Category: Immuno Oncology

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

RR

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

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

The DNA MisMatchRepair (MMR) system is responsible for molecular surveillance and works as an editing tool that identifies errors within the microsatellite regions of DNA and removes them. Defective MMR system leads to MSI (Micro Satellite Instability) and hypermutation, with the expression of tumor-specific neoantigens at the surface of cancer cells, triggering an enhanced antitumor immune response. MSI is therefore a hallmark of defective/deficient DNA MisMatchRepair (dMMR) system and occurs in 15% of all colorectal cancers. 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)

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.

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.

Immune Checkpoint Inhibitor Therapy and Cardiovascular Adverse Events

RR

SUMMARY: Immune checkpoint inhibitors (ICIs) have dramatically transformed the management and prognosis of various malignancies. By enhancing the immune systems ability to identify and destroy cancer cells, ICIs have provided significant improvements in treatment outcomes across a range of tumor types. However, the introduction of these therapies has also been accompanied by a spectrum of immune-related Adverse Events (irAEs), including those affecting the cardiovascular system. These CardioVascular Adverse Events (CVAEs) present a serious concern due to their potential impact on patient health and treatment outcomes.

The cardiovascular manifestations associated with ICIs encompass a range of conditions such as myocarditis, pericarditis, acute coronary syndrome, heart failure, arrhythmias, conduction abnormalities, and cardiac arrest. Although the incidence of these events is relatively low (less than 1% of patients), their severity can be profound. Myocarditis, in particular, is a critical concern due to its association with a high mortality rate, which can be as high as 60%. This underscores the need for vigilant monitoring and management strategies to mitigate these risks.

The objective of the systematic review and meta-analysis was to elucidate the incidence and outcomes of CVAEs associated with ICIs and to assess the effectiveness of various management strategies for myocarditis. This analysis sought to update the clinical understanding of these adverse effects and provide recommendations based on the most recent data.

The researchers review process involved searching several databases, including PubMed, Embase, and the Cochrane Central Register of Controlled Trials, up to April 4, 2023, and with the gathered data, two separate analyses were performed:
1. Phase 1 to 4 Trials Analysis: Focused on trials involving adults with malignant neoplasms treated with FDA- or EMA-approved ICIs. This analysis aimed to gather data on the incidence of CVAEs associated with these therapies.
2. Case Reports and Retrospective Studies Analysis: Concentrated on clinical manifestations and treatment outcomes for patients who developed CVAEs due to ICIs.

Data were meticulously extracted by two independent investigators, with stringent criteria applied to ensure the relevance and quality of the studies included. For instance, studies with dose escalation, small sample sizes, or non-English publications were excluded. The Primary outcome measure was the incidence of CVAEs.

Incidence of Cardiovascular Adverse Events
The meta-analysis of clinical trials included data from 83,315 participants across 589 trials. The therapies investigated included several ICIs such as Pembrolizumab (KEYTRUDA&reg:), Nivolumab (OPDIVO®), Cemiplimab (LIBTAYO®), Atezolizumab (TECENTRIQ®), Durvalumab (IMFINZI®), Avelumab (BAVENCIO®), and Ipilimumab (YERVOY®). The overall incidence of CVAEs in patients treated with anti-PD-1 or anti-PD-L1 therapies was found to be 0.8%. Notably, Cemiplimab was associated with a higher risk of high-grade cardiovascular adverse events compared to other ICIs (2.91% for Cemiplimab versus 0.69% overall).

The incidence of myocarditis specifically was reported as 0.24% for any grade and 0.2% for high-grade myocarditis. While dual ICI therapy was linked to a higher incidence of myocarditis compared to other regimens, the overall incidence of CVAEs did not significantly differ between dual ICI therapy, ICI plus chemotherapy, or ICI plus Tyrosine Kinase Inhibitors.

Management and Outcomes of Myocarditis
In the analysis of myocarditis cases, which included 223 patients (64.5% men), the majority had received PD-1 or PD-L1 inhibitors. A substantial proportion of these patients had cardiovascular risk factors: 41.1% had hypertension, 16.3% had diabetes, and 46.5% had other risk factors. Among 220 evaluable patients, the mortality rate for myocarditis was alarmingly high at 37.7%.

Management strategies for myocarditis varied, with treatments including high-dose Corticosteroids, Methylprednisolone, IV immunoglobulin, Plasma exchange, Mycophenolate mofetil, Infliximab, and Antithymocyte globulin. Outcomes of these treatments showed mixed results. For instance, high-dose Corticosteroids were associated with a 63.5% improvement rate but also a 26% cardiac mortality rate. Abatacept showed promise with an improvement rate of 91.7% among those who received it. Prospective data suggested that systematic screening for respiratory muscle involvement, active ventilation, prompt use of Abatacept, and the addition of Ruxolitinib might reduce mortality rates. However, the review emphasized that the current management strategies are largely empirical, and there is no definitive evidence on the most effective approach.

