Author: RR

Adjuvant KEYTRUDA® Improves Disease Free Survival in Muscle-Invasive Urothelial Carcinoma

RR

SUMMARY: The American Cancer Society estimates that in the United States for 2024, about 83,190 new cases of bladder cancer were diagnosed and approximately 16,840 patients died of the disease. Bladder cancer is the fourth most common cancer in men, but it is less common in women. Bladder cancer accounts for 90% of urothelial cancers, and urothelial cancer can also be found in the renal pelvis, ureter and urethra.

A third of the patients initially present with locally invasive disease. The standard treatment for Cisplatin-eligible patients with Muscle-Invasive Bladder Cancer (MIBC) is neoadjuvant chemotherapy followed by radical cystectomy. However, the high relapse rate and risk of death despite this treatment has prompted further research into optimizing outcomes. There is presently no clear consensus with regards to the routine use of adjuvant Cisplatin-based chemotherapy. Further, not all patients are eligible for adjuvant or neoadjuvant Cisplatin-based chemotherapy.

Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions. By inhibiting checkpoint proteins and their ligands, T cells are unleashed, resulting in T cell proliferation, activation and a therapeutic response. It has been noted that PD-L1 is widely expressed in tumor and immune cells of patients with urothelial carcinoma. This in turn helps cancer cells to evade detection from the immune system by binding to the PD-1 receptor on cytotoxic T lymphocytes.

Pembrolizumab (KEYTRUDA®) 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. By doing so, it unleashes the tumor-specific effector T cells, and is thereby able to undo PD-1 pathway-mediated inhibition of the immune response.

AMBASSADOR trial (Alliance A031501) is a randomized Phase 3 study, conducted to evaluate whether Pembrolizumab could enhance Disease-Free Survival (DFS) and Overall Survival (OS) in patients with high-risk Muscle Invasive Urothelial Carcinoma (MIUC) after radical surgery, compared to observation alone. This study enrolled 702 patients with high-risk MIUC who underwent radical surgery (cystectomy or nephroureterectomy) within 4-16 weeks before registration. Patients were considered to have high-risk MIUC if they were not eligible for or declined neoadjuvant cisplatin-based chemotherapy and had pT3 or higher, or pN+, or microscopic positive surgical margins, or if they have persistent muscle-invasive disease (defined as a pathological stage of ypT2 or higher or ypN+ or microscopic positive surgical margins) despite the receipt of neoadjuvant chemotherapy at the time of radical surgery. Patients were randomized in a 1:1 ratio, to receive Pembrolizumab 200 mg IV every 3 weeks for 1 year (N=354) or to undergo observation (N=348). Both treatment groups were well balanced and stratification factors for randomization included PD-L1 status (positive or negative, with positivity defined as a Combined Positive Score of 10 or more using the PD-L1 IHC 22C3 pharmDx assay), prior receipt of neoadjuvant chemotherapy, and pathological stage. The median age was 69 years and patients with upper tract and urethral urothelial carcinoma were included in this study. The coPrimary endpoints were DFS and OS, and key Secondary endpoints included DFS and OS stratified by PD-L1 expression.

As of July 2024, with a median follow-up of 44.8 months, the median DFS was significantly longer in the Pembrolizumab group (29.6 months) compared to the observation group (14.2 months). The Hazard Ratio (HR) for disease progression or death was 0.73 (P=0.003), demonstrating a clear benefit. The DFS benefit was observed across all subgroups, regardless of age, PD-L1 status, receipt of neoadjuvant chemotherapy, pathological stage, or tumor location. PD-L1 status therefore should not be used to select patients for treatment with adjuvant Pembrolizumab. The Overall Survival data remain immature. The safety profile of Pembrolizumab was consistent with previous studies, though Grade 3 or higher adverse events were more frequent in the Pembrolizumab group (50.6%) compared to the observation group (31.6%).

In conclusion, adjuvant Pembrolizumab significantly improves DFS in patients with high-risk MIUC post-radical surgery, offering a promising treatment option for this population. These results, together with emerging tools such as circulating tumor DNA (ctDNA) may enable more precise patient selection and stratification, optimizing the use of adjuvant therapies. As Overall Survival data mature and biomarker research evolves, the role of Pembrolizumab may become even more defined within the broader context of urothelial carcinoma treatment.

