Category: Hem/Onc Updates

Late Breaking Abstract – ESMO 2024: Adjuvant KISQALI® Shows Deepening Benefit in Patients with Early Stage Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. 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. Breast cancer is the second leading cause of cancer death in women, in the U.S.

About 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors, and Hormone Receptor (HR)-positive/HER2-negative breast cancer is the most frequently diagnosed molecular subtype. About 90% of all breast cancers are detected at an early stage, and these patients are often cured with a combination of surgery, radiotherapy, chemotherapy, and hormone therapy. However approximately 20% of patients will experience local recurrence or distant relapse during the first 10 years of treatment. This may be more relevant for those with high risk disease, among whom the risk of recurrence is even greater during the first 2 years while on adjuvant Endocrine Therapy, due to primary endocrine resistance. More than 75% of the early recurrences are seen at distant sites.

Cyclin Dependent Kinases (CDKs) play a very important role to facilitate orderly and controlled progression of the cell cycle. Genetic alterations in these kinases and their regulatory proteins have been implicated in various malignancies. CDK4 and 6 phosphorylate RetinoBlastoma protein (RB), and initiate transition from the G1 phase to the S phase of the cell cycle. RetinoBlastoma protein has antiproliferative and tumor-suppressor activity. Phosphorylation of RB protein nullifies its beneficial activities. CDK4 and CDK6 are activated in HR-positive breast cancer, by binding to D-cyclins in the ER-positive breast cancer cell, promoting breast cancer cell proliferation. Further, there is evidence to suggest that endocrine resistant breast cancer cell lines depend on CDK4 for cell proliferation. The understanding of the role of CDKs in the cell cycle, has paved the way for the development of CDK inhibitors.

Ribociclib (KISQALI®) is an orally bioavailable, selective, small-molecule inhibitor of CDK4/6, preferentially inhibiting CDK4 and blocking the phosphorylation of RetinoBlastoma protein, thereby preventing cell-cycle progression and inducing G1 phase arrest. The MONALEESA trials of Ribociclib have shown a consistent Overall Survival benefit, regardless of accompanying Endocrine Therapy, line of therapy, or menopausal status, in advanced breast cancer.

NATALEE is a global, multi-center, randomized, open-label Phase III trial, conducted to evaluate the efficacy and safety of Ribociclib with Endocrine Therapy as adjuvant treatment versus Endocrine Therapy alone, in patients with HR+/HER2-negative early breast cancer, who were at risk for disease recurrence. This study conducted in collaboration with Translational Research In Oncology (TRIO), randomly assigned 5,101 eligible men and pre- or postmenopausal women 1:1 to receive either adjuvant Ribociclib 400 mg orally daily for 3 years along with Endocrine Therapy consisting of Letrozole 2.5 mg/day or Anastrozole 1 mg/day, for 5 yrs or more (N= 2,549) or Endocrine Therapy alone for at least 5 years (N = 2,552). This study explored a lower Ribociclib starting dose of 400 mg daily rather than the dose approved for treatment in metastatic breast cancer (600 mg), with the goal to minimize toxicities and disruptions to patient quality of life, without compromising efficacy. Men and premenopausal women also received Goserelin. Eligible patients had an ECOG PS of 0-1 with Stage IIA (either N0 with additional risk factors or N1 with 1-3 axillary lymph nodes), Stage IIB, or Stage III HR-positive, HER2-negative breast cancer who were at risk for disease recurrence. Prior adjuvant Endocrine Therapy was allowed if initiated no more than 1 year before randomization. Stratification factors were menopausal status, disease stage, prior neoadjuvanr/adjuvant chemotherapy, and geographic region. Approximately 44% were premenopausal and 40% had Stage II breast cancer. Majority of patients (88%) received prior chemotherapy. The Primary endpoint of NATALEE was invasive Disease Free Survival (iDFS) as defined by the Standardized Definitions for Efficacy End Points (STEEP) criteria. Secondary endpoints included Distant Disease-Free Survival (DDFS) and Overall Survival (OS).

