Category: Meeting Updates

Late Breaking Abstract – ASCO 2024: IMFINZI® as Consolidation Treatment for Limited Stage Small Cell Lung Cancer

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SUMMARY: The American Cancer Society estimates that for 2024 about 234,580 new cases of lung cancer will be diagnosed and about 125,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Small Cell Lung Cancer (SCLC) accounts for approximately 13-15% of all lung cancers and is aggressive.

Limited Stage-Small Cell Lung Cancer – LS-SCLC (Stage I-III) accounts for approximately 30% of SCLC diagnoses and the disease is confined to one hemithorax. These patients are often treated with a combination of Carboplatin or Cisplatin with Etoposide and radiotherapy. Despite initial response, LS-SCLC typically recurs and progresses rapidly, and only 15-30% of patients are alive five years after diagnosis.

Based on the premise that SCLC has a high mutation rate, it was hypothesized that these tumors may be immunogenic and more recently immunotherapy with checkpoint inhibitors has demonstrated clinical activity in SCLC. IMFINZI® (Durvalumab) is a selective, high-affinity, human IgG1 monoclonal antibody, that blocks the binding of Programmed Death Ligand 1 (PD-L1) to Programmed Death 1 (PD-1) receptor and CD80, thereby unleashing the T cells to recognize and kill tumor cells. IMJUDO® (Tremelimumab) is a human immunoglobulin G2 monoclonal antibody that targets and blocks the activity of CTLA-4, enhancing binding of CD80 and CD86 to CD28. This complimentary mechanisms of action broadens clinical activity, potentially overcoming primary resistance to PD-(L)1 blockade by enabling novel T-cell responses.

The rationale for the ADRIATIC trial was supported by findings from the pivotal Phase III PACIFIC and CASPIAN trial. In the PACIFIC trial, Durvalumab after concurrent chemoradiotherapy for Stage III Non-Small Cell Lung Cancer, improved both Overall Survival (OS) and Progression Free Survival (PFS), whereas in the CASPIAN trial, Durvalumab with Platinum and Etoposide chemotherapy significantly improved OS, compared to chemotherapy alone, in newly diagnosed patients with extensive-stage SCLC.

The ADRIATIC trial is a Phase III, randomized, double-blind, placebo-controlled, multicenter, global study that assessed the efficacy and safety of Durvalumab (IMFINZI®) as consolidation therapy in patients with Limited-Stage Small Cell Lung Cancer (LS-SCLC) who had not progressed after concurrent platinum-based chemoradiotherapy. This trial enrolled 730 patients with Stage I to III LS-SCLC, including those with inoperable Stage I/II disease. Eligible patients had a WHO Performance Status of 0 or 1, and had not experienced disease progression after completing concurrent chemoradiotherapy. Chemotherapy consisted of a combination of Platinum plus Etoposide for up to 4 cycles, and the radiation therapy could either be once daily up to 66 Gy, or twice a day up to 45 Gy. Prophylactic Cranial Irradiation (PCI) was allowed before randomization. Patients were randomized within 6 weeks after completing concurrent chemoradiotherapy to experimental arms Durvalumab monotherapy 1500 mg IV every 4 weeks with or without Tremelimumab 75 mg IV every 4 weeks for up to 4 cycles each, followed by Durvalumab every four weeks for up to 24 months or Placebo every 4 weeks. Baseline characteristics and prior treatment were well balanced between groups. This analysis compared the outcomes in patients assigned to receive Durvalumab monotherapy (N=264) with patients who received placebo (N=266). The dual Primary endpoints were Progression Free Survival (PFS) and Overall Survival (OS) for Durvalumab monotherapy versus placebo. Key secondary endpoints included OS and PFS for Durvalumab plus Tremelimumab versus placebo, Safety, and Quality of Life measures. The median duration of follow-up for OS and PFS in censored patients at this first planned interim analysis was 37.2 and 27.6 months, respectively.

The median OS with Durvalumab was 55.9 months, compared to 33.4 months with placebo. Durvalumab demonstrated a statistically significant improvement in OS compared to placebo (HR=0.73; P=0.0104), translating to a 27% reduction in the risk of death. The median PFS was 16.6 months with Durvalumab versus 9.2 months with placebo, representing a 24% reduction in the risk of disease progression or death (HR=0.76; P=0.0161). The 24-month OS rate was 68% with Durvalumab versus 58.5% with placebo, and the 36-month OS rate was 56.5% versus 47.6%, respectively. The 18-month PFS rate was 48.8% with Durvalumab versus 36.1% with placebo, and the 24-month PFS rate was 46.2% with Durvalumab versus 34.2% with placebo. Treatment benefit was generally consistent across predefined patient subgroups for both OS and PFS.

Grade 3/4 Adverse Events (AEs) were similar in both treatment groups at 24.3%, but treatment discontinuation due to AEs was slightly higher in the Durvalumab arm (16.3% versus 10.6% in the placebo arm). Any grade pneumonitis was reported in 38.0% of patients in the Durvalumab arm compared to 30.2% in the placebo arm.

The results of the ADRIATIC trial represent a significant advancement in the treatment of Limited Stage-Small Cell Lung Cancer (LS-SCLC). Durvalumab consolidation therapy demonstrated a statistically significant and clinically meaningful improvement in both OS and PFS compared to placebo. These findings support Durvalumab as a new standard of care for patients with LS-SCLC following concurrent chemoradiotherapy, potentially changing the treatment landscape for this aggressive disease. Further analyses, including subgroup analyses and assessment of the Durvalumab plus Tremelimumab combination, are ongoing to optimize treatment strategies for LS-SCLC patients.

ADRIATIC: Durvalumab (D) as consolidation treatment (tx) for patients (pts) with limited-stage small-cell lung cancer (LS-SCLC). Spigel DR, Cheng Y, Cho BC, et al. J Clin Oncol. 2024;42(suppl 17):LBA5. doi.org/10.1200/JCO.2024.42.17_suppl.LBA5

Late Breaking Abstract – ASCO 2024: TAGRISSO® after Chemoradiotherapy in Stage III EGFR Mutated Non-Small Cell Lung Cancer

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2024, about 234,580 new cases of lung cancer will be diagnosed and 125,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Approximately one third of all patients with NSCLC have Stage III, locally advanced disease at the time of initial presentation and 60 to 90% of these patients have unresectable disease. These patients are treated with concurrent chemoradiotherapy (CRT) followed by consolidation therapy with Durvalumab (IMFINZI®) in patients without progression, as this regimen confers an Overall Survival advantage, and is considered the standard of care (PACIFIC trial).

