting recurrences, particularly in the liver, and influenced the use of metastasis-directed therapy.
  • Adjuvant chemotherapy showed a clear benefit in MRD-positive patients, further solidifying the role of this assay in personalizing treatment strategies for CRC patients.

This trial positions ctDNA as a pivotal tool in managing CRC, not only as a prognostic marker but also as a means to optimize treatment and improve patient outcomes.

Circulating tumor DNA for detection of molecular residual disease (MRD) in patients (pts) with stage II/III colorectal cancer (CRC): final analysis of the BESPOKE CRC sub-cohort. Shah P, Aushev V, Ensor J, et al. J Clin Oncol. 2025;43(suppl 4):15. doi:10.1200/JCO.2025.43.4_suppl.15

Prolonged Survival Benefit with LYNPARZA® in BRCA Mutated Early Stage Breast Cancer

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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. Approximately 319,750 new cases of breast cancer will be diagnosed in 2025 and about 42,680 individuals will die of the disease, largely due to metastatic recurrence.

DNA can be damaged due to errors during its replication or as a result of environmental exposure to UV radiation from the sun or other toxins. The tumor suppressor genes such as BRCA1 (Breast Cancer 1) and BRCA2 help repair damaged DNA and thus play an important role in maintaining cellular genetic integrity, failing which these genetic aberrations can result in malignancies. The BRCA1 gene is located on the long (q) arm of chromosome 17 whereas BRCA2 is located on the long arm of chromosome 13. Mutations in BRCA1 and BRCA2 account for about 20 to 25 percent of hereditary breast cancers and about 5 to 10 percent of all breast cancers. These mutations can be inherited from either of the parents and a child has a 50 percent chance of inheriting this mutation, and the deleterious effects of the mutations are seen even when a second copy of the gene in an individual is normal. Patients with BRCA mutations can present with aggressive, high-risk disease and are at a high risk of recurrence following completion of multimodality therapy including surgery, radiation, and chemotherapy. This is an area of unmet need, warranting identification of additional novel and effective therapies.

BRCA1 and BRCA2 are tumor suppressor genes and they recognize and repair double strand DNA breaks via Homologous Recombination (HR) pathway. Homologous Recombination 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. The PARP (Poly ADP Ribose Polymerase) family of enzymes include PARP1 and 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.

Olaparib (LYNPARZA®) is a PARP inhibitor, that traps PARP onto DNA at sites of single-strand breaks, thereby preventing their repair and generate double-strand breaks. These breaks cannot be repaired accurately in tumors harboring defects in Homologous Recombination Repair pathway genes, such as BRCA1 or BRCA2 mutations, and this leads to cumulative DNA damage and tumor cell death.

OlympiA is a multicenter, randomized, placebo-controlled, double-blind, Phase III trial of adjuvant Olaparib after neoadjuvant/adjuvant chemotherapy, in patients with germline BRCA1/2 mutations, and high risk HER2-negative early breast cancer. This trial enrolled 1836 patients, including triple-negative and Hormone Receptor positive (HR-positive) breast cancer. All enrolled patients had already received standard adjuvant or neoadjuvant chemotherapy, surgery and if needed, radiation therapy, for early stage breast cancer (Stage II-III). Inclusion criteria required that patients have a high risk of disease recurrence. Patients with triple-negative breast cancer who received adjuvant chemotherapy were required to have axillary node–positive disease or an invasive primary tumor measuring at least 2 cm. Patients who were treated with neoadjuvant chemotherapy were required to have residual invasive breast cancer in the breast or resected lymph nodes (no pathological Complete Response from neoadjuvant therapy). Patients who were treated with adjuvant chemotherapy for HR-positive, HER2-negative breast cancer were required to have 4 or more pathologically confirmed positive lymph nodes. Patients were randomized 1:1 to receive Olaparib 300 mg PO BID continuously for 1 year (N=921) or placebo (N=915). Endocrine therapy and bisphosphonates were allowed. Treatment groups were well balanced. The median age was 42 years, germline mutations were present in BRCA1 in 72% of the patients, in BRCA2 in 27% of the patients, 82% of the patients had triple-negative breast cancer, 18% had HR-positive and HER2 negative disease, 62% were premenopausal and 38% were postmenopausal, 50% of the patients had received adjuvant chemotherapy and 50% had received neoadjuvant chemotherapy. The Primary endpoint was Invasive Disease Free Survival (IDFS) and Secondary endpoints included Distant DFS (DDFS), Overall Survival (OS) and Safety. At the pre-specified interim analysis (2.5 years), the estimated 3-year Invasive DFS was 85.9% for patients who received Olaparib compared with 77.1% for those who received placebo (HR=0.58; P<0.001), representing a 42% reduction in the risk of Invasive DFS with Olaparib compared to placebo. The 3-year Distant DFS was 87.5% versus 80.4% respectively (HR=0.57; P<0.001). The researchers in this updated analysis reported the results of the third pre-specified interim analysis with median follow-up of 6.1 years (maximum follow-up of 9.6 years).