The authors had previously reported that at a median follow up of 34 months, the addition of Ribociclib to Endocrine Therapy significantly improved in invasive DFS compared with Endocrine Therapy alone (HR=0.748; P=0.0014), reducing the risk of disease recurrence by 25%.
The researchers in this updated analysis of the NATALEE trial presented the efficacy and safety data at data cutoff (29 Apr 2024), with all patients in the Ribociclib plus Endocrine Therapy group (N=2549) off treatment with Ribociclib. This update provided a robust framework for understanding the long-term implications of this therapeutic approach.

The updated analysis revealed that invasive DFS significantly favored the Ribociclib plus Endocrine Therapy combination over Endocrine Therapy alone. At the three-year mark, iDFS rates were 90.8% for the Ribociclib plus Endocrine Therapy group compared to 88.1% for those on Endocrine Therapy alone, with an absolute improvement of 2.7%. By the four-year follow-up, this gap widened, with iDFS rates of 88.5% versus 83.6%, reflecting a 4.9% absolute benefit. This benefit was consistent across various subgroups. Patients with node-negative disease (N0) experienced a 5.1% absolute increase in iDFS at four years, while those with node-positive disease (N+) saw a 5.0% improvement. Similarly, patients in Stage II had an absolute benefit of 4.3%, and those in Stage III achieved a 5.9% increase in their iDFS rates.

The Distant DFS data was similar to the iDFS findings, with Ribociclib plus Endocrine Therapy showing a Hazard Ratio of 0.715 (95% CI, 0.604–0.847; P<0.0001), indicating a substantial reduction in the risk of distant recurrence. While Overall Survival data remains immature, trends suggest a favorable outcome for the Ribociclib group.

Safety data revealed that Ribociclib was well tolerated, and remained consistent with previous analyses. The adverse events of special interest, particularly those Grade 3 or higher, included neutropenia (44.4%), liver-related issues (8.6%), and QT interval prolongation (1.0%).

The researchers concluded that in this 4-year landmark analysis, Ribociclib plus Endocrine Therapy reduced the risk of Invasive and Distant disease recurrence by 28.5% compared with Endocrine Therapy alone. Further, this benefit was maintained even after the end of planned 3-year Ribociclib treatment, for both node-positive and node-negative patients. This deepening efficacy, particularly evident in node-negative and high-risk early breast cancer patients, underscores the necessity of evolving treatment strategies in the fight against breast cancer.

Adjuvant ribociclib (RIB) plus nonsteroidal aromatase inhibitor (NSAI) in patients (Pts) with HR+/HER2− early breast cancer (EBC): 4-year outcomes from the NATALEE trial. Fasching PA, Stroyakovskiy D, Yardley D, et al. DOI: 10.1016/j.annonc.2024.08.2251

Late Breaking Abstract – ESMO Congress 2024: IMFINZI® Along with Neoadjuvant Chemotherapy Improves Survival in Muscle Invasive Bladder Cancer

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SUMMARY: The American Cancer Society estimates that in the United States for 2024, about 83,190 new cases of bladder cancer will be diagnosed and approximately 16,840 patients will die of the disease. Bladder cancer is the fourth most common cancer in men, but it is less common in women. Bladder cancer accounts for 90% of urothelial cancers, and urothelial cancer can also be found in the renal pelvis, ureter and urethra. Approximately 12% of urothelial cancer cases at diagnosis are locally advanced or metastatic.

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

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

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

In the pre-planned interim analysis, the results demonstrated a significant improvement in both EFS and OS in the Durvalumab group compared to the chemotherapy-alone group. At 24 months, the estimated EFS was 67.8% in the Durvalumab group, compared to 59.8% in the comparison group. The Hazard Ratio (HR) for EFS in the Durvalumab arm was 0.68; P<0.001). Furthermore, the estimated OS at 24 months was 82.2% in the Durvalumab group versus 75.2% in the comparison group (HR for death=0.75; P=0.01). Notably, the percentage of patients who underwent radical cystectomy was similar between the two groups, with 88% in the Durvalumab group and 83% in the comparison group, indicating that the addition of Durvalumab did not reduce surgical completion rates. Treatment-related adverse events of Grade 3 or 4 severity occurred in 40.6% of patients in the Durvalumab arm and 40.9% in the comparison arm, with treatment-related deaths reported in 0.6% of patients in both groups.