EGFR (Epidermal Growth Factor Receptor) mutations are found in up to one third of patients with unresectable Stage III NSCLC. There are currently no approved targeted treatments for patients with unresectable Stage III EGFR-mutated NSCLC. The current standard of care, which includes consolidation therapy with Durvalumab, may not offer clear benefits to this subset of patients with EGFR mutations.

Osimertinib (TAGRISSO®) is a highly selective third-generation, irreversible Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (TKI), presently approved by the FDA, for the first-line treatment of patients with metastatic NSCLC, whose tumors have Exon 19 deletions or Exon 21 L858R mutations, as well as treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, whose disease has progressed on or after EGFR-TKI therapy. Osimertinib is also approved by the FDA as adjuvant treatment for resected Stage IB–IIIA EGFR-mutated NSCLC. Further, Osimertinib has higher CNS penetration and is therefore able to induce responses in 70-90% of patients with brain metastases.

LAURA was a global, randomized, double-blind, placebo-controlled, multicenter Phase III trial conducted to assess the efficacy and safety of Osimertinib in patients with unresectable Stage III NSCLC harboring EGFR mutations (EGFR exon 19 deletion or exon 21 L858R mutation). The trial enrolled patients who had not experienced disease progression during or after definitive platinum-based chemoradiotherapy (CRT). A total of 216 patients who had undergone CRT were randomly assigned 2:1 to receive Osimertinib 80 mg orally once daily (N=143) or placebo once per day (N=73). Treatment was continued until Blinded Independent Central Review (BICR)–assessed disease progression, unacceptable toxicity, or other discontinuation criteria were met. Upon disease progression, patients in the placebo arm were permitted to receive Osimertinib, allowing for crossover therapy. Stratification factors included method of CRT (concurrent versus sequential) and disease Stage (IIIA versus IIIB/C). Both treatment groups were well balanced. The median patient age was 63 years, approximately 60% of participants were female, 83% were Asian, 69% had never smoked and 85% had Stage IIIA and B disease. Majority of patients received concurrent CRT rather than sequential CRT. The Primary end point was Progression Free Survival (PFS) as assessed by BICR. Key Secondary end points included Overall Survival (OS), survival without progression of CNS disease (CNS Progression Free Survival), Objective Response Rate (ORR), Duration of Response, Quality of Life, and Safety.

Treatment with Osimertinib resulted in significant PFS improvement compared to placebo. The median PFS was 39.1 months in the Osimertinib group versus 5.6 months in the placebo group, representing an 84% reduction in the risk of disease progression or death (HR=0.16; P<0.001). Additionally, a higher percentage of patients in the Osimertinib group remained alive and progression-free at 12 months compared to the placebo group (74% versus 22% respectively). Subgroup analyses were conducted to evaluate the consistency of treatment effects across various demographic and clinical factors. The benefits of Osimertinib were observed across all prespecified subgroups, indicating a consistent treatment effect, regardless of patient characteristics. The incidence of new lesions was lower with Osimertinib compared to placebo (22% versus 68%), and this included new brain lesions (8% versus 29%) and new lung lesions (6% versus 29%) respectively. The Objective Response Rate was higher with Osimertinib than with placebo (57% versus 33%). The median Duration of Response was longer with Osimertinib (36.9 months) than with placebo (6.5 months). Interim OS data showed a favorable trend for Osimertinib, although maturity was limited at the time of analysis. Further follow-up will be conducted to assess OS as a secondary endpoint. The adverse event profile of Osimertinib was generally consistent with previous studies. Grade 3 or higher adverse events occurred more frequently in the Osimertinib group, with radiation pneumonitis being the most common. However, no new safety concerns emerged during the trial.

In summary, treatment with Osimertinib resulted in significantly longer Progression Free Survival than placebo in patients with unresectable Stage III EGFR-mutated NSCLC following definitive CRT, and should be considered the new standard of care for this group of patients. Overall, the LAURA study represents a major breakthrough in the treatment of EGFR-mutated Stage III NSCLC, addressing an unmet need for targeted therapies in this setting. Further follow-up will provide additional insights into the long-term efficacy and safety of Osimertinib in this patient population.

Osimertinib after definitive chemoradiotherapy (CRT) in patients (pts) with unresectable stage  III epidermal growth factor receptor-mutated (EGFRm) NSCLC: primary results of the phase 3 LAURA study. Ramalingam SS, Kato T, Dong X, et al. J Clin Oncol. 2024;42(suppl 17):LBA4.

Late Breaking Abstract – ASCO 2024: SCEMBLIX® Superior to Other TKIs in Newly Diagnosed Chronic Myeloid Leukemia

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SUMMARY: The American Cancer Society estimates that about 9,280 new CML cases will be diagnosed in the United States in 2024 and about 1,280 patients will die of the disease. Chronic Myeloid Leukemia (CML) constitutes about 15% of all new cases of leukemia and the average age at diagnosis of CML is around 64 years. The hallmark of CML, the Philadelphia Chromosome (Chromosome 22), is a result of a reciprocal translocation between chromosomes 9 and 22, wherein the ABL gene from chromosome 9 fuses with the BCR gene on chromosome 22. As a result, the auto inhibitory function of the ABL gene is lost and the BCR-ABL fusion gene is activated resulting in cell proliferation and leukemic transformation of hematopoietic stem cells.

The Tyrosine Kinase Inhibitors (TKIs) approved for newly diagnosed chronic phase CML in the United States share the same therapeutic target, which is the ATP-binding site of BCR-ABL1 kinase. They include first-generation TKI Imatinib (GLEEVEC®) or second-generation TKIs Nilotinib (TASIGNA®), Dasatinib (SPRYCEL®), or Bosutinib (BOSULIF®). Imatinib is associated with lower patient response and a higher incidence of disease progression than those with second-generation TKIs, whereas treatment with second-generation TKIs can result in faster, deeper molecular responses than Imatinib in frontline therapy, but are associated with more adverse events, necessitating dose modifications and switching treatments. Further, close to 50% of clinical resistance is associated with the acquisition of mutations in this region of the kinase, resulting in conformational changes that render TKIs inactive. Therefore resistance to one of the TKIs, will likely result in resistance to the others as well. Further, the “gatekeeper” T315I mutation, which has been reported in 20% of patients with mutations, confers resistance to all clinically available TKIs except Ponatinib (ICLUSIG®). There is therefore an unmet need for a safe and effective frontline therapy for patients with newly diagnosed chronic phase CML

Asciminib (SCEMBLIX®) is a novel, first-in-class, potent and specific, oral BCR-ABL1 inhibitor that does not bind to the ATP-binding site of the kinase. Instead, it specifically targets the ABL1 myristoyl pocket, also known as a STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor, with activity against native unmutated BCR-ABL1, and all clinically observed ATP-site mutants, including T315I. In a Phase I study, Asciminib was active in heavily pretreated patients with CML who had resistance to or unacceptable side effects from TKIs, including patients in whom Ponatinib had failed, and those with a T315I mutation.

