Author: RR

Late Breaking Abstract – ASCO 2024: KRAZATI® Superior to Docetaxel in KRAS G12C Mutated Non Small Cell Lung Cancer

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.

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. The KRAS protein is a GTPase, and converts GTP into GDP. To transmit signals, the KRAS protein must be turned on by binding to a molecule of GTP. When GTP is converted to GDP, the KRAS protein is turned off or inactivated, and when the KRAS protein is bound to GDP, it does not relay signals to the cell nucleus. The 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 25% of Non Small Cell Lung Cancers (NSCLC) and in 3-5% of colorectal cancers and other solid cancers. KRAS G12C is one of the most prevalent driver mutations in NSCLC and accounts for a greater number of patients than those with ALK, ROS1, RET, and TRK 1/2/3 mutations combined. KRAS G12C cancers are genomically more heterogeneous and occur more frequently in current or former smokers, and are likely to be more complex genomically than EGFR mutant or ALK rearranged cancers. G12C is a single point mutation with a Glycine-to-Cysteine substitution at codon 12. This substitution favors the activated state of KRAS, resulting in a predominantly GTP-bound KRAS oncoprotein, amplifying signaling pathways that lead to oncogenesis.

Adagrasib (KRAZATI®) is a potent, orally available, small molecule covalent inhibitor of KRAS G12C. This drug irreversibly and selectively binds KRAS G12C in its inactive, GDP-bound state. Unlike Sotorasib (LUMAKRAS®), which is also a selective covalent inhibitor of KRAS G12C, Adagrasib has a longer drug half-life of 23 hours, as compared to 5 hours for Sotorasib, has dose-dependent extended exposure, and can penetrate the CNS. Approximately, 27-42% of patients with NSCLC harboring KRAS G12C mutations have CNS metastases, with poor outcomes. The U.S. FDA granted accelerated approval for Adagrasib as a targeted treatment for patients with KRASG12C-mutated locally advanced or metastatic NSCLC who have received at least one prior systemic therapy in December 2022.

KRYSTAL-12 trial is a pivotal, open-label, multicenter, randomized, Phase III study designed to compare Adagrasib against standard-of-care chemotherapy (Docetaxel) in patients with KRASG12C-mutated NSCLC who had received prior platinum-based chemotherapy concurrently or sequentially with anti-PD-(L)1 therapy. In this study, 453 patients were randomized 2:1 to receive either Adagrasib 600 mg orally twice a day (N=301) or Docetaxel 75 mg/m2 IV every 3 weeks (N=152). Importantly, patients in the Docetaxel arm had the option to crossover to Adagrasib upon confirmed disease progression. Patients were stratified by region (non-Asia Pacific versus Asia Pacific) and by whether they received concurrent or sequential chemoimmunotherapy. Patients with stable brain metastases were allowed. Both treatment groups were well balanced. The median age was 64.5 years, 95% of patients had adenocarcinoma histology with metastatic disease and approximately 75% of patients were former smokers and previously received concurrent chemoimmunotherapy. The Primary endpoint of the study was Progression Free Survival (PFS) as assessed by Blinded Independent Central Review (BICR). Secondary endpoints included Overall Survival (OS), Overall Response Rate (ORR), Duration of Response (DOR), Safety assessments and Patient-Reported Outcomes. At the time of this analysis, 29% of patients had crossed over from Docetaxel treatment to receive Adagrasib.

With a median follow-up of 9.4 months, the trial met its Primary endpoint, with Adagrasib demonstrating a significant improvement in PFS over Docetaxel (median PFS 5.5 versus 3.8 months; HR=0.58, P<0.0001). The benefit of Adagrasib over Docetaxel was maintained across key subgroups. The ORR was also significantly higher with Adagrasib compared with Docetaxel (32% versus 9%; Odds Ratio 4.68; P<0.0001). The median Duration of Response was 8.3 months versus 5.4 months respectively, and responses were sustained at least 6 months in 64% and 39% of patients, respectively. Among those patients with CNS metastases at baseline, intracranial responses were observed in 24% of patients receiving Adagrasib and 11% of patients receiving Docetaxel, with intracranial Disease Control Rate of 82% and 56%, respectively. There was also a significant benefit in the Patient-Reported Outcomes of median time to deterioration. There were no new safety signals noted with Adagrasib and the safety data was consistent with the known safety profile. Grade 3 or more treatment-related adverse events occurred in 47% of patients treated with Adagrasib and 45.7% of patients treated with Docetaxel and treatment discontinuation rates were 7.7% versus 14.3%, respectively.

In summary, the KRYSTAL-12 trial confirmed Adagrasib as a superior treatment option compared to Docetaxel in patients with previously treated KRASG12C-mutated locally advanced or metastatic NSCLC. Adagrasib significantly improved Progression Free Survival, Overall Response Rate, and Duration of Response, with a notable impact on intracranial disease control rates. Its safety profile was manageable, aligning with expectations from earlier studies. These findings underscore the potential of Adagrasib in this patient population and highlight ongoing research efforts to further optimize treatment strategies in this challenging patient population.