Recommendations and Conclusions
The review highlighted a critical need for standardized diagnostic and therapeutic approaches due to the variability in management strategies and the lack of prospective clinical trials. The findings underscore the importance of early recognition, cessation of ICI therapy, and prompt initiation of corticosteroid therapy for optimal management of myocarditis. The review also suggests that further research, including prospective clinical trials and the establishment of international registries, is necessary to enhance the understanding and management of ICI-induced CVAEs.

In summary, while cardiovascular adverse events related to ICIs are rare, their potential severity, particularly myocarditis, warrants heightened awareness and proactive management by clinicians. Early identification and intervention are crucial to improving patient outcomes and reducing mortality associated with these adverse effects.

Immune Checkpoint Inhibitor–Induced Cardiotoxicity. A Systematic Review and Meta-Analysis. Nielsen DL, Juhl CB, Nielsen OH, et al. JAMA Oncol. 2024;doi:10.1001/jamaoncol.2024.3065.

FDA Approves IMFINZI® after Chemoradiotherapy in Limited-Stage Small Cell Lung Cancer

RR

SUMMARY: The FDA on December 4, 2024, approved Durvalumab (IMFINZI®) for adults with Limited Stage-Small Cell Lung Cancer (LS-SCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy. 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. Durvalumab (IMFINZI®) 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. Tremelimumab (IMJUDO®) 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 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 randomized 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. There was a protocol amendment in November 2020, and patients were randomly assigned in a 1:1 ratio to the Durvalumab group or placebo group only. Baseline characteristics and prior treatment were well balanced between groups. The median age was 62 years and 87% of patients had Stage III disease at diagnosis. 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.

Durvalumab demonstrated a statistically significant improvement in OS compared to placebo (HR=0.73; P=0.01), translating to a 27% reduction in the risk of death. The estimated median OS with Durvalumab was 55.9 months, compared to 33.4 months with placebo. 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 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=0.02). 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.

Durvalumab after Chemoradiotherapy in Limited-Stage Small-Cell Lung Cancer. Cheng Y, Spigel DR, Cho BC, et al. for the ADRIATIC Investigators. N Engl J Med 2024;391:1313-1327.

IMFINZI® after Chemoradiotherapy in Limited-Stage Small Cell Lung Cancer

RR

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. Durvalumab (IMFINZI®) 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. Tremelimumab (IMJUDO®) 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 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 randomized 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. There was a protocol amendment in November 2020, and patients were randomly assigned in a 1:1 ratio to the Durvalumab group or placebo group only. Baseline characteristics and prior treatment were well balanced between groups. The median age was 62 years and 87% of patients had Stage III disease at diagnosis. 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.

Durvalumab demonstrated a statistically significant improvement in OS compared to placebo (HR=0.73; P=0.01), translating to a 27% reduction in the risk of death. The estimated median OS with Durvalumab was 55.9 months, compared to 33.4 months with placebo. 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 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=0.02). 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.

Durvalumab after Chemoradiotherapy in Limited-Stage Small-Cell Lung Cancer. Cheng Y, Spigel DR, Cho BC, et al. for the ADRIATIC Investigators. N Engl J Med 2024;391:1313-1327.

Neoadjuvant Immunotherapy in Early Breast cancer

RR

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. 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.

Neoadjuvant chemotherapy is commonly used for patients with locally advanced Triple-Negative Breast Cancer (TNBC) and HER2-positive breast cancer. Alongside this standard treatment, there has been a push to develop new strategies aimed at increasing pathologic Complete Response (pCR) rates and improving survival outcomes. The introduction of Immune Checkpoint Inhibitors (ICIs) marked a major shift in cancer treatment, initially proving effective in melanoma and later showing promise in metastatic TNBC. This success led researchers to test ICIs in early-stage breast cancer as well.

Multiple randomized clinical trials have studied the impact of combining ICIs with chemotherapy in the neoadjuvant setting, some continuing ICI therapy as adjuvant treatment. These trials have gone beyond TNBC, exploring their use in other breast cancer subtypes like HER2-positive and Hormone Receptor-positive (HR-positive)/HER2-negative cancers. While some trials achieved their goals, the best way to integrate ICIs into early treatment remains debated, with concerns about cost and safety still under discussion.