Asciminib is approved in the US for the treatment of adults with Philadelphia Chromosome positive chronic phase CML who have previously been treated with two or more TKIs. It is also approved in patients with Philadelphia Chromosome positive chronic phase CML with the T315I mutation.

The ASC4FIRST study is a pivotal Phase III, multi-center, open-label, randomized trial aimed at evaluating the efficacy and safety of Asciminib compared to investigator-selected Tyrosine Kinase Inhibitors (TKIs) in adult patients with newly diagnosed Philadelphia chromosome positive Chronic Myeloid Leukemia in chronic phase (CML-CP). A total of 405 patients were enrolled and were randomly assigned in a 1:1 ratio to receive either Asciminib 80 mg orally once daily (N=201) or investigator-selected TKIs which included Imatinib and second generation TKIs such as Bosutinib, Dasatinib or Nilotinib given at approved doses (N=204). Before randomization, investigators after discussing with patients selected a TKI (either Imatinib or one of the second-generation TKIs a patient would take, if randomly assigned to the comparator group-prerandomization selected TKI), considering treatment goals, disease and patient characteristics, and coexisting conditions. Randomization was stratified by European Treatment and Outcome Study long-term survival score category (low, intermediate, or high risk), and by TKI selected by investigators before randomization. The two Primary objectives of this study were to compare the efficacy of Asciminib with that of investigator-selected TKIs (all members of this class considered together as a group), and to compare the efficacy of Asciminib with that of Imatinib. Asciminib was not compared with second-generation TKIs as a primary objective. The Primary end point for both objectives was Major Molecular Response (defined as BCR/ABL1 transcript levels 0.1% or less on the International Scale at week 48 that did not meet any treatment failure criteria. The Secondary objective of this study was assessment of Major Molecular Response (MMR) at week 48 with Asciminib, as compared with investigator-selected TKIs among patients with second-generation TKIs as their prerandomization-selected TKI. The median follow-up was 16.3 months in the Asciminib group and 15.7 months in the investigator-selected TKI group.

At the 48-week mark, Asciminib demonstrated a significantly higher MMR rate compared to investigator-selected TKIs (67.7% versus 49.0%; P<0.001). Deep molecular response rates (BCR/ABL1 transcript levels 0.01% or less, were also superior in the Asciminib group compared to investigator-selected TKIs (38.8% versus 20.6%). Patients preselected for Imatinib who were randomized to Asciminib achieved an MMR rate of 69.3% compared to 40.2% in the Imatinib group. Among those preselected for second-generation TKIs, the MMR rate was 66.0% for Asciminib versus 57.8% for the second-generation TKI group.

Asciminib exhibited a favorable safety profile with fewer Grade 3 or higher Adverse Events and lower rates of treatment discontinuation due to Adverse Events. Grade 3 or higher Adverse Events for Asciminib was 38%, for Imatinib was 44.4% and for second-generation TKIs was 54.9%. Discontinuation due to Adverse Events for Asciminib was 4.5%, for Imatinib was 11.1% and for Second-generation TKIs was 9.8%.

It was concluded that Asciminib is the only agent to demonstrate superiority over investigator selected standard-of-care TKIs in achieving higher MMR rates at 48 weeks in newly diagnosed chronic phase CML patients, alongside a better safety and tolerability profile. These findings indicate that Asciminib could significantly improve the treatment landscape for this group of patients, offering hope for better disease control and quality of life, thereby addressing key unmet needs in CML management.

ASC4FIRST, a pivotal phase 3 study of asciminib (ASC) vs investigator-selected tyrosine kinase inhibitors (IS TKIs) in newly diagnosed patients (pts) with chronic myeloid leukemia (CML): Primary results. Hughes TP, Hochhaus A, Takahashi N, et al. J Clin Oncol 42, 2024 (suppl 17; abstr LBA6500)

Bispecific Immune Checkpoint Inhibitor Improves Survival in Gastric and GEJ Cancer Regardless of PD-L1 Status

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SUMMARY: The American Cancer Society estimates that in the US about 26,890 new gastric cancer cases will be diagnosed in 2024 and about 10,880 people will die of the disease. It is one of the leading causes of cancer-related deaths in the world. Several hereditary syndromes such as Hereditary Diffuse Gastric Cancer (HDGC), Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer) and Familial Adenomatous Polyposis (FAP) have been associated with a predisposition for gastric cancer. Additionally, one of the strongest risk factor for gastric adenocarcinoma is infection with Helicobacter pylori (H.pylori), which is a gram-negative, spiral-shaped microaerophilic bacterium.

Patients with localized disease (Stage II and Stage III) are often treated with multimodality therapy and 40% of the patients may survive for 5 years or more. However, majority of the patients with gastric and gastroesophageal junction (GEJ) adenocarcinoma have advanced disease at the time of initial presentation and have limited therapeutic options with little or no chance for cure. The five-year relative survival rate for patients at the metastatic stage is approximately 15%. These patients frequently are treated with platinum containing chemotherapy along with a Fluoropyrimidine such as modified FOLFOX6 or CAPOX. Patients with HER2-positive disease are usually treated with chemotherapy plus Trastuzumab, and for those patients with HER2-negative disease, patients receive chemotherapy along with a checkpoint inhibitor, or checkpoint inhibitor alone, if the tumors express PD-L1.

Cadonilimab (AK104) is a human, bispecific IgG1 antibody with high binding avidity especially to high density of PD-1 and CTLA-4 due to its tetravalent design, and could simultaneously bind different cells expressing PD-1 and CTLA-4, respectively. By effective blocking both PD-1 and CTLA-4 pathways, Cadonilimab activates T cells by increasing interleukin-2 (IL-2) and interferon-gamma secretion to similar extent, as compared with anti-PD-1 and anti-CTLA-4 combination.