Adjuvant Pembrolizumab versus Observation in Muscle-Invasive Urothelial Carcinoma. Apolo AB, Ballman KV, Sonpavde G, et al. N Engl J Med 2025;392:45-55

10 Year Survival Benefit in Advanced Melanoma with OPDIVO® plus YERVOY®

RR

SUMMARY: The American Cancer Society estimates that in 2024, about 100,640 new cases of melanoma were diagnosed in the United States and 8,290 people died of the disease. The rates of melanoma have been rising rapidly over the past few decades, but this has varied by age.

A better understanding of Immune checkpoints has opened the doors for the discovery of novel immune targets. Immune checkpoints are cell surface inhibitory proteins/receptors that harness the immune system and prevent uncontrolled immune reactions. Survival of cancer cells in the human body may be related to their ability to escape immune surveillance, by inhibiting T lymphocyte activation. Under normal circumstances, inhibition of an intense immune response and switching off the T cells of the immune system is accomplished by Immune checkpoints or gate keepers. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies have been developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152), PD-1(Programmed cell Death 1), etc. By blocking the Immune checkpoint proteins, T cells are unleashed, resulting in T cell proliferation, activation and a therapeutic response.

YERVOY® (Ipilimumab) is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4, and was the first systemic therapy in randomized Phase III trials, to show prolonged Overall Survival (OS) in patients with advanced melanoma. YERVOY® in a pooled analysis of data from 12 studies showed a 3-year Overall Survival of 26% among treatment naive patients, and survival up to 10 years in approximately 20% of all patients, with advanced melanoma. The two PD-1 inhibitors of interest are OPDIVO® (Nivolumab) and KEYTRUDA® (Pembrolizumab), which are fully human, Immunoglobulin G4, anti-PD-1 targeted monoclonal antibodies that bind to the PD-1 receptor, and block its interaction with ligands PD-L1 and PD-L2, following which the tumor-specific effector T cells are unleashed. They are thus able to undo PD-1 pathway-mediated inhibition of the immune response. When compared with YERVOY® in patients with advanced melanoma, PD-1 inhibitors, both OPDIVO® and KEYTRUDA® have demonstrated superior Overall Survival (OS), Progression Free Survival (PFS), and Objective Response Rate (ORR), with a better safety profile. OPDIVO® in combination with YERVOY® in a Phase I study resulted in an Overall Survival of 68% at 3 years among patients with advanced melanoma, regardless of prior therapies.

CheckMate 067 is a double-blind Phase III study in which patients with previously untreated advanced melanoma were randomly assigned in a 1:1:1 ratio to receive one of the three regimens: OPDIVO® 1 mg/kg every 3 weeks plus YERVOY® 3 mg/kg every 3 weeks for four doses, followed by OPDIVO® 3 mg/kg every 2 weeks (N=314); OPDIVO® 3 mg/kg every 2 weeks plus placebo (N=316); or YERVOY® 3 mg/kg every 3 weeks for four doses plus placebo (N=315). Randomization was stratified according to BRAF mutation status, metastasis stage, and Programmed cell Death Ligand 1 (PD-L1) status. Treatment was continued until disease progression or unacceptable toxicities. The two Primary end points were PFS and OS in the OPDIVO® plus YERVOY® group, and in the OPDIVO® group versus the YERVOY® group.

The researchers had previously reported the results from the 6.5 year analysis, which showed durable improved outcomes with OPDIVO® plus YERVOY®, and OPDIVO® alone, when compared to single agent YERVOY®, among patients with advanced melanoma. The authors in this publication reported the final 10-year results for the CheckMate 067 trial, including results for Overall Survival and Melanoma-Specific Survival, as well as Durability of Response.

With a minimum follow-up of 10 years, median Overall Survival for patients treated with OPDIVO® plus YERVOY® combination therapy was 71.9 months, for those treated with single agent OPDIVO® was 36.9 months, and 19.9 months with single agent YERVOY®. The Hazard Ratio for death was 0.53 for OPDIVO® plus YERVOY® as compared with YERVOY® and was 0.63 for single agent OPDIVO® as compared with YERVOY®. Median Melanoma-Specific Survival was more than 120 months with OPDIVO® plus YERVOY® combination therapy (Not Reached, with 37% of the patients alive at the end of the trial), 49.4 months with single agent OPDIVO®, and 21.9 months with YERVOY®. Among patients who had been alive and progression free at 3 years, 10-year Melanoma-Specific Survival was 96% with OPDIVO® plus YERVOY®, 97% with single agent OPDIVO®, and 88% with YERVOY®.