KRYSTAL-12: Phase 3 study of adagrasib versus docetaxel in patients with previously treated advanced/metastatic non-small cell lung cancer (NSCLC) harboring a KRASG12C mutation. Mok TSK, Yao W, Duruisseaux M, et al. J Clin Oncol. 2024;42(suppl 17):LBA8509.

Duration of Androgen Deprivation Therapy with Postoperative Radiotherapy for Prostate Cancer: 24 Months versus 6 Months

RR

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 299,010 new cases of prostate cancer will be diagnosed in 2024 and 35,250 men will die of the disease.

The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced prostate cancer, and is the first treatment intervention. Treatment options for patients with intermediate and high risk prostate cancer include Radical Prostatectomy and External Beam Radiation Therapy. Three Phase III randomized studies have previously assessed the addition of Androgen Deprivation Therapy (ADT) to postoperative radiotherapy after Radical Prostatectomy, but none of these studies compared different durations of ADT and the optimal duration of Androgen Deprivation Therapy has remained unclear.

RADICALS was a multicenter, international, open-label, randomized, controlled, Phase III trial in prostate cancer.
This study addressed two important questions:
1) Which is the best way to use radiotherapy after surgery?
2) Which is the best way to use hormone treatment with any radiotherapy given after surgery?

The full background and other details related to the RADICALS trial is published elsewhere.

RADICALS-HD is a component of the RADICALS trial and the researchers hypothesized that long-course ADT would be more effective than short-course ADT in patients receiving postoperative radiotherapy. They therefore designed a prospective, international, randomized controlled trial to compare long-course versus short-course use of ADT in this setting. In the RADICALS-HD trial, 1523 patients were randomly assigned 1:1 to receive short-course ADT (N=761) or long-course ADT (N=762) in addition to postoperative radiotherapy at 138 centers in Canada, Denmark, Ireland, and the UK. Radiotherapy was started approximately 2 months after the start of hormone treatment, and patients received either 52.5 Gy in 20 fractions over 4 weeks or 66.0 Gy in 33 fractions over 6.5 weeks. Radiotherapy was given in the adjuvant setting for 43% of patients, and in the early salvage setting for 57% patients. Androgen Deprivation Therapy (ADT) consisted of Gonadotropin Releasing-Hormone analog given subcutaneously monthly for 6 months in the short-course ADT group and every 3 months for 24 months in the long-course ADT group. Outside Canada, Bicalutamide monotherapy 150 mg daily or monthly subcutaneous Degarelix were acceptable alternatives. Randomization was stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT. The two treatment groups were well balanced. The median age was 65 years, 93% of patients had Gleason score of 7 or higher and 30% had Stage T3b disease or higher. The Primary outcome measure was Metastasis-Free Survival, defined as metastasis arising from prostate cancer or death from any cause.

With a median follow-up of 8.9 years, the long-course ADT for 24 months resulted in a superior Metastasis-Free Survival compared to short-course ADT for 6 months. The 10-year Metastasis-Free Survival was 78.1% in the long-course ADT group compared to 71.9% in the short-course ADT group (HR=0.77; P=0.029). This finding was consistent across all prespecified subgroups, including baseline PSA. Grade 3 or higher toxicity was reported in 19% of patients in the long-course ADT group, and in 14% of patients receiving short-course ADT (P=0.025).

It was concluded that compared to adding 6 months of ADT, adding 24 months of ADT to patients receiving postoperative radiotherapy after radical prostatectomy for prostate cancer, significantly improved Metastasis-Free Survival. Long-course ADT should therefore be offered in addition to postoperative radiotherapy to individuals who are willing to accept the additional duration of adverse effects. The researchers added that this is the first trial to compare different durations of ADT with postoperative radiotherapy after Radical Prostatectomy in prostate cancer.

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial. Parker CC, Kynaston H, Cook AD, et al. The Lancet. 2024;403:2416-2425

Late Breaking Abstract – ASCO 2024: ENHERTU® Improves PFS in HR-Positive, HER2-Low and HER-Ultralow Metastatic 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. It is estimated that in the US, approximately 310,720 new cases of female breast cancer will be diagnosed in 2024, and about 42,250 individuals will die of the disease, largely due to metastatic recurrence.

The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. Patients with high levels of HER2 expression (IHC 3+ or 2+/FISH+) are classified as HER2-positive. Patients with HER2-positive metastatic breast cancer are often treated with anti-HER2 targeted therapy along with chemotherapy, irrespective of hormone receptor status, and this has resulted in significantly improved treatment outcomes. Tumors that are not classified as HER2-positive are classified as HER2-negative. Despite being classified as HER2-negative, majority these tumors still have some level of HER2 expression.