The treatment benefit with Olaparib was maintained with longer follow up, and was similar to previously reported results. The Invasive DFS at 6 years was 79.6% in the Olaparib-treated group versus 70.3% in the placebo group, with an absolute difference of 9.3%, favoring the addition of Olaparib (HR=0.65). The Distant DFS at 6 years was 83.5% versus 75.7%, respectively, with an absolute difference of 7.8% (HR=0.65). The 6-year Overall Survival rate was 87.5% in the Olaparib group versus 83.2% in the placebo group, with a 28% reduction in the risk of death (HR=0.72). The benefit with adjuvant Olaparib was consistent across all key subgroups, including for patients with high risk and HR-positive disease.

Fewer cases of BRCA-associated cancers such as contralateral invasive and non-invasive breast cancers, new primary ovarian cancer and new primary fallopian tube cancer were reported, with adjuvant Olaparib versus placebo. Further, there was no increase in the risk of developing secondary myelodysplastic syndrome or acute myeloid leukemia.

It was concluded that at 6.1 years median follow-up, one year of adjuvant treatment with Olaparib after neoadjuvant or adjuvant chemotherapy continues to demonstrate meaningful improvements in Invasive DFS, Distant DFS and OS in patients with germline BRCA pathogenic variants and high risk, HER2-negative breast cancer, including those with HR-positive tumors. This study highlights the importance of BRCA testing in early stage breast cancer. Perhaps considering one year of adjuvant Olaparib followed by a CDK4/6 inhibitor in HR-positive, BRCA-positive, high risk HER2-negative early stage breast cancer patients, may be a reasonable approach.

Garber J: OlympiA-Phase 3, multicenter, randomized placebo-controlled trial of adjuvant olaparib after (neo)adjuvant chemotherapy in patients with germline BRCA1/BRCA2 pathogenic variants and high-risk HER2-negative primary breast cancer: Longer-term follow-up. 2024 San Antonio Breast Cancer Symposium. Abstract GS1-09. Presented December 11, 2024.

FDA Approves LUMAKRAS® with VECTIBIX® for KRAS G12C-mutated Colorectal Cancer

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SUMMARY: The FDA on January 16, 2025, approved Sotorasib (LUMAKRAS®) with Panitumumab (VECTIBIX®) for adult patients with KRAS G12C-mutated metastatic ColoRectal Cancer (mCRC), as determined by an FDA-approved test, who have received prior Fluoropyrimidine, Oxaliplatin, and Irinotecan-based chemotherapy. The FDA also approved the therascreen KRAS RGQ PCR Kit (QIAGEN GmbH) as a companion diagnostic device to aid in identifying patients with colorectal cancer whose tumors harbor KRAS G12C mutations and who may be eligible for LUMAKRAS® with VECTIBIX®.

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.