In conclusion, these 10-year data have shown ongoing survival benefits with OPDIVO® plus YERVOY® and with single agent OPDIVO®, as compared with YERVOY® monotherapy, in patients with advanced melanoma, potentially offering a curative therapy for responding patients.

Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in Advanced Melanoma. Wolchok JD, Chiarion-Sileni V, Rutkowsk P, et al. for the CheckMate 067 Investigators. N Engl J Med 2025;392:11-22.

No Additional Benefit When Oxaliplatin is Added to 5-FU Based Adjuvant Chemotherapy in High Risk Stage II Colon Cancer

RR

SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 152,810 new cases of CRC were diagnosed in the United States in 2024 and about 53,010 patients died of the disease. The lifetime risk of developing CRC is about 1 in 23.

Colon cancer treatment strategies have advanced significantly over the years. Since 2004, the introduction of Oxaliplatin into adjuvant chemotherapy regimens has been a cornerstone in improving outcomes for patients with Stage III colon cancer. The most commonly adopted protocols include FOLFOX (a combination of Folinic acid or Leucovorin, 5-fluorouracil (5-FU), and Oxaliplatin) and a regimen combining Capecitabine with Oxaliplatin. These regimens gained validation through critical trials such as MOSAIC, NSABP C-07, and XELOXA, which demonstrated the survival benefits of Oxaliplatin-based combinations.

However, for patients with Stage II colon cancer, the role of adjuvant chemotherapy remains controversial. While many oncologists recommend adjuvant therapy for Stage II patients, its effectiveness is not universally supported by clinical data. The QUASAR trial showed limited benefits of Leucovorin and 5-FU in this population. Adding Oxaliplatin to adjuvant regimens has been explored to improve outcomes, particularly for high-risk patients. However, Oxaliplatin can be associated with neuropathy which can be long lasting or permanent, depending on the duration of therapy. Additional toxicities with longer duration of chemotherapy include diarrhea, fatigue as well as more office visits.

High-risk Stage II colon cancer is a heterogeneous group, and definitions of high-risk features vary across studies. High-risk features have included T4 tumors, bowel perforation, obstruction, poor histological differentiation, vascular invasion, or fewer than 10 lymph nodes examined. The heterogeneity of high-risk Stage II colon cancer complicates treatment decisions, with new clinical prognostic factors such as the site of tumor origin in the colon (tumor sidedness), age, and BMI having been described, in addition to the stage of the disease.

To clarify the benefits of Oxaliplatin in Stage II colon cancer, researchers performed a pooled analysis of the MOSAIC and NSABP C-07 trials. These studies collectively included 4,654 patients, of whom 1,595 had Stage II colon cancer, and were treated with either 5-FU and Leucovorin alone or 5-FU and Leucovorin plus Oxaliplatin. The Primary objective was to determine whether the addition of Oxaliplatin to 5-FU and Leucovorin provided a significant survival advantage for Stage II patients, particularly those with high-risk features. The analysis examined outcomes such as Overall Survival (OS) and Time to Relapse (TTR). Prognostic variables included T stage, presence of bowel perforation or obstruction, lymph node count, tumor sidedness, sex, age, and histological differentiation. Multivariable models and Kaplan-Meier survival analyses were employed to assess the impact of these variables. Patients with Stage III colon cancer were included only for interaction tests to compare treatment effects across stages.

The data from this pooled analysis revealed several important findings.
1. Prognostic Factors: Independent prognostic variables for Stage II colon cancer included sex, age, bowel perforation/obstruction, and tumor sidedness. These factors were associated with OS but did not predict a benefit from Oxaliplatin-based treatment.
2. Survival Outcomes: The addition of Oxaliplatin to 5-FU and Leucovorin did not significantly improve OS or TTR in Stage II colon cancer, even among high-risk subgroups. In contrast, a clear benefit was observed in Stage III colon cancer patients, suggesting a differential effect of Oxaliplatin based on cancer stage.
3. High-Risk Subgroup Analysis: Among patients with high-risk features such as T4 tumors or inadequate lymph node sampling, there was no statistically significant OS or TTR benefit from addition of Oxaliplatin to 5-FU and Leucovorin.
4. Interaction Between Stage and Therapy: The analysis confirmed an interaction between cancer Stage (II versus III) and the benefit of Oxaliplatin. Stage II colon cancer patients derived no added advantage from Oxaliplatin, while Stage III patients experienced substantial improvements in survival outcomes.