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. It is estimated that approximately 60-65% of HR-positive/HER2-negative breast cancers are HER2-low and potentially an additional 25% may be HER2-ultralow. These patients are often treated with single agent endocrine therapy, endocrine therapy in combination with CDK4/6 inhibitor, or chemotherapy. Resistance to hormonal therapy occurs in a majority of the patients and there is therefore an unmet need for agents with novel mechanisms of action. Further, there are no targeted therapies specifically approved for patients with HER2-low or HER2-ultralow expression, prior to chemotherapy.

ENHERTU® (Trastuzumab Deruxtecan) is an Antibody-Drug Conjugate (ADC) composed of a humanized monoclonal antibody specifically targeting HER2, with the amino acid sequence similar to Trastuzumab, a cleavable tetrapeptide-based linker, and a potent cytotoxic Topoisomerase I inhibitor as the cytotoxic drug (payload). ENHERTU® has a favorable pharmacokinetic profile and the tetrapeptide-based linker is stable in the plasma and is selectively cleaved by cathepsins that are up-regulated in tumor cells. Unlike KADCYLA® (ado-Trastuzumab emtansine), another ADC targeting HER2, ENHERTU® has a higher drug-to-antibody ratio (8 versus 4), released payload easily crosses the cell membrane with resulting potent cytotoxic effect on neighboring tumor cells regardless of target expression, and the released cytotoxic agent (payload) has a short half-life, thus minimizing systemic exposure.

DESTINY-Breast06 is a global, randomized, open-label Phase III trial evaluating the efficacy and safety of ENHERTU® versus chemotherapy in patients with HR-positive, HER2-low, or HER2-ultralow advanced or metastatic breast cancer. This study enrolled 866 patients (N=713 for HER2-low and N=153 for HER2-ultralow). HER2-low was defined as IHC 1+ or 2+ or FISH negative and HER2-ultralow was defined as IHC 0 with membrane staining. Patients were randomized 1:1 to receive ENHERTU® 5.4 mg/kg every 3 weeks (N=436) or physicians choice of chemotherapy which included Capecitabine, Paclitaxel, or nab-Paclitaxel (N=430). Patients in the trial had no prior chemotherapy for advanced or metastatic disease and received at least two lines of prior endocrine therapy in the metastatic setting. Patients were also eligible if they had received one prior line of endocrine therapy combined with a CDK4/6 inhibitor in the metastatic setting and experienced disease progression within six months of starting 1st-line treatment, or received endocrine therapy as an adjuvant treatment and experienced disease recurrence within 24 months. Patients were stratified based on prior CDK4/6 inhibitor use, HER2 expression and prior taxane use in the non-metastatic setting. Patients in the trial had received a median of two prior lines of endocrine therapy. In the overall trial population, 14.9% of patients in the ENHERTU® group and 19.2% in the chemotherapy group had received one prior line of endocrine therapy. No patients had received prior chemotherapy for metastatic disease. The Primary endpoint was Progression Free Survival (PFS) in the HER2-low patient population as measured by Blinded Independent Central Review (BICR). Key Secondary endpoints included Progression Free Survival (PFS) in the overall trial population (HER2-low and HER2-ultralow), Overall survival (OS) in the HER2-low patient population, Objective Response Rate (ORR), Duration of response (DOR) and Safety. The median duration of follow-up was 18.2 months.

In the primary analysis of this study, results showed that in the HER2-low expression patients, ENHERTU® reduced the risk of disease progression or death by 38%, with a median PFS was 13.2 months in the ENHERTU® group, compared to 8.1 months for chemotherapy (HR=0.62; P<0.0001). For the overall trial population (HER2-low and HER2-ultralow), the median PFS results were similar and the median PFS was 13.2 months for ENHERTU® versus 8.1 months for chemotherapy (HR=0.63; P<0.0001). ENHERTU® reduced the risk of disease progression or death by 37% compared to chemotherapy.

A prespecified exploratory analysis showed that the improvement in PFS was consistent between patients with HER2-low and HER2-ultralow expression. In patients with HER2-ultralow expression, ENHERTU® reduced the risk of disease progression or death by 22% compared to chemotherapy, with a median PFS of 13.2 months versus 8.3 months, respectively (HR=0.78).

The Objective Response Rate (ORR) in HER2-Low Population was 56.5% for ENHERTU® compared to 32.2% for chemotherapy, in the Overall Trial Population was 57.3% for ENHERTU® versus 31.2% for chemotherapy, and in the HER2-Ultralow Subgroup was 61.8% for ENHERTU® versus 26.3% for chemotherapy. The median duration of response across these three groups was 14.3 months.

The safety profile of ENHERTU® was consistent with previous breast cancer clinical trials and no new safety concerns identified. The most common Grade 3 or higher treatment-related adverse events occurring in 5% or more of patients treated with ENHERTU® were neutropenia (20.7%) and anemia (5.8%). Interstitial Lung Disease (ILD), adjudicated as drug-related by an independent committee, occurred in 11.3% of patients treated with ENHERTU®. The majority of ILD events were low grade.