Approximately 15-25% of the patients with CRC present with metastatic disease at the time of diagnosis (synchronous metastases) and 50-60% of the patients with CRC will develop metastatic disease during the course of their illness. First line treatment of metastatic CRC includes Oxaliplatin or Irinotecan, in combination with a Fluoropyrimidine and Leucovorin (FOLFOX or FOLFIRI respectively), along with a VEGF targeting agent such as Bevacizumab or EGFR targeting agents such as Cetuximab (ERBITUX®) and Panitumumab. Patients with Stage IV colorectal cancer are now routinely analyzed for extended RAS and BRAF mutations. KRAS mutations are predictive of resistance to EGFR targeted therapy. Patients who progress following these therapies are considered to have refractory disease. These patients sometimes are rechallenged with previously administered chemotherapeutic agents, but often receive Regorafenib (STIVARGA®), an oral multikinase inhibitor with antiangiogenic activity, or LONSURF® (a fixed dose combination of Trifluridine and Tipiracil). These therapies, however, have shown limited efficacy.

The KRAS (Kirsten rat sarcoma viral oncogene homologue) proto-oncogene encodes a protein that is a member of the small GTPase super family. The KRAS gene provides instructions for making the KRAS protein, which is a part of a signaling pathway known as the RAS/MAPK pathway. By relaying signals from outside the cell to the cell nucleus, the protein instructs the cell to grow, divide and differentiate. KRAS gene is in the Ras family of oncogenes, which also includes two other genes, HRAS and NRAS. When mutated, oncogenes have the potential to change normal cells to cancer cells. KRAS is the most frequently mutated oncogene in human cancers and these cancers are often associated with resistance to targeted therapies and poor outcomes. The KRAS G12C mutation occurs in approximately 12-15% of Non Small Cell Lung Cancers (NSCLC) and in 3-5% of colorectal cancers and other solid cancers. G12C is a single point mutation with a Glycine-to-Cysteine substitution at codon 12. This substitution favors the activated state of KRAS, amplifying signaling pathways that lead to oncogenesis.

Sotorasib is a small molecule that specifically and irreversibly inhibits KRAS G12C protein and traps KRAS G12C in the inactive GDP-bound state, thus blocking downstream proliferation and survival signaling. Unlike the efficacy of single-agent KRAS G12C inhibitors in Non Small Cell Lung Cancer with KRAS G12C mutation, KRAS G12C inhibition alone has limited activity in patients with colorectal cancer. This has been attributed to upstream reactivation of the Epidermal Growth Factor Receptor (EGFR) pathway resulting in treatment-induced resistance, following selective inhibition of KRAS G12C. However, dual KRAS G12C and EGFR blockade can overcome treatment resistance in patients with colorectal cancer with KRAS G12C mutation. In the CodeBreaK 101 Phase 1b trial involving patients with chemorefractory colorectal cancer with mutated KRAS G12C, the Response Rate was 30% with Sotorasib plus Panitumumab, as compared with 9.7% with Sotorasib monotherapy.

The present FDA approval was based on CodeBreaK 300 trial, which is an international, multicenter, open-label, randomized, active-controlled Phase III study, conducted to evaluate the efficacy and safety of two different doses of Sotorasib (960 mg and 240 mg) in combination with Panitumumab as compared with the investigator’s choice of standard-care therapy (Trifluridine-Tipiracil or Regorafenib) in patients with chemorefractory metastatic colorectal cancer with KRAS G12C mutation. A lower dose of Sotorasib 240 mg orally once daily was tested in this study because of the nonlinear pharmacokinetic properties of Sotorasib. A total of 160 patients were randomly assigned in a 1:1:1 ratio to receive Sotorasib 960 mg orally once daily plus Panitumumab 6 mg/kg IV every 2 weeks (the 960 mg Sotorasib/Panitumumab group; N=53), Sotorasib 240 mg orally once daily plus Panitumumab (the 240 mg Sotorasib/Panitumumab group; N=53), with each treatment cycle repeating every 28 days, or the investigator’s choice of standard of care therapy which could be either Trifluridine-Tipiracil 35 mg/m2 (up to a maximum of 80 mg per dose) orally twice daily on days 1-5 and days 8-12 every 28 days, or Regorafenib 160 mg orally once daily for the first 21 days of each 28-day cycle (N=54). Treatment continued until disease progression or unacceptable toxicities. The median age was 61 years and majority of patients had more than 2 or more lines of previous anti-cancer therapy. KRAS G12C mutation was confirmed by prospective central molecular testing. Randomization was stratified according to previous use of antiangiogenic therapy, the time from initial diagnosis of metastatic disease to randomization and ECOG-PS. The Primary end point was Progression Free Survival (PFS) as assessed by Blinded Independent Central Review (BICR). Key Secondary end points included Overall Survival (OS) and Objective Response Rate (ORR) and Duration of Response (DOR).