In response to the need for clarity, a comprehensive systematic review and meta-analysis was conducted to assess the efficacy of neoadjuvant ICI therapy combined with chemotherapy in early-stage breast cancer. The analysis reviewed randomized controlled trials retrieved from the PubMed database up until December 2023. These trials focused on comparing ICIs plus chemotherapy versus chemotherapy alone in patients with early-stage breast cancer. The meta-analysis included 5114 patients from nine randomized controlled trials. These patients were subdivided into three major subgroups – TNBC (N=2097) patients, HR-positive/HER2-negative (N=1924) patients, and HER2-positive (N=1115) patients. The Primary outcomes evaluated were pathologic Complete Response (pCR) and Event-Free Survival (EFS) stratified by molecular phenotype and PD-L1 status. Secondary outcomes included incidence of Adverse Events (AEs), with a focus on immune-related toxicities.
The following are the Key Findings:
Pathologic Complete Response (pCR):
Triple-Negative Breast Cancer: Neoadjuvant ICIs improved the pCR rate significantly, with an increase from 46.6% to 59.9% (absolute improvement of 13.3%), regardless of PD-L1 status.
Hormone Receptor-Positive, HER2-Negative Tumors: There was a significant benefit of ICIs in PD-L1-positive tumors. The pCR rate increased from 14.8% to 24.6% in these cases (absolute improvement of 9.8%). However, there was no significant benefit in PD-L1-negative HR-positive/HER2-negative patients.
HER2-Positive Tumors: No significant pCR improvement was observed with the addition of ICIs in this subtype.

Event-Free Survival (EFS):
TNBC Patients with pCR: For those with TNBC who achieved a pCR, ICIs improved EFS (HR=0.65, 95% CI 0.42–1.00). The 5-year EFS was 92.0% for patients treated with ICIs compared to 88.0% without ICIs.
TNBC Patients with Residual Disease: ICIs also showed better EFS (HR=0.77, 95% CI 0.61–0.98) in patients who had residual disease after treatment, with a 5-year EFS of 63.3% compared to 56.1% without ICIs.
Adjuvant ICI in TNBC: No additional survival benefit was found with the use of adjuvant ICIs (after surgery) in TNBC patients, regardless of whether they achieved pCR or had residual disease.

Safety Profile:
Adverse Events (AEs): During neoadjuvant treatment, grade 3 or higher immune-related adverse events (AEs) were observed in 10.3% of patients treated with ICIs. The overall incidence of severe AEs (grade 3 or worse) was higher in ICI-treated patients (63.6%) compared to chemotherapy alone (54.1%). This reflects the toxicity costs associated with ICIs

Implications:
Neoadjuvant vs. Adjuvant ICI: The findings suggest that ICIs have greater efficacy when used in the neoadjuvant setting compared to adjuvant treatment. This is likely due to the tumor presence during neoadjuvant therapy, which allows for immune system priming through exposure to tumor antigens.
PD-L1 as a Biomarker: PD-L1 expression appears to be a more reliable biomarker of response to ICIs in HR-positive/HER2-negative tumors than in TNBC, where ICI benefit seems independent of PD-L1 status.
TNBC and Residual Disease: In patients with residual disease after neoadjuvant therapy, the benefit of continuing ICIs in the adjuvant setting is limited. This raises the question of whether continuing ICIs postoperatively is necessary or whether alternative strategies, like the use of other novel therapies, may be more effective.

In conclusion, Neoadjuvant Immune Checkpoint Inhibitors improve pathologic Complete Response rates and Event-Free Survival in early-stage breast cancer, especially in TNBC and PD-L1-positive HR-positive/HER2-negative tumors. However, their use in the adjuvant setting does not appear to provide added benefit. Ongoing trials, like the OptimICE-PCR trial, are designed to answer this question definitively by randomizing patients who achieve pCR to either continued ICI therapy or observation. For patients with residual disease post-neoadjuvant therapy, novel treatment approaches like Antibody-Drug Conjugates such as Sacituzumab Govitecan combined with ICIs are being investigated, offering potential new treatment paradigms.

Neoadjuvant Immune Checkpoint Inhibitors Plus Chemotherapy in Early Breast Cancer: A Systematic Review and Meta-Analysis. Villacampa G, Navarro V, Matikas A, et al. JAMA Oncol. 2024;10(10):1331-1341. doi:10.1001/jamaoncol.2024.3456.

Measuring Lymphocyte Count May Predict Response to CAR T-Cell Therapy in Multiple Myeloma

RR

SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 35,780 new cases will be diagnosed in 2024 and 12,540 patients are expected to die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, Immunomodulatory agents and CD38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, multiple myeloma in 2024 remains an incurable disease.

Multiple myeloma patients triple refractory to Immunomodulatory drugs (IMiD), Proteasome Inhibitors (PIs), and anti-CD38 monoclonal antibodies have a poor prognosis with a median Progression-Free Survival (PFS) of 3-4 months and a median Overall Survival (OS) of 8-9 months. With the introduction of new combinations of antimyeloma agents in earlier lines of therapy, patients with relapsed or refractory myeloma often have disease that is refractory to multiple drugs.