The results from the DESTINY-Breast06 trial underscore the significant clinical benefits of ENHERTU® in improving PFS and ORR in patients with HR-positive, HER2-low, and HER2-ultralow metastatic breast cancer, offering a promising alternative to standard chemotherapy. These findings highlight the potential of ENHERTU® to become a new standard of care for this patient population, pending further investigation and regulatory approval. The detailed positive outcomes underscore the clinical benefits and reinforce the promise of ENHERTU® in treating this challenging cancer subtype.

Trastuzumab deruxtecan (T-DXd) vs physician’s choice of chemotherapy (TPC) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-low or HER2-ultralow metastatic breast cancer (mBC) with prior endocrine therapy (ET): Primary results from DESTINY-Breast06 (DB-06). Curigliano G, Hu X, Dent RA, et al. J Clin Oncol. 2024;42(suppl 17):LBA1000. doi:10.1200/JCO.2024.42.17_suppl.LBA1000.

Late Breaking Abstract – ASCO 2024: IMFINZI® as Consolidation Treatment for 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. IMFINZI® (Durvalumab) is a selective, high-affinity, human IgG1 monoclonal antibody, that blocks the binding of Programmed Death Ligand 1 (PD-L1) to Programmed Death 1 (PD-1) receptor and CD80, thereby unleashing the T cells to recognize and kill tumor cells. IMJUDO® (Tremelimumab) is a human immunoglobulin G2 monoclonal antibody that targets and blocks the activity of CTLA-4, enhancing binding of CD80 and CD86 to CD28. This complimentary mechanisms of action broadens clinical activity, potentially overcoming primary resistance to PD-(L)1 blockade by enabling novel T-cell responses.

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

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

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

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

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

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

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

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. Approximately one third of all patients with NSCLC have Stage III, locally advanced disease at the time of initial presentation and 60 to 90% of these patients have unresectable disease. These patients are treated with concurrent chemoradiotherapy (CRT) followed by consolidation therapy with Durvalumab (IMFINZI®) in patients without progression, as this regimen confers an Overall Survival advantage, and is considered the standard of care (PACIFIC trial).

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

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

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

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

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

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

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

RR

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

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

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

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

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

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

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

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

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

Benign Breast Disease and Increased Breast Cancer Risk

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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 approximately 310,720 new cases of breast cancer were 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.

Benign breast disease comprises approximately 75% of breast biopsy diagnoses, performed following abnormal mammographic findings. Benign breast disease can be, based on Dupont and Page, classified into nonproliferative diseases such as fibroadenomas, cysts, microcalcifications, fibrosis, apocrine, metaplasia, atrophy, fatty tissue necrosis, inflammatory tissue and ectasia, or proliferative disease which includes scar, hyperplasia, sclerosing adenosis, papilloma, adenosis, intraductal hyperplasia, lobular hyperplasia, benign Phylloides tumor, benign mesenchymal tumors, epithelial benign tumors, atypia, atypical ductal hyperplasia, and lobular intraepithelial neoplasia. Surgical biopsy specimens diagnosed as nonproliferative disease, proliferative disease without atypia, or atypical ductal hyperplasia are associated with long term risk of breast cancer. However, there is limited knowledge on breast cancer risk associated with percutaneously diagnosed benign breast diseases.

The researchers conducted this retrospective cohort study to estimate breast cancer risk among women diagnosed with benign breast disease (BBD) through percutaneous biopsies from 2002 to 2013. The study included 4,819 women with a median age of 51 years. The participants were followed from 6 months after biopsy until breast cancer diagnosis, or December 2021. Researchers compared breast cancer risk for women with benign breast disease with the female breast cancer incidence rates obtained from the Iowa Surveillance, Epidemiology, and End Results (SEER) program. The Primary outcome was overall breast cancer diagnoses, as well as diagnoses stratified as Ductal Carcinoma In Situ (DCIS) or invasive breast cancer. About 79% of women underwent core biopsy only, 10% underwent core biopsy and surgical excision and 11% underwent excisional biopsy only. Based on the most severe lesion identified, 50.8% of biopsy specimens were nonproliferative, 42% were proliferative disease without atypia, and 7.2% were atypical hyperplasia.

It was noted that women with benign breast disease diagnosed by percutaneous biopsies had a significantly higher overall breast cancer risk compared to the general population (Standard Incidence Ratio [SIR] = 1.95).

(The SIR is an estimate of the number of cancer cases in a given population compared to what might be “expected” based on a comparison with the cancer experience in a larger population.)

Breast cancer risk increased with the severity of benign breast disease, with SIR = 1.42 for nonproliferative lesions, SIR = 2.19 for proliferative disease without atypia and SIR = 3.91 for atypical hyperplasia. This pattern was comparable to surgical cohorts with benign breast disease.