COMPASSION-15 is a double-blind, randomized, multicenter, Phase III trial that enrolled 610 patients diagnosed with locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) cancer. They were randomly assigned 1:1 to receive either Cadonilimab in combination with Oxaliplatin and Capecitabine chemotherapy, or placebo plus the same chemotherapy. Chemotherapy with Oxaliplatin and Capecitabine was given every 3 weeks for up to six cycles. Capecitabine was administered at 1000 mg/m2 orally twice daily on days 1 through 14 every 3 weeks and Oxaliplatin IV at 130 mg/m2 every 3 weeks. Cadonilimab 10 mg/kg IV or placebo was given on day 1 of each cycle every 3 weeks. Following the 6 cycles, patients then received Cadonilimab 10 mg/kg IV monotherapy or placebo every 3 weeks. Stratification factors included ECOG performance status (0 versus 1), PD-L1 expression (CPS 5% or more, or less than 5%), and the presence or absence of liver metastasis. The Primary endpoint was Overall Survival (OS) in the Intent to Treat (ITT) population.

The researchers herein presented the interim analysis data of COMPASSION-15 trial. The results revealed a significant improvement in Overall Survival with Cadonilimab combination therapy compared to placebo. The median OS was 15.0 months with Cadonilimab combination, compared with 10.8 months for those in the placebo arm (HR=0.60; P<0.001). The 18-month Overall Survival rate was 45.8% in the Cadonilimab group versus 25.5% in the placebo group.

Subgroup analysis based on PD-L1 expression levels (CPS 5% or more, or less than 5%) also demonstrated favorable outcomes with Cadonilimab across all strata. Among patients with a PD-L1 CPS of less than 5%, Cadonilimab combination achieved a median OS of 14.8 months, compared with 11.1 months in the placebo group. The 18-month OS rates were 44.1% compared with 27.5%, respectively.

Progression-Free Survival (PFS), another critical measure of treatment efficacy, showed consistent benefits with Cadonilimab combination compared to placebo plus chemotherapy, irrespective of PD-L1 expression. Median PFS was 7 months versus 5.3 months in the ITT population, with similar trends observed in CPS 5% or more, and less than 5% subgroups.

The safety analysis revealed no new safety signals. However, Grade 3 or higher treatment-related adverse events were more commonly reported in the combination therapy group compared to the placebo group. Treatment-related adverse events leading to therapy discontinuation were also more frequent in the Cadonilimab group.

It was concluded from this study that Cadonilimab is the first PD-1/CTLA-4 bispecific antibody to demonstrate substantial improvements in Overall Survival and Progression-Free Survival benefit in combination with chemotherapy, offering a potential new standard of care for patients diagnosed with locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) cancer. This study represents a significant milestone in the quest for improved first-line treatments for gastric and GEJ cancers, even for patients with low PD-L1 expression tumors.

Cadonilimab plus chemotherapy versus chemotherapy as first-line treatment for unresectable locally advanced or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma (COMPASSION-15): A randomized, double-blind, phase 3 trial. Ji J, Shen L, Li Z, et al. Presented at: 2024 AACR Annual Meeting; April 5-10, 2024; San Diego, CA.

Neoadjuvant KEYTRUDA® plus Chemotherapy Significantly Improves EFS in Early Stage High Risk Triple Negative 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. The American Cancer Society estimates that in the US, approximately 310,720 new cases of female breast cancer will be diagnosed in 2024, and about 42,250 individuals will die of the disease, largely due to metastatic recurrence.

Triple Negative Breast Cancer (TNBC) is a heterogeneous, molecularly diverse group of breast cancers and are ER (Estrogen Receptor), PR (Progesterone Receptor) and HER2 (Human Epidermal Growth Factor Receptor-2) negative. TNBC accounts for 15-20% of invasive breast cancers, with a higher incidence noted in young patients. It is usually aggressive, and tumors tend to be high grade and patients with TNBC are at a higher risk of both local and distant recurrence. Those with metastatic disease have one of the worst prognoses of all cancers with a median Overall Survival (OS) of 13 months. The majority of patients with TNBC who develop metastatic disease do so within the first 3 years after diagnosis, whereas those without recurrence during this period of time have survival rates similar to those with ER-positive breast cancers.

Neoadjuvant chemotherapy is the preferred treatment approach in this group of patients and can potentially increase the likelihood of tumor resectability and breast conservation. Further, a pathological Complete Response (pCR) after neoadjuvant chemotherapy can result in a longer Event-Free Survival and Overall Survival. Pathological Complete Response is therefore used as an end point for clinical testing of neoadjuvant treatment in patients with early triple-negative breast cancer.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response, and unleashes the tumor-specific effector T cells. The rationale for combining chemotherapy with immunotherapy is that cytotoxic chemotherapy releases tumor-specific antigens, and immune checkpoint inhibitors such as Pembrolizumab when given along with chemotherapy can enhance endogenous anticancer immunity. Single agent Pembrolizumab in metastatic TNBC demonstrated durable antitumor activity in several studies, with Objective Response Rates (ORRs) ranging from 10-21% and improved clinical responses in patients with higher PD-L1 expression. When given along with chemotherapy as a neoadjuvant treatment for patients with high-risk, early-stage TNBC, Pembrolizumab combination achieved pathological Complete Response rate of 65%, regardless of PD-L1 expression.