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

Perioperative Durvalumab with Neoadjuvant Chemotherapy in Operable Bladder Cancer. Powles T, Catto J, Galsky MD, for the NIAGARA Investigators. Published September 15, 2024. DOI: 10.1056/NEJMoa2408154

FDA Approves RYBREVANT® plus Chemotherapy for EGFR-Mutated NSCLC

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SUMMARY: The FDA on September 19, 2024 approved Amivantamab-vmjw (RYBREVANT®) with Carboplatin and Pemetrexed for adult patients with locally advanced or metastatic Non-Small Cell Lung Cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor. 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 10-15% of Caucasian patients and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR mutations and 90% of these mutations are either exon 19 deletions or L858R substitution mutation in exon 21. Epidermal Growth Factor Receptor (EGFR) plays an important role in regulating cell proliferation, survival and differentiation, and is overexpressed in a variety of epithelial malignancies. EGFR targeted Tyrosine Kinase Inhibitors (TKIs) such as Gefitinib, Erlotinib, Afatinib, Dacomitinib and Osimertinib target the EGFR signaling cascade. However, patients eventually will develop drug resistance due to new EGFR mutations. Another important cause of drug resistance to TKIs is due to the activation of parallel RTK (Receptor Tyrosine Kinase) pathways such as Hepatocyte Growth Factor/Mesenchymal-Epithelial Transition factor (HGF/MET) pathway, thereby bypassing EGFR TKI inhibitors. These patients are often treated with platinum-based chemotherapy as the next line of therapy, resulting in a median Progression Free Survival of 5 months.

Amivantamab (RYBREVANT®) is a fully-human bispecific antibody directed against EGFR and MET receptors. Amivantamab binds extracellularly and simultaneously blocks ligand-induced phosphorylation of EGFR and c-MET, inhibiting tumor growth and promoting tumor cell death. Further, Amivantamab downregulates receptor expression on tumor cells thus preventing drug resistance mediated by new emerging mutations of EGFR or c-MET. By binding to the extracellular domain of the receptor protein, Amivantamab can bypass primary and secondary TKI resistance at the active site. Amivantamab also engages effector cells such as Natural Killer cells, monocytes, and macrophages via its optimized Fc domain. Amivantamab demonstrated activity against a wide range of activating and resistance mutations in EGFR-mutated NSCLC, and in patients with MET exon 14 skip mutations, and is approved for the treatment of patients with EGFR exon 20 insertion mutations, whose disease progressed on or after platinum-based chemotherapy.

The efficacy of Amivantamab was assessed in the Phase 3 MARIPOSA-2 trial, a multicenter, open-label study involving 657 patients. These participants, all with EGFR-mutant NSCLC, who had progressed on Osimertinib treatment, were randomly assigned in a 1:2:2 ratio to receive either Amivantamab with Carboplatin and Pemetrexed (referred to as Amivantamab plus chemotherapy-N=131), Carboplatin and Pemetrexed alone (chemotherapy alone-N=263), or Amivantamab combined with other regimens (N=263). Eligible patients had documented presence of EGFR exon 19 deletion or exon 21 L858R mutation and experienced disease progression after receiving Osimertinib as their most recent line of therapy. Patients received Amivantamab 1400 mg IV (1750 mg for body weight 80 kg or greater) weekly for the first 4 weeks, then 1750 mg (2100 mg for body weight 80 kg or greater) every 3 weeks starting at cycle 3 (week 7). The first Amivantamab infusion was split over 2 days, with 350 mg IV on cycle 1, day 1 and the remainder on cycle 1, day 2. Chemotherapy consisted of Carboplatin AUC 5 IV, starting on day 1 every 3 weeks for the first 4 cycles along with Pemetrexed 500 mg/m2 IV every 3 weeks until disease progression. The median age was 62 years, 48% of patients were Asian and approximately 70% of patients had Osimertinib as first line treatment and 30% had Osimertinib as second line treatment. Randomization was stratified by Osimertinib line of therapy (first or second), and race (Asian or non-Asian). All three treatment groups were well balanced. The Primary endpoint of the study was Progression-Free Survival (PFS), assessed by Blinded Independent Central Review (BICR). Key Secondary endpoints included Overall Survival (OS), Overall Response Rate (ORR), Time to Treatment Discontinuation (TTD), Time to Subsequent Therapy (TTST), Progression-Free Survival after first subsequent therapy (PFS2) and Time to Symptomatic Progression (TTSP).