The risk of breast cancer also increased with the multiplicity of lesions. Women with three or more foci of nonproliferative lesions had an SIR of 2.40, proliferative disease without atypia had an SIR of 3.72, and atypical hyperplasia had an SIR of 5.29, all compared with the general population.

Women with benign breast disease had an increased risk for both invasive breast cancer (SIR = 1.56) and Ductal Carcinoma In Situ (DCIS) (SIR = 3.10), compared to the general population.

The 10-year cumulative breast cancer incidence was 4.3% for nonproliferative lesions, 6.6% for proliferative disease without atypia and 14.6% for atypical hyperplasia, compared with the expected population cumulative incidence of 2.9%.

It was concluded from this study that there is an increased breast cancer risk among women with benign breast diseases diagnosed through percutaneous biopsies. The findings from this study emphasize the importance of considering both the severity and multiplicity of benign breast disease lesions for improved breast cancer risk stratification. The authors also suggest that advancements in digital imaging and computational pathology approaches may enhance future analysis of benign breast disease biopsy specimens, for better risk prediction.

Benign Breast Disease and Breast Cancer Risk in the Percutaneous Biopsy Era. Sherman ME, Vierkant RA, Winham SJ, et al. JAMA Surg. 2024;159:193-201.

Gene Therapy for Sickle Cell Disease

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SUMMARY: Sickle Cell Disease or Sickle Cell anemia is an Autosomal Recessive disorder caused by mutations in the hemoglobin beta-globin gene, and affects approximately 100,000 Americans. It is estimated that it affects 1 out of every 365 African-American births and 1 out of every 16,300 Hispanic-American births. The average life expectancy for patients with Sickle Cell Disease in the US is approximately 40-60 years.

HbSS disease or Sickle Cell anemia is the most common Sickle Cell Disease genotype and is associated with the most severe manifestations. HbSS disease is caused by a mutation substituting thymine for adenine in the sixth codon of the beta-globin chain gene. This in turn affects the hemoglobin’s ability to carry oxygen and causes it to polymerize. This results in decreased solubility thereby distorting the shape of the red blood cells, increasing their rigidity and resulting in red blood cells that are sickle shaped rather than biconcave. These sickle shaped red blood cells limit oxygen delivery to the tissues by restricting the flow in blood vessels, leading to severe pain and organ damage (Vaso-Occlusive Crises). Oxidative stress is an important contributing factor to hemoglobin polymerization with polymer formation occurring only in the deoxy state. HbS/b-0 Thalassemia (double heterozygote for HbS and b-0 Thalassemia) is clinically indistinguishable from HbSS disease. Management of Sickle Cell Disease includes pain control, transfusion support and Hydroxyurea. None of the presently available therapies addresses the underlying cause of this disease nor do they fully ameliorate disease manifestations. Allogeneic bone marrow transplantation can cure this genetic disorder, but less than 20% of eligible patients have a related HLA-matched donor. There is therefore a great unmet need to find new therapies for Sickle Cell Disease.

Fetal hemoglobin which consists of two alpha and two gamma chains is produced in utero, but the level of gamma-globulin decreases postnatally as the production of beta-globin and adult hemoglobin, which consists of two alpha and two beta chains, increases. It has been noted that elevated levels of fetal hemoglobin facilitates oxygen delivery, prevents the sickling of red blood cells, and is associated with decreased morbidity and mortality in patients with Sickle Cell Disease. BCL11A gene is a repressor of gamma-globin expression, and fetal hemoglobin production in adult red blood cells. Downregulating BCL11A can therefore reactivate gamma-globin expression and increase fetal hemoglobin in RBC.

The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 nuclease gene editing technique can be directed to cut DNA in targeted areas, enabling the ability to accurately edit (remove, add, or replace) DNA where it was cut. The modified hematopoietic stem cells are transplanted back into the patient where they engraft within the bone marrow and increase the production of fetal hemoglobin.

The researchers in this study used this gene-editing technique in Hematopoietic Stem and Progenitor Cells at the erythroid-specific enhancer region of BCL11A to down-regulate BCL11A expression in erythroid-lineage cells, restore gamma-globin synthesis, and reactivate production of fetal hemoglobin. CASGEVY&reg: (Exagamglogene Autotemcel) is the first cell-based gene therapy for the treatment of Sickle Cell Disease in patients 12 years and older. This product is made from the patients own hematopoietic stem cells, which are collected and modified, and are given back as a one-time, single-dose infusion as part of a Hematopoietic Stem Cell Transplant. Prior to this infusion, patient must undergo myeloablative conditioning (high-dose chemotherapy), a process that removes cells from the bone marrow, so they can be replaced with the modified cells.