KEYNOTE-522 trial is a multicenter, randomized, double-blind, placebo-controlled Phase III trial, conducted to evaluate the efficacy and safety of neoadjuvant Pembrolizumab plus chemotherapy as compared with neoadjuvant placebo plus chemotherapy, followed by adjuvant Pembrolizumab or placebo in patients with early stage, high-risk, Triple Negative Breast Cancer. In this study, total of 1174 patients (N=1174) regardless of tumor PD⁠-⁠L1 expression, were randomly assigned 2:1 to receive Pembrolizumab plus chemotherapy (N=784) or placebo plus chemotherapy (N=390). Eligible patients had newly diagnosed, previously untreated, Triple Negative Breast Cancer, with tumor size more than 1 cm but 2 cm or less in diameter with nodal involvement, or tumor size more than 2 cm in diameter regardless of nodal involvement. Patients in the neoadjuvant phase received four cycles of Pembrolizumab 200 mg IV or placebo once every 3 weeks plus Paclitaxel 80 mg/m2 once weekly plus Carboplatin AUC 5 IV once every 3 weeks or Carboplatin AUC 1.5 IV once weekly in the first 12 weeks (first neoadjuvant treatment), followed by four cycles of Pembrolizumab or placebo along with Doxorubicin 60 mg/m2 IV or Epirubicin 90 mg/m2 IV plus Cyclophosphamide 600 mg/m2 IV once every 3 weeks in the subsequent 12 weeks (second neoadjuvant treatment). Patients then underwent definitive surgery (breast conservation or mastectomy with sentinel lymph-node evaluation or axillary dissection) 3-6 weeks after the last cycle of the neoadjuvant phase. In the adjuvant phase, patients received radiation therapy as indicated and Pembrolizumab or placebo once every 3 weeks for up to nine cycles. Adjuvant Capecitabine was not allowed. The median age was 49 yrs, 64% were white, 56% were premenopausal, and overall 75% had Stage II disease and 25% had Stage III disease. Both treatment groups were well balanced with regard to age, ECOG performance status, PD-L1-positivity, tumor size and nodal involvement. The Primary end points were a pathological Complete Response (pCR) at the time of definitive surgery and Event-Free Survival (EFS) in the intent-to-treat population. Pathological Complete Response was defined as absence of invasive cancer in the breast and lymph nodes (ypT0/Tis ypN0), and was assessed by the blinded local pathologist at the time of definitive surgery. EFS was defined as the time from randomization to the first occurrence of progression of disease that precludes definitive surgery, local or distant recurrence, second primary malignancy, or death due to any cause.

The pathological Complete Response rate was 63% in the Pembrolizumab plus chemotherapy group and 55.6% in the placebo plus chemotherapy group, and this difference were statistically significant. The EFS after median follow up of 63.1 months showed a 5-year EFS rate of 81.3% with Pembrolizumab plus chemotherapy and 72.3% with placebo plus chemotherapy (HR=0.63). The median EFS had not been reached in either group. The EFS benefit appeared consistent across subgroups, including those assessed by nodal status, disease stage, PD-L1 expression, menopausal status and Carboplatin schedule. A prespecified, exploratory analysis showed higher 5-year EFS rates with Pembrolizumab among patients who achieved pathologic Complete Response (92.2% versus 88.2%) and among those who did not achieve pathologic Complete Response (62.6% versus 52.3%).

It was concluded that the addition of Pembrolizumab with neoadjuvant chemotherapy followed by Pembrolizumab monotherapy in the adjuvant setting resulted in a durable Event Free Survival benefit, for patients with early stage Triple Negative Breast Cancer, and this benefit was noted across key subgroups, as well as among patients who did or did not achieve pathologic Complete Response.

Neoadjuvant pembrolizumab or placebo plus chemotherapy followed by adjuvant pembrolizumab or placebo for early-stage triple-negative breast cancer: updated event-free survival results from the phase 3 KEYNOTE-522 study. Schmid P, Cortés J, Dent R, et al. Presented at the 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, TX; abstract LBO1-01.

Stockholm3 Blood Test Identifies Aggressive Prostate Cancer

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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.

PSA (Prostate Specific Antigen) is one of the most widely used prostate cancer biomarkers, and the widespread use of PSA testing in the recent years has resulted in a dramatic increase in the diagnosis and treatment of prostate cancer. The management of clinically localized prostate cancer that is detected based on PSA levels remains controversial, and management strategies for these patients have included Surgery, Radiotherapy or Active Monitoring. However, it has been proposed that given the indolent nature of prostate cancer in general, majority of the patients do not benefit from treatment intervention and many patients die of competing causes. PSA test CANNOT distinguish between aggressive and benign cancer. As a result, many men have to undergo unnecessary follow-ups with a biopsy of the prostate. Further, treatment intervention can result in adverse effects on sexual, urinary, or bowel function. PSA test is also difficult to interpret, and PSA elevation can be associated with several non-malignant conditions such as older age, infection, inflammation and Benign Prostatic Hypertrophy. The U.S. Preventive Services Task Force (USPSTF) has recommended that population screening for prostate cancer with PSA should not be adopted as a public health policy, because the risks appeared to outweigh benefits, from detecting and treating PSA-detected prostate cancer.

Stockholm3 is a blood test that combines 5 protein biomarkers, 101 genetic markers, and clinical data with an advanced algorithm, in order to detect almost 100% of aggressive prostate cancers at an early stage. The Stockholm3 test has been validated in over 75, 000 men and has been used in health systems in Sweden, Norway, Finland, Germany, Switzerland, UK and Turkey, and results have been published in international peer-reviewed journals. Evidence suggests that Stockholm3 is more effective at predicting risk than PSA testing alone, for men aged 45-74 with PSA of at least 1.5ng/ml. Several studies have shown that the application of this test can reduce the number of biopsies by 32%, without compromising the diagnostic capacity of intermediate grade prostate cancers (Gleason 7 or higher), in comparison with the use of the PSA value 3 ng/ mL as cut-off value for biopsy recommendation. However, none of the validation studies included ethnically diverse population.

SEPTA is a prospective trial conducted to validate Stockholm3 in an ethnically diverse population, for prostate cancer risk stratification, and determine whether it could achieve noninferior sensitivity and superior specificity in this diverse population. This trial included men who were referred for prostate biopsy at North American sites from 2019 to 2023. Study participants had no previous diagnosis of prostate cancer. This study also used bio-banked specimens from 2008 to 2020. The cohort comprised 912 enrolled men and 1,217 with bio-banked blood. The median age was 63 years, 46% were White, 24% Black, 16% Asian and 14% were Hispanic.

This trial had 2 prespecified Primary goals: 1) Demonstrate noninferiority of the test in detecting Clinically Significant Prostate Cancer (defined as Gleason Grade group 2 or more), compared to PSA testing. 2) Prove superior specificity of the test versus PSA testing, thereby reducing the number of biopsies in men with benign or Gleason Grade group 1 biopsies. A Secondary goal was to evaluate Stockholm3 and PSA across ethnic subgroups. The study assessed Stockholm3 performance using prespecified thresholds and compared it to PSA across different ethnic subgroups. Statistical analysis plans were established before data analysis.

It was noted that the median PSA and Stockholm3 values among the participants were 6.1 ng/mL and 17, respectively. A total of 16% underwent MRI-targeted biopsies, and 20% had a prior benign biopsy. On biopsy, 29% were diagnosed with Clinically Significant Prostate Cancer, 14% with Gleason Grade group 1 cancer, and 57% with benign findings. The detection rate for Clinically Significant Prostate Cancer varied across ethnic groups: African American/Black (37%), White/Caucasian (28%), Hispanic/Latino (29%), and Asian (21%).