At a median follow-up of 8.7 months, the PFS was significantly longer for Amivantamab plus chemotherapy versus chemotherapy alone. The median PFS was 6.3 months in the Amivantamab plus chemotherapy group and 4.2 months in the chemotherapy alone group (HR for disease progression or death=0.48; P<0.0001), indicating a a 52% reduction in the risk of progression or death. The ORR was significantly higher in the Amivantamab plus chemotherapy group at 53%, compared to 29% in the chemotherapy alone group (P<0.0001).

In the prespecified second interim analysis, a numerical improvement in OS was noted for the Amivantamab plus chemotherapy group with a median OS of 17.7 months compared to 15.3 months for the chemotherapy alone group (HR=0.73; P=0.039). However, this did not meet the prespecified significance level.

With regards to Post-Progression Endpoints, the median TTD was significantly longer in the Amivantamab plus chemotherapy group versus chemotherapy alone group (10.4 months versus 4.5 months; HR=0.42; P<0.0001). The Median TTST was also prolonged in the Amivantamab plus chemotherapy group versus chemotherapy alone group (12.2 months compared to 6.6 months HR=0.51; P< 0.0001). The median PFS2 was significantly longer in the Amivantamab plus chemotherapy group compared to the chemotherapy alone group (16.0 months versus 11.6 months (HR= 0.64; P=0.002). Common adverse reactions observed in patients receiving Amivantamab plus chemotherapy included rash, infusion-related reactions, fatigue, nail toxicity, nausea, constipation, edema, stomatitis, decreased appetite, musculoskeletal pain, vomiting, and COVID-19 infection.

In conclusion, the results from the MARIPOSA-2 trial provide compelling evidence for the use of Amivantamab in combination with Carboplatin and Pemetrexed in the treatment of advanced EGFR-mutant NSCLC post-Osimertinib progression. While the PFS outcomes were significantly improved, the OS benefits, promising as they may be, require further follow-up for conclusive results. The final Overall Survival analysis will be eagerly awaited, as it will further illuminate the long-term efficacy of this treatment approach.

Amivantamab plus chemotherapy vs chemotherapy in EGFR-mutated, advanced non-small cell lung cancer after disease progression on osimertinib: Second interim overall survival from MARIPOSA-2. Popat S, Reckamp KL, Califano R, et al. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. LBA54.

FDA Approves SARCLISA® with VRd Regimen for Newly Diagnosed Multiple Myeloma

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SUMMARY: The FDA on September 20, 2024, approved Isatuximab-irfc (SARCLISA®) with Bortezomib, Lenalidomide, and Dexamethasone for adults with newly diagnosed multiple myeloma who are not eligible for Autologous Stem Cell Transplant (ASCT). 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.

Newly diagnosed multiple myeloma patients are often treated with Bortezomib, Lenalidomide, and Dexamethasone (VRd), after the SWOG S0777 trial established this regimen as a standard first-line treatment, regardless of their transplantation eligibility. With the introduction of CD38 targeted therapies, new treatment combinations are being explored to increase the depth of response and attain long-term disease control.

Isatuximab-irfc (SARCLISA®) is a CD38-targeting IgG1monoclonal antibody, similar to Daratumumab (DARZALEX®), but unlike Daratumumab, is not associated with complement activation, and can therefore be more readily given to patients with asthma or Chronic Obstructive Pulmonary Disease. Further, Isatuximab targets a specific epitope on the CD38 receptor, and this distinction from Daratumumab allows use of Isatuximab in cases when Daratumumab fails. Additionally, Isatuximab infusions are less cumbersome. The FDA in 2021, approved Isatuximab in combination with Carfilzomib (KYPROLIS®) and Dexamethasone, for the treatment of adult patients with Relapsed or Refractory multiple myeloma who have received one to three prior lines of therapy.

