Category: Meeting Updates

Late Breaking Abstract – ASCO 2023: ENHERTU® Effective in Multiple HER2 Expressing Solid Tumors

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SUMMARY: The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers as well as advanced Gastric and GastroEsophageal (GE) junction cancers overexpress or have amplification of the HER2 oncogene. These patients often receive first line treatment with a combination of chemotherapy plus anti-HER2 antibody. Several other cancer types including gynecologic and urothelial cancers overexpress HER oncogene.

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.

ENHERTU® is approved by the FDA for use in unresectable or metastatic HER2-positive breast cancer, HER2-low breast cancer, HER2-mutant non–small cell lung cancer, and locally advanced or metastatic HER2-positive gastric cancer. ENHERTU® in a Phase I trial, demonstrated clinically meaningful activity in multiple advanced solid tumors expressing HER2 oncogene.

DESTINY-PanTumor-02 is an international, open-label Phase II study conducted to evaluate the effectiveness of ENHERTU® in patients with HER2-expressing biliary tract, bladder, cervical, endometrial, ovarian, pancreatic, or other tumors. This study involved 267 patients (N=267) across 7 different cohorts, including 6 tumor-specific cohorts (urothelial bladder, biliary tract, cervical, endometrial, ovarian, and pancreatic cancers) as well as a rare tumor cohort that included several other tumor types for which ENHERTU® is currently either not available or not being investigated (including head and neck cancers and intestinal adenocarcinoma). Patients with breast, gastric, colorectal and non-small cell lung cancers were excluded. Patients in this study had HER2-expressing (IHC 3+ or IHC 2+) locally advanced or metastatic disease that progressed after at least one systemic treatment or that had no treatment options. Among those studied 75 patients were IHC 3+ and 125 were IHC 2+ by central testing. Study patients were treated with at least one dose of ENHERTU® 5.4 mg/kg IV every 3 weeks and efficacy and safety were analyzed in all patients who received one or more doses of ENHERTU®. The Primary endpoint was investigator-assessed confirmed Objective Response Rate (ORR). Secondary endpoints included Duration of Response (DOR), Disease Control Rate, Progression Free Survival (PFS), Overall Survival, and Safety.

At data cutoff and after a median follow-up, 9.7 months, the ORR among all patients was 37.1% with a median DOR of 11.8 months. In patients with IHC 3+ expression, the ORR was 61.3% and the median DOR was 22.1 months whereas among those patients with IHC 2+ expression, the ORR was 27.2% and the median DOR was 9.8 months.

Treatment with ENHERTU resulted in the following Objective Response Rates across different tumor types:
• Endometrial cancer: 57.5% for all patients, 84.6% for IHC 3+, and 47.1% for IHC 2+
• Cervical cancer: 50% for all patients, 75% for IHC 3+, 40% for IHC 2+
• Ovarian cancer: 45% for all patients, 63.6% for IHC 3+, 36.8% for IHC 2+
• Urothelial cancer: 39% for all patients, 56.3% for IHC 3+, 35% for IHC 2+
• Biliary tract cancer: 22% for all patients, 56.3% for IHC 3+, 0% for IHC 2+
• Pancreatic cancer: 4% for all patients, 0% for IHC 3+, 5.3% for IHC 2+

The most common treatment-related side effects were nausea, fatigue, and cytopenias and there were no new safety signals.

It was concluded from this study results that ENHERTU® is a potential new treatment option for patients with HER2-expressing solid tumors, based on the encouraging Objective Response Rate, durable clinical benefit, and a manageable safety profile, in this heavily pretreated population. The authors added that this is the first tumor-agnostic global study of ENHERTU® in a broad range of HER2-expressing solid tumors.

Efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-expressing solid tumors: DESTINY-PanTumor02 (DP-02) interim results. Meric-Bernstam F, Makker V, Oaknin A, et al. J Clin Oncol 41, 2023 (suppl 17; abstr LBA3000)

Late Breaking Abstract – ASCO 2023: Avoiding Radiation Therapy in Select Patients with Locally Advanced Rectal Cancer

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SUMMARY: The American Cancer Society estimates that 46,050 new cases of rectal cancer will be diagnosed in the US in 2023. Based on the information from the SEER database, the 5-year relative survival rates for rectal cancer all SEER stages combined is 67%.

Management of invasive locally advanced rectal cancer, defined as Stage II (T3-4, N0) or Stage III (T1-4, N+) disease, mandates a multidisciplinary approach. Neoadjuvant chemoradiation therapy (CRT) followed by Total Mesorectal Excision (TME) and adjuvant chemotherapy is often recommended, whereas standard therapy for early-stage lesions involves surgery with or without adjuvant chemoradiation. The trimodality treatment approach was established as the standard of care for locally advanced rectal cancer based on the findings from the landmark German trial. Preoperative neoadjuvant CRT decreased the local recurrence rate in the pelvis from 25% to less than 10%. However, this treatment modality is associated with short-term and long-term toxicities and can adversely affect quality of life and physical function. With regards to chemotherapy, 4 months of adjuvant systemic chemotherapy following 2 months of Fluoropyrimidine-based chemotherapy with concurrent RT and surgery, is the recommended guideline by the National Comprehensive Cancer Network.