Overall, Stockholm3 value 15 or higher demonstrated noninferiority to a PSA value of 4 ng/mL or higher and nearly three times superior specificity. These results were consistent across ethnic subgroups. The researchers noted that using a Stockholm3 value of 15 or higher would have reduced benign and Gleason Grade group 1 biopsies by 45% overall and between 42-52% across ethnic subgroups, compared to PSA of 4 ng/ml or higher.

The study concluded that in an ethnically diverse population, Stockholm3 could significantly reduce unnecessary biopsies and diagnoses of low-grade tumors, while maintaining similar sensitivity to PSA, for detecting Clinically Significant Prostate Cancer. The results suggest that
Stockholm3 could improve risk stratification and reduce harms associated with prostate cancer screening in diverse populations.

Stockholm3 validation in a multi-ethnic cohort for prostate cancer (SEPTA) detection: A multicentered, prospective trial. Vigneswaran HT, Eklund M, Discacciati A, et al. J Clin Oncol 42, 2024 (suppl 4; abstr 262). DOI 10.1200/JCO.2024.42.4_suppl.262. Abstract#262.

Late Breaking Abstract – 2024 ASCO GU Cancers Symposium: Adjuvant KEYTRUDA® Improves Overall Survival in Renal cell Carcinoma

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SUMMARY: The American Cancer Society estimates that 81,610 new cases of kidney and renal pelvis cancers will be diagnosed in the United States in 2024 and about 14,390 people will die from the disease. Renal Cell Carcinoma (RCC) is by far the most common type of kidney cancer and is about twice as common in men as in women. Modifiable risk factors include smoking, obesity, workplace exposure to certain substances and high blood pressure. The five year survival of patients with advanced RCC is less than 10% and there is a significant unmet need for improved therapies for this disease.

The prognosis for patients with Renal Cell Carcinoma (RCC) is dependent on the stage of disease and risk factors. Two validated models, the University of California Los Angeles Integrated Staging System (UISS) and the Stage, Size, Grade, and Necrosis (SSIGN) score were developed, to assess the risk for relapse. UISS is based on ECOG Performance Status, Fuhrman nuclear grading and TNM pathological stage, whereas the SSIGN score takes Stage, Size, Grade and Necrosis into consideration. Approximately 16% of patients with RCC present with Locoregional disease, and up to 40% of these patients relapse with metastatic disease, following nephrectomy. The 5-year survival for locoregional (Stage III) disease is 53%, and 8% for metastatic disease. The standard management of high risk patients following nephrectomy has been surveillance, as there has been limited data demonstrating the benefit of adjuvant therapy in reducing the risk of relapse. Adjuvant therapy with immune check point inhibitors therapy is a potentially attractive treatment strategy for this patient group.

KEYNOTE-564 is a multicenter, double-blind, Phase III trial in which the benefit of adjuvant therapy with KEYTRUDA® was compared with placebo, following nephrectomy, in patients with clear cell RCC. In this study, 994 patients were randomized 1:1 to receive either KEYTRUDA® or placebo at least 12 weeks after surgery. Enrolled patients had histologically confirmed clear cell RCC, with Intermediate-High risk (pT2, Grade 4 or Sarcomatoid, N0 M0; or pT3, any Grade, N0 M0), High risk (pT4, any Grade, N0 M0; or pT any Stage, any Grade, N+ M0), or M1 with No Evidence of Disease (NED) after primary tumor and soft tissue metastases were completely resected, 1 year or less from nephrectomy. Treatment consisted of KEYTRUDA® 200 mg IV every 3 weeks (N=496) or placebo (N=498), every 3 weeks, for approximately 1 year. Both treatment groups were well balanced. The Primary end point of the trial was Disease Free Survival (DFS) assessment in all randomized patients and Secondary end points included Overall Survival (OS) and Safety.

The Primary endpoint of DFS was met at the first prespecified interim analysis, with a median follow up of 24.1 months. The median DFS was not reached for both treatment groups. KEYTRUDA® reduced the risk of recurrence or death by 32% compared with placebo, and this difference was statistically significant (HR=0.68; P=0.0010). Survival data were not mature at that time, and additional follow up was planned for OS. Based on this data, the FDA in November 2021 approved KEYTRUDA® for the adjuvant treatment of patients with RCC.

In this updated analysis, at a median follow up of approximately 57 months, there was a statistically significant improvement in OS with KEYTRUDA®, compared to placebo (medians not reached, HR=0.62, P=.0024). This represented a 38% reduction in the risk of death for patients receiving KEYTRUDA®, and at the 48-month mark, the estimated OS rate was 91.2% for the KEYTRUDA® group compared to 86.0% for the placebo group. The OS benefit was observed across key subgroups, including in patients with M0 disease, or M1 NED, patients with PD-L1 CPS less than 1 or CPS 1 or more, and with presence or absence of sarcomatoid features. The observed DFS benefit with KEYTRUDA® versus placebo was consistent with prior interim analyses. No new safety signals were observed.

It was concluded, that after a median of about 57 months of follow up, KEYTRUDA® demonstrated a statistically significant and clinically meaningful improvement in Overall Survival compared to placebo, in patients with Renal Cell Carcinoma, at a high risk of recurrence following surgery. The authors added that this is the first positive Phase III study with a checkpoint inhibitor to demonstrate survival benefit in adjuvant Renal Cell Carcinoma, and these practice changing results support KEYTRUDA® as a new standard of care for this patient group. Studies are underway exploring the potential of combining KEYTRUDA® with other agents, such as the Hypoxia-Inducible Factor-2 (HIF-2) inhibitor Belzutifan, to further optimize treatment outcomes for patients with clear cell Renal Cell Carcinoma.

Overall survival results from the phase 3 KEYNOTE-564 study of adjuvant pembrolizumab versus placebo for the treatment of clear cell renal cell carcinoma (ccRCC). Choueiri TK, Tomczak P, Park SH, et al.Journal of Clinical Oncology 42(4_suppl):LBA359. DOI:10.1200/JCO.2024.42.4_suppl.LBA359.

Pregnancy after Breast Cancer Treatment in BRCA Carriers

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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 310,720 new cases of female breast cancer will be diagnosed in 2024, and about 42,250 individuals will die of the disease, largely due to metastatic recurrence.