CASGEVY® is the first FDA-approved non-viral cell therapy to utilize CRISPR/Cas9 genome editing technology, to modify patients (autologous) CD34+ Hematopoietic Stem and Progenitor Cells (HSPCs) at the erythroid-specific enhancer region of BCL11A. The FDA approval of CASGEVY® in December 2023 is based on a open-label, single-group, multi-center Phase 3 trial, involving adult and adolescent patients with Sickle Cell Disease. The trial focused on individuals with a history of at least two protocol-defined severe Vaso-Occlusive Crises (VOC) during each of the two years prior to screening.

This study included 44 patients, and their CD34+ HSPCs were edited with the use of CRISPR-Cas9. Patients underwent myeloablative conditioning with pharmacokinetically dose-adjusted Busulfan before the CASGEVY® infusion. The Primary end point was freedom from severe VOC for at least 12 consecutive months. A key Secondary end point was freedom from inpatient hospitalization for severe VOC for at least 12 consecutive months. Additionally, the safety of CASGEVY® was also assessed. The median follow-up was 19.3 months.

Out of the 44 patients treated with CASGEVY®, 30 patients had sufficient follow-up time, to be evaluated. Notably, all treated patients achieved successful engraftment, a crucial aspect confirming the efficacy of the CRISPR/Cas9 genome editing technology in modifying hematopoietic stem cells, and no instances of graft failure or rejection were reported, affirming the safety and viability of CASGEVY® as a therapeutic option.

This study met the Primary endpoint, and it was noted that 97% (29 patients) were free from VOC for at least 12 consecutive months and 100% (all 30 patients) were free from hospitalizations for VOC for at least 12 consecutive months (P<0.001 for both comparisons against the null hypothesis of a 50% response). Patients were free from VOC for a mean duration of 22.4 months. Early and sustained increases in total and fetal hemoglobin levels was noted, with a total hemoglobin level of 10.4 to 13.4 gm/dL at month 3, 10.7 to 14.3 gm/dL at month 6, and normal or near-normal levels (12.1 to 17.2 gm/dL) maintained thereafter. Improvements were also seen in all markers of hemolysis, including normalization of LDH and detectable haptoglobin levels, suggesting resolution of intravascular hemolysis. The safety profile of this intervention was generally consistent with that of myeloablative conditioning with Busulfan and autologous HSPC transplantation. No cancers occurred.

It was concluded that one-time treatment with non-viral ex-vivo CRISPR-Cas9 editing of the erythroid-specific enhancer region of BCL11A reactivated fetal hemoglobin production in erythrocytes, eliminating vaso-occlusive crises in 97% of patients with sickle cell disease for a period of 12 months or more. This high success rate underscores the therapeutic potential of CASGEVY® in mitigating the recurrent and debilitating crises associated with Sickle Cell Disease.

Exagamglogene Autotemcel for Severe Sickle Cell Disease. Frangoul H, Locatelli F, Sharma A, et al. for the CLIMB SCD-121 Study Group. N Engl J Med 2024;390:1649-1662.

FDA Approves Bispecific T-Cell Engager IMDELLTRA® for Small Cell Lung Cancer

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SUMMARY: The FDA on May 16, 2024, granted accelerated approval to IMDELLTRA® (Tarlatamab-dlle) for Extensive Stage-Small Cell Lung Cancer (ES-SCLC) with disease progression on or after platinum-based chemotherapy. Small Cell Lung Cancer (SCLC) originates from neuroendocrine cells and accounts for approximately 13-15% of all lung cancers. It is lethal and aggressive. The 5 year survival rate for Extensive Stage SCLC (ES-SCLC) is less than 5%, with a median survival of 9-10 months from the time of diagnosis. Treatment decisions was SCLC are typically based on the VA Lung Group 2-Staging system, which classifies disease as either Limited Stage (LS) or Extensive Stage (ES). In Limited Stage patients, the disease burden is limited to one hemithorax and regional nodes, without presence of extra-thoracic disease, and amenable to definitive-intent thoracic Radiation Therapy (RT). Extensive Stage encompasses all other SCLC patients.

Patients with ES-SCLC are often treated with chemoimmunotherapy with or without radiation in the first line setting. Second-line treatment options are limited, and the response duration is short varying from 3-5 months, with Overall Survival rarely exceeding 8 months. There are presently no approved therapies for third line and beyond and these patients face a dire prognosis.

Delta-like protein 3 also known as DLL3, is encoded by the DLL3 gene and is expressed on the surface of tumor cells but not in normal adult tissues. Patients with high-grade pulmonary NeuroEndocrine Tumors, Small Cell Lung Cancer (SCLC) and Large Cell NeuroEndocrine Carcinoma (LCNEC) have increased expression of DLL3 protein (increased expression seen in approximately 85-96% of the SCLC tumors), making this a a potential target in the treatment of Small Cell Lung Cancer.