The IMROZ trial (NCT03319667) was an international, multicenter, open-label, Phase 3 randomized controlled trial, designed to evaluate the efficacy and safety of Isatuximab in combination with the established regimen of Bortezomib, Lenalidomide, and Dexamethasone (VRd) compared to VRd alone. This study aimed to address a critical gap in treatment options for patients with newly diagnosed multiple myeloma who are ineligible for ASCT, a situation often faced by older patients or those with significant comorbidities. A total of 446 patients, aged 18 to 80 years, with symptomatic, previously untreated multiple myeloma were randomly assigned in a 3:2 ratio to receive either the Isatuximab-VRd regimen (N=263) or the standard VRd regimen alone (N=181). The Induction phase of the treatment consisted of 4 cycles, with each cycle lasting 6 weeks. Patients in the Isatuximab-VRd Group received Isatuximab 10 mg/kg IV weekly during Cycle 1, then every 2 weeks for subsequent cycles. Patients received subcutaneous Bortezomib (1.3 mg/m²) on specified days, along with oral Lenalidomide (25 mg daily for 14 days) and Dexamethasone (20 mg on specified days). The VRd group received the same VRd regimen without Isatuximab. Following the induction phase, both groups continued treatment with a regimen consisting of Lenalidomide and Dexamethasone. For the Isatuximab-VRd group, Isatuximab was given every 2 weeks, transitioning to monthly administration starting at Cycle 18. The median patient age was 72 years and treatment groups were well balanced. The Primary endpoint of the trial was Progression-Free Survival (PFS), assessed by an Independent Review Committee in accordance with International Myeloma Working Group criteria. Secondary endpoints included Complete Response (CR) or better, Minimal Residual Disease (MRD) negativity in patients achieving a Complete Response, assessed at a sensitivity level of 10⁻⁵ using Next-Generation Sequencing, Overall Survival (OS) and Quality of Life measures.

The results from the interim analysis at a median follow-up of 59.7 months demonstrated a significant improvement in PFS for the Isatuximab-VRd group compared to the VRd group. The 60-month PFS was estimated at 63.2% in the Isatuximab-VRd group versus 45.2% in the VRd group (HR=0.60; P<0.001), indicating a 40% reduction in the risk of disease progression or death for the Isatuximab group. Approximately 75% of patients in the Isatuximab-VRd group achieved a Complete Response or better compared to 64.1% in the VRd group (P=0.01). Higher rates of MRD negativity (55.5% vs. 40.9%; P=0.003) were also observed in the Isatuximab group. The safety profile of the Isatuximab-VRd combination mirrored that of established regimens, with no new safety signals identified. Incidences of serious adverse events were comparable between the two groups, though a slight increase in infections and neutropenia was noted with the addition of Isatuximab.

In conclusion, the results from the IMROZ trial clearly indicate that the addition of Isatuximab to the VRd regimen provides significant benefits in terms of Progression-Free Survival and Response Rates in patients with newly diagnosed multiple myeloma who are ineligible for transplantation, addressing an important unmet need. Further follow-up and analyses will continue to elucidate the long-term benefits and safety of this promising therapeutic strategy.

Isatuximab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. Thierry Facon, M.D., Meletios-Athanasios Dimopoulos, M.D., Xavier P. Leleu, et al. for the IMROZ Study Group. Published June 3, 2024. DOI: 10.1056/NEJMoa2400712.

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

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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.

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.

Optimal Approach for Integrating Immune Checkpoint Inhibitors in Early-Stage Breast Cancer: A Meta-Analysis

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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.

The integration of Immune Checkpoint Inhibitors (ICIs) into early-stage breast cancer treatment, particularly when combined with neoadjuvant chemotherapy, represents a significant advancement in oncology. Recent studies have explored combining ICIs with neoadjuvant chemotherapy to improve pathologic Complete Response (pCR) rates and survival outcomes. While ICIs have revolutionized treatment in metastatic settings, their role in early-stage breast cancer remains debated. This meta-analysis aims to evaluate the optimal approach for incorporating ICIs into early-stage breast cancer therapy by assessing their impact on pCR, Event-Free Survival (EFS), and safety profiles.