Chimeric Antigen Receptor (CAR) T-cell therapy has been associated with long-term disease control in some hematologic malignancies and showed promising activity in a Phase III studies involving patients with relapsed or refractory myeloma.

The researchers conducted an insightful study aimed at identifying predictive biomarkers to enhance the efficacy of CAR T-cell therapy for patients with relapsed or refractory multiple myeloma (MM). While CAR T-cell therapy has revolutionized treatment for B-cell malignancies and other blood cancers, the high cost of therapy and variability in patient response highlight the need for precise biomarkers that could guide clinicians in selecting the best candidates for this therapy. This research delves into the factors that affect patient response, specifically focusing on the role of the Absolute Lymphocyte Count (ALC) in predicting treatment success and disease progression.

The researchers analyzed data from 156 patients with relapsed or refractory multiple myeloma, treated with two BCMA-targeting CAR T-cell therapies: Ciltacabtagene autoleucel (CARVYKTI®) and Idecabtagene vicleucel (ABECMA®). These patients, who were treated between 2017 and 2023, had previously undergone several lines of therapy, rendering them refractory to conventional treatments. The research team collected and analyzed Absolute Lymphocyte Counts (ALC), a key immune marker, from 5 days before the CAR-T infusion for up to 15 days post-infusion, to determine if ALC could be used as a predictive biomarker for patient outcomes. The focus on this early post-infusion window was based on the hypothesis that the expansion of T cells, which is critical for the effectiveness of CAR T-cell therapy, would be reflected in the ALC levels. This study sought to correlate early ALC levels with long-term outcomes such as depth of response, Progression-Free Survival (PFS), and overall Duration of Response (DoR).

The findings demonstrated that ALC is a strong predictor of response to CAR T-cell therapy, with higher ALC values correlating with deeper responses and longer PFS. Specifically, patients who had an ALC maximum (ALCmax) above 1.0 x 103/µL during the first 15 days after infusion experienced a significant improvement in PFS, more than five times greater, compared to those with lower ALC counts. Patients with ALCmax above 1.0 x 103/µL had a median PFS of 33.1 months, while those with counts at or below 0.5 x 103/µL had a significantly shorter PFS of 6 months. The high-risk group, with an ALCmax of 0.5 or less x 103/µL, showed over three times the likelihood of early disease progression compared to their counterparts with higher ALC counts, making them a vulnerable population within the study cohort. The analysis also took into account a variety of potential confounding factors, such as patient age, previous therapies, high-risk cytogenetics, and the specific CAR T-cell product used. Even when these factors were considered, ALC remained an independent prognostic indicator, making it a reliable marker for predicting the depth and duration of response in this setting.

The researchers also explored the biological mechanisms underlying this phenomenon. CAR T-cell therapy relies heavily on the expansion of the infused T cells within the patient’s body. ALC, which includes a count of lymphocytes such as T cells, may serve as a surrogate marker for this expansion. Patients with higher ALC are likely to experience more robust CAR T-cell proliferation, leading to deeper and more durable anti-tumor responses. This aligns with previous findings that T-cell expansion after infusion is closely linked to treatment success. Additionally, the study noted that patients with higher ALC levels were also more likely to experience Cytokine Release Syndrome (CRS), a common side effect of CAR T-cell therapy that results from the rapid activation and expansion of T cells. While CRS can be a challenging complication to manage, its occurrence might also be a marker of effective CAR T-cell therapy.

The identification of ALC as a biomarker has significant implications for clinical practice. Physicians can now use ALC levels measured within the first 15 days post-infusion to guide treatment decisions. For patients with low ALC counts, this early biomarker could signal the need for alternative treatment approaches or additional therapeutic interventions to manage potential relapse. Given the limited options for patients who relapse after CAR T-cell therapy, having this early warning could be vital for planning the next steps in their treatment journey. Conversely, patients with high ALC levels can be reassured that they are more likely to achieve a deep and sustained response, allowing clinicians to optimize follow-up care and monitoring accordingly.

The researchers are further investigating the biological factors that influence ALC levels after CAR T-cell infusion. By analyzing patient samples and conducting deeper biological studies, they aim to uncover why some patients experience robust lymphocyte expansion while others do not. Understanding these underlying mechanisms could lead to new interventions that enhance CAR T-cell expansion, ultimately improving outcomes for a broader range of patients. Identifying potential pre-infusion markers that could predict whether a patient will have a favorable ALC response may be relevant. If such biomarkers can be identified, clinicians might be able to intervene even earlier, adjusting treatment plans before CAR T-cell therapy begins.

Absolute lymphocyte count after BCMA CAR-T therapy is a predictor of response and outcomes in relapsed multiple myeloma. Saldarriaga MM, Pan D, Unkenholz C, et al. Blood Adv (2024) 8 (15): 3859–3869. https://doi.org/10.1182/bloodadvances.2023012470