Tarlatamab is a first-in-class bispecific T-cell engager immunotherapy that directs the patient’s T cells to cancer cells expressing delta-like ligand 3 (DLL3), independent of major histocompatibility complex (MHC) class I. Tarlatamab binds to both DLL3 on cancer cells and CD3 on T cells, leading to T-cell–mediated lysis of cancer cells.

The present FDA approval was based on the efficacy of Tarlatamab in the open-label, global, multicenter, multi-cohort, Phase 2 DeLLphi-301 trial, which included patients with Relapsed/Refractory Extensive Stage Small Cell Lung Cancer with disease progression after platinum-based chemotherapy. In this Phase 2 study, patients received a step dose of Tarlatamab 1 mg IV on day 1 of cycle 1, after which they received the target dose of either 10 mg or 100 mg on day 8 and day 15 of cycle 1 and every 2 weeks thereafter in 28-day cycles (two doses per cycle) until disease progression or unacceptable toxicity. Overall 134 patients received Tarlatamab 10 mg IV, the median age in this group was 64 years and the median duration of treatment in this group was 5.1 months. Positivity for DLL3 expression on tumor cells was not required for trial entry and patients with symptomatic brain metastases, interstitial lung disease or non-infectious pneumonitis, and active immunodeficiency were excluded.

The Primary end point was Objective Response Rate (Complete or Partial Response), as assessed by Blinded Independent Central Review. Secondary end points included Duration of Response, Progression-Free Survival and Overall Survival. Efficacy was evaluated in 99 patients with disease progression enrolled in this study, who received Tarlatamab 10 mg IV, following platinum-based chemotherapy.

The Objective Response Rate was 40% and median Duration of Response was 9.7 months. The researchers noted that this Objective Response Rate far exceeded the historical control benchmark of 15% for the Primary end point. Of the 69 patients with available data regarding platinum sensitivity status, the ORR was 52% in 27 patients with platinum-resistant Small Cell Lung Cancer (defined as progression less than 90 days after last dose of platinum therapy) and 31% in 42 patients with platinum-sensitive Small Cell Lung Cancer (defined as progression 90 or more days after last dose of platinum therapy). The median Overall Survival was 14.3 months, with final and complete survival data still not mature. The most common adverse reactions were Cytokine Release Syndrome (CRS), fatigue, pyrexia, dysgeusia, decreased appetite, musculoskeletal pain, and constipation, anemia and nausea.

It was concluded that Tarlatamab represents a new immunotherapeutic approach for Small Cell Lung Cancer. It is the first and only DLL3-targeting Bispecific T-cell Engager therapy, establishing itself as an effective and innovative treatment option for patients with previously treated Small Cell Lung Cancer.

Tarlatamab for Patients with Previously Treated Small-Cell Lung Cancer. Ahn M-J, Cho BC, Felip E, et al. for the DeLLphi-301 Investigators. N Engl J Med 2023;389:2063-2075

FDA Approves BREYANZI® for Relapsed/Refractory Follicular Lymphoma

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SUMMARY: The FDA on May 15, 2024, granted accelerated approval to BREYANZI® (Lisocabtagene maraleucel) for adults with Relapsed or Refractory Follicular Lymphoma who have received two or more prior lines of systemic therapy. The American Cancer Society estimates that in 2024, about 80,620 people will be diagnosed with Non-Hodgkin Lymphoma (NHL) in the United States and about 20,140 individuals will die of this disease. Indolent Non-Hodgkin Lymphomas are mature B cell lymphoproliferative disorders and include Follicular Lymphoma, Nodal Marginal Zone Lymphoma (NMZL), Extranodal Marginal Zone Lymphoma (ENMZL) of Mucosa-Associated Lymphoid Tissue (MALT), Splenic Marginal Zone Lymphoma (SMZL), LymphoPlasmacytic Lymphoma (LPL) and Small Lymphocytic Lymphoma (SLL).

Follicular Lymphoma is the most indolent form and second most common form of all NHLs and they are a heterogeneous group of lymphoproliferative malignancies. Approximately 20% of all NHLs are Follicular Lymphomas and the average age of diagnosis is 65 years. Advanced stage indolent NHL is not curable and as such, prolonging Progression Free Survival (PFS) and Overall Survival (OS), while maintaining Quality of Life, have been the goals of treatment intervention. Asymptomatic patients with indolent NHL are generally considered candidates for “watch and wait” approach. Patients with advanced stage symptomatic Follicular Lymphoma are often treated with induction chemoimmunotherapy followed by maintenance RITUXAN® (Rituximab). This can result in a median Progression Free Survival (PFS) of 6-8 yrs and a median Overall Survival (OS) of 12-15 yrs. However, approximately 30% of the patients will relapse in 3 years, with prognosis worsening after each subsequent relapse. Despite advances in treatment for Follicular Lymphoma, there remains an unmet need for additional options that offer treatment-free intervals with durable, complete responses.