This study utilized the PubMed database, with a search conducted on December 10, 2023, to identify relevant randomized clinical trials (RCTs). Inclusion criteria focused on RCTs assessing the efficacy of neoadjuvant or adjuvant ICI plus chemotherapy in early-stage breast cancer. The studies had to provide data on pCR, EFS, and adverse events. Two independent reviewers extracted data from the selected RCTs. An individual patient data meta-analysis and a trial-level random-effect meta-analysis were conducted to synthesize findings. Nine RCTs involving 5114 patients were included. The population comprised 2097 patients with Triple-Negative Breast Cancer (TNBC), 1924 patients with Hormone Receptor–positive/HER2-negative (HR+/HER2-negative) tumors, and 1115 patients with HER2-positive tumors.

The Primary objectives of this study were to 1) Evaluate the association of neoadjuvant ICIs with pCR (defined as ypT0/is ypN0) across different molecular phenotypes of breast cancer 2) Quantify EFS assessed in patients with and without pCR and 3) Evaluate the severity of Adverse Events associated with ICIs including Grade 3 or higher immune-related Adverse Events (irAEs).

Efficacy of Neoadjuvant ICIs:
TNBC: Neoadjuvant ICIs led to a significant improvement in pCR rates, with an absolute increase of more than 10%. The efficacy was consistent across different PD-L1 expression statuses. Neoadjuvant ICIs also improved EFS for both patients achieving pCR (HR=0.65) and those with residual disease (HR=0.77). In patients with TNBC achieving a pCR, the addition of ICIs was associated with a 5-year EFS of 92.0% compared with 88.0% without them. In patients with residual disease, treatment with ICIs resulted in 5-year EFS of 63.3%, and 56.1% without them.
HR+/HER2-negative Tumors: ICIs improved pCR rates predominantly in the PD-L1+ subgroup, with an absolute increase of 12.2%. No significant benefit was observed in the PD-L1 negative subgroup or in HER2-positive tumors.

Adjuvant ICI Therapy:
No numerical improvement was observed with adjuvant ICI therapy, regardless of whether patients had achieved pCR or had residual disease. Hazard ratios were greater than 1, suggesting a lack of benefit.

The incidence of Grade 3 or higher irAEs during neoadjuvant therapy was 10.3%. This was consistent with known AEs of ICIs. Chemotherapy-related AEs, such as gastrointestinal and hematologic complications, was not significantly increased with ICI addition.

In conclusion, this meta-analysis indicates that neoadjuvant ICI therapy is beneficial in enhancing pCR rates and improving survival outcomes in early-stage TNBC and PD-L1+ HR+/HER2-negative tumors. The results suggest a preference for neoadjuvant over adjuvant ICI therapy, given the lack of benefit from adjuvant ICIs. Future research should focus on optimizing patient selection for neoadjuvant ICIs and exploring whether adjuvant therapy can be safely omitted, potentially reshaping treatment paradigms in early-stage breast cancer.

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. Published online August 29, 2024. doi:10.1001/jamaoncol.2024.3456.

Unfulfilled Potential: The Gap in Genetic Testing for 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. 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.

The availability of multigene panel testing and next-generation sequencing is changing the landscape of cancer prevention and treatment. The necessity for genetic testing in breast cancer has gained support due to its critical role in treatment management and family risk assessment. Clinical guidelines have evolved to expand eligibility for genetic testing, yet many patients who could benefit from these tests either do not receive them or face delays in testing. This is concerning, as genetic testing informs treatment decisions, surveillance for second cancers, and risk management for relatives. This present study aimed to explore the receipt of genetic testing and communication with relatives about results in women diagnosed with early-stage breast cancer, examining patterns from initial diagnosis through survivorship, a time that is often overlooked for its importance in continued care. Specifically, it aimed to assess how these factors influence survivorship and familial risk communication over time.