After a median follow up of 7.8 months, both Sotorasib combinations (960 mg and 240 mg) plus Panitumumab demonstrated significantly longer PFS compared to standard of care therapy. The median PFS was 5.6 months and 3.9 months in the 960 mg Sotorasib/Panitumumab and 240 mg Sotorasib/Panitumumab groups, respectively, as compared with 2.2 months in the standard of care group (HR for 960 mg group=0 49; P=0.006) (HR for 240 mg group=0.58; P=0.03). The improvement in PFS was observed across key subgroups, including tumor sideness/primary tumor location, prior lines of therapy, and the presence or absence of liver metastases. The Objective Response Rate was 26.4%, 5.7%, and 0% in the 960 mg Sotorasib/Panitumumab, 240 mg Sotorasib/Panitumumab, and standard of care groups, respectively and the median DOR was 4.4 months in the 960 mg Sotorasib/Panitumumab group. Overall Survival data is immature. While this trial was not powered to compare the two Sotorasib/Panitumumab groups directly, the 960 mg dose appeared to yield more clinically significant benefits than the 240 mg dose, across all efficacy endpoints, without additional toxic effects. The final analysis of PFS for patients randomized to the 240 mg Sotorasib/Panitumumab arm compared to the standard of care groups was not statistically significant.
Grade 3 or higher treatment-related adverse events occurred in 35.8%, 30.2%, and 43.1% of patients, respectively. Skin-related toxic effects and hypomagnesemia were the most common adverse events observed with Sotorasib/Panitumumab.

It was concluded from this study that Sotorasib 960 mg in combination with Panitumumab resulted in significantly longer Progression Free Survival and a higher Objective Response Rate than standard of care treatment. Ongoing analysis and longer follow-up will provide additional insights into Overall Survival outcomes.

Sotorasib plus Panitumumab in Refractory Colorectal Cancer with Mutated KRAS G12C. Fakih MG, Salvatore L, Esaki T, et al. N Engl J Med 2023;389:2125-2139.

FDA Grants Accelerated Approval to BIZENGRI® for Non Small Cell Lung Cancer and Pancreatic Adenocarcinoma

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SUMMARY: The FDA on December 4, 2024, granted accelerated approval to Zenocutuzumab-zbco (BIZENGRI®) for adults with advanced, unresectable, or metastatic Non-Small Cell Lung Cancer (NSCLC) harboring a neuregulin 1 (NRG1) gene fusion with disease progression on or after prior systemic therapy, or advanced, unresectable, or metastatic pancreatic adenocarcinoma harboring a NRG1 gene fusion with disease progression on or after prior systemic therapy. This represents the first FDA approval of a systemic therapy for patients with NSCLC or pancreatic adenocarcinoma harboring an NRG1 gene fusion.