The median age at the time of breast cancer diagnosis in the US is 62 years. However approximately 5% of new diagnoses each year occur in those who are under 40 years. These young patients with Hormone Receptor (HR)-positive breast cancer receiving modern adjuvant endocrine therapy have excellent long-term outcomes. Nonetheless, 40-60% of patients who are diagnosed with breast cancer at age 40 or younger are concerned about their future fertility and pregnancy, as many have not completed their family planning at diagnosis due to delay in childbearing. The POSITIVE (Pregnancy Outcome and Safety of Interrupting Therapy for Women with Endocrine Responsive Breast Cancer) trial designed to evaluate whether temporary interruption of adjuvant endocrine therapy to attempt pregnancy was associated with a higher risk of breast cancer recurrence, did indeed suggest that women with a history of HR-positive breast cancer could safely pause hormonal therapy to have a child. (N Engl J Med 2023; 388:1645-1656)

Young women diagnosed with breast cancer, especially those harboring a BRCA mutation, often desire to conceive post-treatment. However, concerns loomed over the safety of pregnancy following a breast cancer diagnosis. Previous studies provided limited data, necessitating further exploration to guide patients and physicians adequately.

This international Hospital-Based Cohort Study was conducted to investigate if pregnancy after breast cancer among women carrying germline BRCA pathogenic variants was associated with adverse maternal or fetal outcomes. The study encompassed a vast cohort comprising 4,732 women with a BRCA mutation, all diagnosed with invasive breast cancer at the age of 40 or younger, between January 2000 and December 2020. This extensive retrospective cohort study spanned numerous international hospital centers, ensuring a diverse and comprehensive representation of patients. The Primary end points of this study were cumulative incidence of pregnancy after breast cancer and Disease Free Survival (DFS). Secondary end points included Breast Cancer–Specific Survival, Overall Survival, pregnancy, fetal and obstetric outcomes. The median follow up was 7.8 years.

Out of the entire cohort of 4,732 women with a BRCA mutation, 659 patients had at least 1 pregnancy after their breast cancer diagnosis. The cumulative pregnancy incidence at 10 years after diagnosis was 22%. The median time from breast cancer diagnosis to conception was 3.5 years, and 28% of pregnancies occurred after 5 years. Compared with women who did not get pregnant, women who became pregnant were more likely to have a BRCA1 mutation alone (73% versus 63%), be younger at breast cancer diagnosis (median age 30 yrs versus 35 yrs), have node-negative disease (62.5% versus 52%), and have HR-negative disease (68% versus 52%).

The cumulative incidence of pregnancy at 10 years was 18% in patients with HR-positive disease and 26% in patients with HR-negative disease (P<0.001) and the median time from diagnosis to conception was 4.3 years and 3.2 years, respectively (P<0.001). The proportion of pregnancies occurring after 5 years was 40% and 22%, respectively.

Overall, the median age at pregnancy was 35 years, 79% of patients had a spontaneous pregnancy without the use of any assisted reproductive technology, and 80% delivered a child. Of all pregnancies, 8% had an induced abortion and 10% had a miscarriage, and majority of patients (86%) did not experience pregnancy complications. There was no significant difference in Disease Free Survival observed between patients with or without a pregnancy after breast cancer, and patients who had a pregnancy had significantly better Breast Cancer–Specific Survival and Overall Survival.

The authors from this study concluded that 1 in 5 young BRCA carriers conceived within 10 years after breast cancer diagnosis. They added that pregnancy following breast cancer in BRCA carriers was not associated with decreased Disease Free Survival and conceiving after proper treatment and follow up for breast cancer should not be contraindicated anymore in young BRCA carriers. Coupled with the analysis from the POSITIVE trial, which suggests that fertility preservation and assisted reproductive technologies do not heighten the risk of recurrence, these results alleviate many concerns surrounding post-breast cancer pregnancy.

This international, large-scale study offers critical insights into the safety and feasibility of pregnancy post-breast cancer diagnosis, for women with BRCA mutations. The findings provide valuable guidance for patients and healthcare providers, potentially reshaping clinical practices and decision-making processes. In essence, this pioneering research represents a pivotal milestone in the field of breast cancer management, offering hope, reassurance, and clarity to countless young women navigating the intersection of cancer treatment and fertility preservation.

Pregnancy After Breast Cancer in Young BRCA Carriers. Lambertini M, Blondeaux E, Agostinetto E, et al. JAMA. 2024;331:49-59.

Late Breaking Abstract – 2024 ASCO GU Cancers Symposium: Subcutaneous Nivolumab Offers Efficiency and Efficacy in Renal Cell Carcinoma

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SUMMARY: The American Cancer Society estimates that 81,610 new cases of kidney and renal pelvis cancers will be diagnosed in the United States in 2024 and about 14,390 people will die from the disease. Renal Cell Carcinoma (RCC) is by far the most common type of kidney cancer and is about twice as common in men as in women. Modifiable risk factors include smoking, obesity, workplace exposure to certain substances and high blood pressure. The five year survival of patients with advanced RCC is less than 10% and there is a significant unmet need for improved therapies for this disease.

OPDIVO® (Nivolumab) 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. Blocking the Immune checkpoint proteins unleashes the T cells, resulting in T cell proliferation, activation, and a therapeutic response. The emergence of immunotherapy has offered new avenues for patients, with Nivolumab demonstrating efficacy across various tumor types. However, the conventional Intravenous (IV) administration of Nivolumab has been associated with significant treatment burden, prompting the exploration of alternative delivery methods. The CheckMate 67T trial aimed to address this challenge by assessing the efficacy and convenience of Subcutaneous (SC) Nivolumab compared to its IV counterpart.

The CheckMate 67T trial is an international, multicenter, randomized, open-label, Phase III study, conducted to evaluate the pharmacokinetics of Subcutaneous versus Intravenous delivery of Nivolumab in patients with locally advanced or metastatic clear cell Renal Cell Carcinoma (RCC). In this study, a total of 495 patients (N=495) were randomly assigned 1:1 to receive Nivolumab 1200 mg SC plus recombinant human hyaluronidase PH20 every 4 weeks (N=248), or Nivolumab 3 mg/kg IV every 2 weeks (N=247), until disease progression, unacceptable toxicity or completion of 2 years of treatment. The median age was 65 years, 67% were men and enrolled patients had measurable disease that progressed during or after 1–2 prior systemic regimens, had no prior immunotherapy treatment, and had a Karnofsky Performance Score of 70 or more. Hispanic patients accounted for at least 34% of study participants in both treatment arms, ensuring diverse representation.