The study utilized a cohort of women aged 20-79 years diagnosed with early-stage breast cancer in 2014-2015, sourced from the Georgia and Los Angeles County SEER registries. A total of 1,412 women were surveyed approximately 7 months after diagnosis and again 6 years later. The surveys collected data on genetic counseling, testing, and communication about test results. Participants were categorized based on clinical guidelines into three groups:
• Indications at Baseline: Women who had indications for genetic testing at the time of initial diagnosis.
• Indications at Follow-up Only (FUPs): Women who had indications for testing only during follow-up.
• No Indications: Women who did not have indications for genetic testing at any point.

The findings revealed that nearly half (47.4%) of the women had indications for genetic testing at some point- 28.0% at baseline and an additional 19.4% during follow-up. Among those who had an indication at baseline, 71.9% reported having undergone genetic testing. This rate was significantly higher compared to those with an indication only at follow-up (53.3%) and those with no indication (35.0%). Statistical analysis showed significant differences in testing rates between these groups (P<0.001). Importantly, racial and ethnic differences did not significantly affect the receipt of testing when controlling for age and clinical indications (P=0.239). The results for genetic counseling were similar.

Only a small fraction (3.4%) of the women pursued Direct-to-Consumer genetic testing (DTCt) for cancer.

Women who tested positive for a Pathogenic Variant (N = 62) were significantly more likely to discuss their results with most or all of their first-degree relatives compared to those with a Variant of Unknown Significance (N = 49) or a negative result (N = 419). Specifically, 62.7% of women with Pathogenic Variants communicated results to their relatives, compared to those with a Variant of Unknown Significance (38.8%) or a negative result (38.0%), (P<0.001).

In conclusion, this study underscores a significant gap in the uptake of genetic counseling and testing among women who are eligible for it based on clinical guidelines. While the proportion of women with indications for genetic testing increased over time, many women did not receive it. This gap was consistent across racial and ethnic groups, suggesting that the issue is widespread rather than confined to specific subpopulations. The study emphasizes that positive genetic results lead to increased family communication about cancer risk, whereas the uptake of DTCt remains low, reaffirming its limited role in replacing clinical-grade genetic testing in this population.

Genetic Counseling, Testing, and Family Communication Into Survivorship After Diagnosis of Breast Cancer. Katz SJ, Abrahamse P, Furgal A, et al. J Clin Oncol. 2024;doi:10.1200/JCO.24.00122.

Immune Checkpoint Inhibitor Therapy and Cardiovascular Adverse Events

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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.

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.

Sotorasib plus Panitumumab in Refractory Colorectal Cancer with Mutated KRAS G12C

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SUMMARY: Colorectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 153,020 new cases of CRC were diagnosed in the United States in 2023 and about 52,550 patients died of the disease. The lifetime risk of developing CRC is about 1 in 23.

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

The KRAS (Kirsten rat sarcoma viral oncogene homologue) proto-oncogene encodes a protein that is a member of the small GTPase super family. The KRAS gene provides instructions for making the KRAS protein, which is a part of a signaling pathway known as the RAS/MAPK pathway. By relaying signals from outside the cell to the cell nucleus, the protein instructs the cell to grow, divide and differentiate. KRAS gene is in the Ras family of oncogenes, which also includes two other genes, HRAS and NRAS. When mutated, oncogenes have the potential to change normal cells cancerous. KRAS is the most frequently mutated oncogene in human cancers and are often associated with resistance to targeted therapies and poor outcomes. The KRAS G12C mutation occurs in approximately 12-15% of Non Small Cell Lung Cancers (NSCLC) and in 3-5% of colorectal cancers and other solid cancers. G12C is a single point mutation with a Glycine-to-Cysteine substitution at codon 12. This substitution favors the activated state of KRAS, amplifying signaling pathways that lead to oncogenesis. Currently, no targeted therapies driven by a positive-selection biomarker are approved specifically for the treatment of patients with KRAS-mutated colorectal cancer.

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

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

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

It was concluded from this study that both doses of Sotorasib (960 mg and 240 mg) in combination with Panitumumab resulted in significantly longer Progression Free Survival and a higher incidence of Response Rate than standard treatment. Ongoing analysis and longer follow up will provide additional insights into Overall Survival outcomes.

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