Genomic rearrangements involving the neuregulin 1 (NRG1) gene have been implicated in a variety of solid tumors, including lung, breast, pancreas, ovarian, and prostate cancers. NRG1 fusions are rare oncogenic drivers occurring in less than 1% of solid tumors, highly enriched in KRAS-wild-type pancreatic adenocarcinoma and invasive mucinous adenocarcinoma of the lung. NRG1 fusions produce chimeric ligands that activate the ERBB Receptor Tyrosine Kinase (RTK) family, a group of proteins frequently exploited by cancer cells to promote tumor growth. In lung cancer, NRG1 fusions are associated with poor prognosis in patients with lung cancer, with low Response Rates to standard chemotherapy and immunotherapy, and a short Overall Survival.

The ERBB RTK family includes EGFR (ERBB1), HER2 (ERBB2), HER3 (ERBB3), and HER4 (ERBB4). These proteins mediate crucial cell signaling pathways that regulate growth and survival. They can be oncogenically activated by ligand stimulation such as NRG1 fusion proteins binding to HER3 or HER4, mutations and translocations that may confer constitutive enzymatic activity, such as EGFR kinase domain mutations, the EGFRvIII variant (where the extracellular region of EGFR is deleted), EGFR fusions or gene amplification, or protein overexpression resulting in increasing receptor abundance on cell surfaces to amplify signaling.

NRG1 preferentially binds to HER3 and HER4, promoting their heterodimerization with other ERBB family members like HER2 and EGFR. This interaction is critical because HER3, a pseudokinase, lacks intrinsic enzymatic activity and depends on phosphorylation by its heterodimer partners. The activated HER3 forms docking sites for SH2-domain proteins, triggering multiple downstream signal transduction pathways like the PI3K pathway, which drive proliferation and survival.

Zenocutuzumab is a bispecific humanized immunoglobulin G1 (IgG1) containing two different Fab arms targeting the extracellular domains of HER2 and HER3. The HER2-targeting arm binds HER2, concentrating the antibody locally and positioning it (Dock) to block NRG1 binding to HER3 (Dock-and-block mechanism). The HER3-targeting arm prevents HER3 from undergoing the conformational changes necessary for heterodimerization with HER2 and EGFR. This dual targeting halts HER3 phosphorylation, disrupting downstream oncogenic signaling. Moreover, the glycoengineered IgG1 backbone of Zenocutuzumab enhances its affinity for Fc receptors, boosting Antibody-Dependent Cellular Cytotoxicity (ADCC)-a mechanism by which immune cells destroy antibody-coated tumor cells.

The present approval is supported by the Phase 1/2 eNRGy ongoing trial, which is an open-label, multicenter, multicohort, dose-escalation study of Zenocutuzumab, in patients with solid tumors with a NRG1 fusion. Enrolled patients had a median of one prior line of therapy, including platinum chemotherapy (72%) and Afatinib (11%). The median patient age was 64 years and most were female (62%), and 51% were Asian. The most common NRG1 fusion partners were CD74 (57%), SLC3A2 (22%), SDC4/7 (9%), and CDH1/2 (3%). Most NRG1 fusions were identified by RNA sequencing (81%), followed by DNA sequencing (14%). Patients received Zenocutuzumab 750 mg IV every 2 weeks until disease progression. The major efficacy outcome measures were confirmed Overall Response Rate (ORR) and Duration of Response (DOR), determined by Blinded Independent Central Review.

The ORR for NSCLC was 33% and median DOR was 7.4 months. The ORR for pancreatic adenocarcinoma was 40% and the DOR was 3.7-16.6 months. In the pooled safety population, the most common adverse reactions were diarrhea, musculoskeletal pain, fatigue, nausea, infusion-related reactions, dyspnea, rash, constipation, vomiting, abdominal pain, and edema. The most common Grade 3 or 4 laboratory abnormalities were increased gamma-glutamyl transferase, anemia, thrombocytopenia and hyponatremia.

It was concluded from this analysis that Zenocutuzumab provided robust and durable efficacy in advanced NRG1 positive NSCLC and pancreatic adenocarcinoma, with a well-tolerated safety profile, and represents a potential first and best-in-class therapy for patients with NRG1 fusion solid tumors.

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zenocutuzumab-zbco-non-small-cell-lung-cancer-and-pancreatic