These results challenge existing guidelines from the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO), which recommend Oxaliplatin-based regimens for high-risk Stage II colon cancer. The findings suggest that current definitions of high-risk features are insufficient to justify the use of Oxaliplatin in this population. Moreover, discrepancies between Disease-Free Survival (DFS) and OS in Stage II colon cancer indicate that DFS is not a reliable surrogate endpoint in this group. The lack of benefit from Oxaliplatin emphasizes the need for more precise prognostic tools to identify Stage II patients who might benefit from adjuvant therapy.

Several limitations affected the study. Key data on biomarkers, such as MicroSatellite Instability (MSI) and MisMatch Repair (MMR) status, were unavailable for nearly half the cohort, preventing their inclusion in prognostic analyses. Emerging tools like circulating tumor DNA (ctDNA), which show promise in identifying relapse risk, were also unavailable during the study period. Despite the lack of benefit observed with Oxaliplatin, novel prognostic approaches are needed to identify Stage II colon cancer patients at a high risk of relapse. Future clinical trials incorporating ctDNA-based stratification may refine treatment approaches and reduce unnecessary exposure to neurotoxic agents like Oxaliplatin.

In conclusion, for patients with Stage II colon cancer, the addition of Oxaliplatin to 5-FU based adjuvant therapy does not improve Overall Survival or Time To Relapse. Current clinical and pathologic criteria for high-risk classification fail to justify the routine use of Oxaliplatin, emphasizing the need for alternative risk stratification tools. These findings call for a reevaluation of treatment guidelines to ensure that therapeutic decisions are informed by robust, individualized risk assessments.

Assessment of the Addition of Oxaliplatin to Fluoropyrimidine-Based Adjuvant Chemotherapy in Patients with High-Risk Stage II Colon Cancer: An ACCENT Pooled Analysis. Chibaudel B, Raeisi M, Cohen R, et al. J Clin Oncology 2024;42:4187-4195

FDA Approves OPDIVO Qvantig® for Subcutaneous Injection

RR

SUMMARY: The FDA on December 27, 2024, approved Nivolumab and hyaluronidase-nvhy (OPDIVO Qvantig®) for subcutaneous injection across approved adult, solid tumor Nivolumab indications as monotherapy, monotherapy maintenance following completion of Nivolumab plus Ipilimumab (YERVOY®) combination therapy, or in combination with chemotherapy or Cabozantinib. The approval includes indications for renal cell carcinoma, melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, urothelial carcinoma, colorectal cancer, hepatocellular carcinoma, esophageal carcinoma, gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma. OPDIVO Qvantig® is not indicated in combination with intravenous Ipilimumab.

The American Cancer Society estimates that 81,610 new cases of kidney and renal pelvis cancers were diagnosed in the United States in 2024 and about 14,390 people died 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 OPDIVO Qvantig® 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 (OPDIVO Qvantig®) 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  OPDIVO Qvantig® versus IV delivery of Nivolumab, which included whether blood levels of the drug were comparable in the two groups over time and whether OPDIVO Qvantig® 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 OPDIVO Qvantig® not only matched the pharmacokinetic profile (noninferior) and Objective Response Rate of IV Nivolumab, but also drastically reduced administration time. The ORR for the OPDIVO Qvantig® group was noninferior to the Intravenous group, at 24.2% versus 18.2%, respectively. The Median Progression Free Survival was 7.23 months for the OPDIVO Qvantig® group versus 5.65 months for the IV group. The median treatment duration was under 5 minutes for the OPDIVO Qvantig® 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 OPDIVO Qvantig® 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.

Ivonescimab may be Superior to Pembrolizumab as First-Line Treatment in NSCLC

RR

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.

Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options, by improving Overall Response Rate and prolongation of survival, across multiple tumor types. These agents target Programmed cell Death protein-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system. Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response. Biomarkers predicting responses to ICIs include Tumor Mutational Burden (TMB), Mismatch Repair (MMR) status, and Programmed cell Death Ligand 1 (PD‐L1) expression.

