Author: RR

OJEMDA® (Tovorafenib)

RR

The FDA on April 23, 2024, the Food and Drug Administration granted accelerated approval to OJEMDA® (Tovorafenib) for patients 6 months of age and older with relapsed or refractory pediatric Low-Grade Glioma (LGG) harboring a BRAF fusion or rearrangement, or BRAF V600 mutation. OJEMDA® is a product of Day One Biopharmaceuticals, Inc.

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

RR

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

RR

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.