Chimeric Antigen Receptor (CAR) T-cell therapy is a type of immunotherapy and consists of T cells collected from the patient’s blood in a leukapheresis procedure, and genetically engineered to produce special receptors on their surface called Chimeric Antigen Receptors (CAR). These reprogrammed cytotoxic T cells with the Chimeric Antigen Receptors on their surface are now able to recognize a specific antigen on tumor cells. These genetically engineered and reprogrammed CAR T-cells are grown in the lab and are then infused into the patient. These cells in turn proliferate in the body of patients and the engineered receptor on the cell surface help recognize and kill cancer cells that expresses that specific antigen.

Patients, following treatment with CAR T-cells, develop B-cell aplasia (absence of CD19 positive cells) due to B-cell destruction and may need immunoglobin replacement. Hence, B-cell aplasia can be a useful therapeutic marker, as continued B-cell aplasia has been seen in all patients who had sustained remission, following CAR T-cell therapy. Cytokine Release Syndrome, an inflammatory process, is the most common and serious side effect of CAR T-cell therapy and is associated with marked elevation of Interleukin-6. Cytokine release is important for T-cell activation and can result in high fevers and myalgias. This is usually self limiting although if severe can be associated with hypotension and respiratory insufficiency. Tocilizumab (ACTEMRA®), an Interleukin-6 receptor blocking antibody, produces a rapid improvement in symptoms. This is however not recommended unless the symptoms are severe and life threatening, as blunting the cytokine response can in turn negate T-cell proliferation. Elevated serum ferritin and C-reactive protein levels are surrogate markers for severe Cytokine Release Syndrome. The CAR T-cells have been shown to also access sanctuary sites such as the CNS and eradicate cancer cells. CD19 antigen is expressed by majority of the B-cell malignancies and therefore most studies using CAR T-cell therapy have focused on the treatment of advanced B-cell malignancies.

BREYANZI® is a CD19-directed genetically modified autologous T cell immunotherapy, that seeks out cancer cells expressing the antigen CD19, which is found uniquely on B cells and destroy them. BREYANZI® contains a 4-1BB costimulatory domain, which enhances the expansion and persistence of the CAR T cells. BREYANZI® was previously approved in the US for the treatment of Relapsed or Refractory Large B-Cell Lymphoma (LBCL) after at least one prior line of therapy, and also received accelerated approval for the treatment of Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma after at least two prior lines of therapy.

TRANSCEND-FL is a global, multicenter, open-label, single-arm Phase II trial which included patients with Relapsed or Refractory Follicular Lymphoma after two or more lines of systemic therapy including an anti-CD20 antibody and an alkylating agent. This study included 94 eligible patients (N=94) and these patients also needed to have an ECOG PS of 1 or less, as well as adequate bone marrow function to receive lymphodepleting chemotherapy. Eligible patients had PET-positive disease at baseline or after bridging therapy and had at least 9 months of follow up from first response. Patients were excluded if they had evidence or a history of composite Diffuse Large B-Cell Lymphoma and Follicular Lymphoma, or transformed Follicular Lymphoma, a WHO subclassification of duodenal-type Follicular Lymphoma, CNS-only involvement by malignancy, or prior CAR T-cell therapy or other genetically modified cell therapy. Following apheresis and collection of T cells, patients received lymphodepleting chemotherapy consisting of Fludarabine 30 mg/m2 IV and Cyclophosphamide 300 mg/m2 IV daily for 3 days. Patients could receive bridging therapy for disease control following apheresis and prior to lymphodepletion and subsequent administration of BREYANZI®. Patients received a single dose of BREYANZI® 2-7 days, following the completion of lymphodepleting chemotherapy at a target dose of 100 x 106 CAR-positive T cells.

The Primary efficacy endpoint was the Overall Response Rate (ORR), defined as the percentage of patients achieving a Partial or Complete Response per Lugano criteria as assessed by an Independent Review Committee (IRC). Secondary endpoints included Complete Response (CR) rate, Duration of Response (DOR), Progression-Free Survival (PFS), Overall Survival (OS), and Safety. Responses were evaluated using PET scans, providing a comprehensive assessment of treatment efficacy.

The study demonstrated impressive efficacy outcomes, with an ORR of 95.7% and a CR rate of 73.4% in the primary analysis set. Responses were rapid, with a median time to response of one month. After a median follow up of 16.8 months, the median Duration of Response was Not Reached. Approximately 81% of responders remained in response at 12 months, and 77% of responders remained in response at 18 months, underscoring the potential of this therapy to induce long-lasting remissions. The most common non-laboratory adverse reactions were Cytokine Release Syndrome (CRS), headache, musculoskeletal pain, fatigue, constipation, and fever.

In this largest primary analysis assessing CAR T-cell therapy for Relapsed or Refractory Follicular Lymphoma, a treatment option with a one-time infusion of BREYANZI® with the potential for lasting remission, addresses the unmet need of these patients, heralding a new era in the management of this challenging disease.

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-lisocabtagene-maraleucel-follicular-lymphoma