Pembrolizumab (KEYTRUDA®) 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, thereby unleashing the T cells. Five year results from the Phase III KEYNOTE-042 study which included eligible patients with locally advanced/metastatic NSCLC without EGFR/ALK alterations and with PD-L1 Tumor Proportion Score (TPS) 1% or more favored Pembrolizumab over chemotherapy, regardless of PD-L1 TPS.

Ivonescimab (AK112) is a novel bispecific antibody designed to target both PD-1 and Vascular Endothelial Growth Factor (VEGF). Its dual targeting mechanism is intended to enhance the therapeutic efficacy against advanced NSCLC, and has shown promising results in early-phase trials. Dual inhibition of PD-1 and VEGF by Ivonescimab might provide synergistic effects, enhancing therapeutic efficacy beyond what is achieved with PD-L1 inhibition alone.

The HARMONi-2 (AK112-303) is a randomized Phase III study designed to evaluate the efficacy and safety of Ivonescimab compared to Pembrolizumab, a well-established PD-1 inhibitor, in patients with advanced NSCLC. In this study, 398 eligible patients (N=398) from 55 centers in China with untreated locally advanced (Stage IIIB or IIIC) or metastatic (Stage IV) NSCLC were randomly assigned in a 1:1 ratio to receive either Ivonescimab 20 mg/kg administered IV every 3 weeks or Pembrolizumab 200 mg administered IV every 3 weeks. Patients were required to have PD-L1 positive tumors (TPS 1% or more), and patients with known EGFR mutations, ALK rearrangements, or prior systemic therapy were excluded. Randomization was stratified by histology (squamous versus non-squamous), clinical stage (IIIB/IIIC versus IV), and PD-L1 expression levels (TPS 1-49% versus TPS 50% or more).
The Primary endpoint was Progression-Free Survival (PFS), assessed by an Independent Radiographic Review Committee (IRRC). Secondary endpoints included Overall Survival (OS), Investigator-assessed PFS, Objective Response Rate (ORR), Duration of Response (DoR), Disease Control Rate (DCR), and Safety.

The interim analysis of this study was conducted after a median follow-up of 8.7 months, from November 2022 to August 2023. The median PFS was significantly longer with Ivonescimab compared to Pembrolizumab. Patients receiving Ivonescimab had a median PFS of 11.14 months versus 5.82 months with Pembrolizumab. The Hazard Ratio (HR) was 0.51 (P<0.0001), indicating a 49% reduction in the risk of disease progression or death. The PFS benefit of Ivonescimab was consistent across various subgroups including histology, PD-L1 expression and metastatic sites. Ivonescimab demonstrated superior outcomes in ORR and DCR compared to Pembrolizumab with an ORR for Ivonescimab of 50%, compared to 38.5% for Pembrolizumab. The DCR was 89.9% with Ivonescimab and 70.5% with Pembrolizumab.

Both treatments showed similar safety profiles with no new safety signals for Ivonescimab. Treatment-Related Serious Adverse Events (TRSAEs) occurred in 20.8% of Ivonescimab-treated patients and 16.1% of Pembrolizumab-treated patients. Grade 3 or more immune-related Adverse Events (irAEs) were comparable: 7.1% with Ivonescimab and 8.0% with Pembrolizumab. Specifically, in patients with squamous cell carcinoma, TRSAEs were 18.9% with Ivonescimab and 18.7% with Pembrolizumab. Ivonescimab was associated with slightly higher rates of proteinuria and hypertension but overall demonstrated a manageable safety profile. Overall survival data and long-term safety data are awaited to confirm the clinical benefits of Ivonescimab.

In conclusion, the HARMONi-2 trial provided compelling evidence that Ivonescimab offers a statistically significant and clinically meaningful improvement in PFS compared to Pembrolizumab, in PD-L1 positive advanced NSCLC patients, with manageable safety profile. If subsequent data continue to support these findings, Ivonescimab may be a valuable alternative to existing therapies. One limitation is that the trial was conducted exclusively in China, which might affect the generalizability of the results to other populations.

Phase 3 study of ivonescimab (AK112) vs pembrolizumab as first-line treatment for PD-L1–positive advanced NSCLC: Primary analysis of HARMONi-2. Zhou C, Chen J, Wu L, et al. 2024 World Conference on Lung Cancer. Abstract PL02.04. Presented September 8, 2024. San Diego, CA.