The Primary objective of the study was to evaluate the pharmacokinetics of SC versus IV delivery of Nivolumab, which included whether blood levels of the drug were comparable in the two groups over time and whether SC Nivolumab was noninferior to IV Nivolumab. The daily average concentration of the drug in the blood over 28 days and the concentration of the drug at the end of the dosing cycle were measured. Key Secondary endpoint included Objective Response Rate (ORR) by Blinded Independent Central Review (BICR).

The trial revealed compelling findings, indicating that SC Nivolumab not only matched the pharmacokinetic profile (noninferior) and Objective Response Rate of IV Nivolumab, but also drastically reduced administration time. The ORR for the Subcutaneous group was noninferior to the Intravenous group, at 24.2% versus 18.2%, respectively. The Median Progression Free Survival stood was 7.23 months for the Subcutaneous group versus 5.65 months for the IV group. The median treatment duration was under 5 minutes for the Subcutaneous group, in contrast to the 30-minute infusion sessions required for IV therapy. Local injection site reactions occurred in 8.1% of patients. Reactions were low grade and transient and most deaths were due to disease progression.

It was concluded that Subcutaneous Nivolumab showed comparable pharmacokinetic profile and Overall Response Rates (ORR) compared to Intravenous Nivolumab, in addition to significant reduction in administration time. With over 20 FDA-approved indications for Nivolumab, the convenience of Subcutaneous administration and its potential impact extends far beyond Renal Cell Carcinoma, promising greater accessibility and streamlined treatment experiences for patients nationwide. By alleviating treatment burdens and enhancing efficiency, this innovative formulation heralds a new era in oncology, offering hope to patients and clinicians alike.

Subcutaneous nivolumab (NIVO SC) vs intravenous nivolumab (NIVO IV) in patients with previously treated advanced or metastatic clear cell renal cell carcinoma (ccRCC): Pharmacokinetics (PK), efficacy, and safety results from CheckMate 67T. George S, Bourlon MT, Chacon MR, et al. Journal of Clinical Oncology. Volume 42, Number 4_suppl. https://doi.org/10.1200/JCO.2024.42.4_suppl.LBA360.

Avoiding Regional Nodal Irradiation after Neoadjuvant Chemotherapy in Some Breast Cancer Patients

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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 310,720 new cases of female breast cancer will be diagnosed in 2024, and about 42,250 individuals will die of the disease, largely due to metastatic recurrence.

Neoadjuvant or preoperative therapy is often a component of combined-modality treatment, and facilitates the rapid assessment of new cancer therapies. In addition to increasing the likelihood of tumor resectability and breast preservation, patients achieving a pathological Complete Response (pCR) following neoadjuvant chemotherapy have a longer Event Free Survival (EFS) and Overall Survival (OS).

When patients with early stage breast cancer present with pathologically positive axillary nodes, neoadjuvant chemotherapy is often recommended to eradicate cancer cells. These patients are often treated with adjuvant regional nodal irradiation including the chest wall after mastectomy and with whole breast irradiation after breast conserving surgery.

However, there is no established protocol for treatment when chemotherapy converts node-positive disease to node-negative disease. There is an ongoing debate whether these individuals should be treated as lymph node-positive disease (as it was at the time of diagnosis) and treated with radiation treatment, or as node-negative disease (presentation after neoadjuvant chemotherapy and following surgery). Radiation Therapy can be associated with fatigue, radiation dermatitis, lymphedema, and can have an impact on breast reconstruction. The following study was conducted to evaluate whether radiation treatment can be safely omitted in this patient population

The NRG Oncology/NSABP B-51/RTOG 1304 was conducted to evaluate the impact of Regional Nodal Irradiation (RNI) on patient outcomes following neoadjuvant chemotherapy. In this Phase III clinical trial, 1,641 enrolled patients had clinical cT1-3, N1, M0 invasive breast cancer (biopsy-proven node positive by FNA/core needle bx), and had completed 8 weeks or more of neoadjuvant chemotherapy and anti-HER2 therapy if HER2-positive), and were ypN0 after mastectomy or breast conserving surgery and sentinel node biopsy (2 or more nodes), axillary lymph node dissection, or both. These patients were then randomly assigned 1:1 to either the “no RNI” group (observation after mastectomy, or whole breast irradiation after breast-conserving surgery) or the “RNI” group (chest wall irradiation plus RNI after mastectomy, or whole breast irradiation plus RNI after breast-conserving surgery). Both treatment groups were well balanced. The median age was 52 years, majority of the patients (60%) were cT2, 23% were triple-negative, 21% HR+/HER2-negative, 56% were HER2-positive and 78% had breast pathologic Complete Response. The Primary endpoint was Invasive Breast Cancer Recurrence-Free Interval (IBC-RFI). Secondary endpoints reported here included Loco-Regional Recurrence-Free interval (LRRFI), Distant Recurrence-Free Interval (DRFI), Disease-Free Survival (DFS), and Overall Survival (OS). The median follow up was 59.5 months and 1,556 patients were available for primary event analysis.

In the evaluable patients (N=1556), similar outcomes were noted whether the patients received adjuvant Regional Nodal Irradiation (RNI) or not. Approximately 92% of patients in the “no RNI” group and 92.7% of those in the “RNI” group were free of Invasive Breast Cancer Recurrences five years after surgery. Distant Recurrence and Overall Survival rates were also similar between the treatment groups, with 93.4% of patients in each treatment group free from Distant Recurrence five years after surgery, and 94% of those in the “no RNI” group and 93.6% of those in the “RNI” group alive after five years. There were no study-related deaths and no unexpected toxicities.

It was concluded from this study that certain breast cancer patients who respond well to neoadjuvant chemotherapy and achieve negative lymph nodes after surgery may safely omit adjuvant lymph node radiation without compromising outcomes. If confirmed by further research and endorsed by medical guidelines, these findings could spare many breast cancer patients from unnecessary radiation therapy, thereby reducing treatment-related side effects and improving quality of life. This study underscores the importance of individualized treatment approaches in oncology, highlighting the need to reassess treatment strategies based on evolving evidence.

Loco-regional irradiation in patients with biopsy-proven axillary node involvement at presentation who become pathologically node-negative after neoadjuvant chemotherapy: Mamounas E, Bandos H, White J, et al: Primary outcomes of NRG Oncology/NSABP B-51/RTOG 1304. 2023 San Antonio Breast Cancer Symposium. Abstract GS02-07. Presented December 7, 2023.