More recently, optimizing the delivery of therapy by intensifying neoadjuvant treatment has gained popularity. Moving chemotherapy from the postoperative (adjuvant) to the preoperative setting allows administration of full doses of systemic treatment with fewer adverse events and better compliance, assessment of the tumor response after neoadjuvant therapy, down staging tumors to increase the likelihood of pathological Complete Response (pCR) and complete resection, as well as opportunities for the selective omission of Radiation Therapy. Further, earlier administration of uninterrupted systemic chemotherapy can potentially eradicate occult micrometastases and help assess chemosensitivity.

FOLFOX chemotherapy regimen has been shown to be associated with high response rates when administered before chemoradiotherapy in patients with locally advanced rectal cancer. In a single institution study, neoadjuvant FOLFOX resulted in favorable outcomes, with few patients requiring radiation therapy and none of the patients developing local recurrence.

The PROSPECT trial is a multicenter, unblinded, noninferiority, randomized Phase III study, conducted to investigate whether neoadjuvant treatment with FOLFOX chemotherapy regimen could allow the elimination of chemoradiotherapy, without increasing the risk of recurrence, in patients with locally advanced rectal cancer that was amenable to sphincter-sparing surgery. This study was designed to test the hypothesis that neoadjuvant FOLFOX (with chemoradiotherapy given only if the primary tumor decreased in size by less than 20% or if FOLFOX was discontinued because of side effects) would be noninferior to neoadjuvant chemoradiotherapy alone, in patients with locally advanced rectal cancer that was amenable to sphincter-sparing surgery.

Eligible patients had pathologically confirmed, locally advanced rectal cancer that had been clinically staged as T2 node-positive, T3 node-negative, or T3 node-positive, and who were candidates for sphincter-sparing surgery. This group accounts for more than half the patients with a diagnosis of locally advanced rectal cancer in the United States. Patients with T4 tumors, four or more pelvic lymph nodes larger than 10 mm, or tumor visible within 3 mm of the radial margin seen on baseline pelvic imaging were ineligible. All patients had a pelvic MRI or contrast-enhanced CT of the chest, abdomen, and pelvis plus endorectal ultrasonography at baseline.

Patients were randomized 1:1 to neoadjuvant FOLFOX (N=585) or chemoradiotherapy (N=543). Patients in the FOLFOX group received 6 cycles of modified FOLFOX6 administered IV every 2 weeks, followed by restaging with pelvic imaging and rectal endoscopy. Patients whose primary tumor had decreased in size by at least 20% underwent surgery. Postoperative chemoradiotherapy was recommended for patients in the FOLFOX group whose resection was not pathologically complete (R0). Patients who were unable to complete at least five cycles of FOLFOX and those whose primary tumor had decreased in size by less than 20% also received chemoradiotherapy. Patients in the chemoradiotherapy group received pelvic radiotherapy with 50.4 Gy delivered in 28 fractions, along with either continuous infusion 5-FU chemotherapy given as a radiosensitizer at a dose of 225 mg/m2 daily or Capecitabine 825 mg/m2 orally twice daily, 5 days per week on days of radiation therapy. The median age was 57 years, a third of the patients were women and approximate 62% had clinically positive lymph nodes. Majority of tumors were in the mid-rectum, with a median distance of 8 cm from the anal verge The Primary end point was Disease Free Survival. Secondary end points included Overall Survival, local recurrence (in a time-to-event analysis), complete pathological resection, Complete Response, and toxicities.

At a median follow up of 58 months, FOLFOX was noninferior to chemoradiotherapy and the study met its Primary endpoint for DFS (HR for disease recurrence or death, 0.92; P=0.005 for noninferiority). Five-year DFS was 80.8% in the FOLFOX group and 78.6% in the chemoradiotherapy group. The Overall Survival was similar in the two treatment groups and the percentage of patients free from local recurrence was also similar in the two groups and exceeded 98% at 5 years. In the FOLFOX group, only 9.1% received preoperative chemoradiotherapy and only 1.4% received postoperative chemoradiotherapy. Over 89% of patients assigned to receive neoadjuvant FOLFOX were ultimately able to avoid receiving chemoradiotherapy.

The authors concluded that in patients with locally advanced rectal cancer who were eligible for sphincter-sparing surgery, preoperative FOLFOX chemotherapy with selective use of chemoradiotherapy was noninferior to preoperative chemoradiotherapy with nearly identical outcomes. These data provide additional treatment options for this patient group without compromising efficacy, and toxicities associated with radiation therapy can be avoided.

Preoperative Treatment of Locally Advanced Rectal Cancer. Schrag D, Shi Q, Weiser MR, et al. June 4, 2023. DOI: 10.1056/NEJMoa2303269

Late Breaking Abstract – ASCO 2023: Overall Survival with TAGRISSO® in Resected EGFR-Mutated 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 2023, about 238,340 new cases of lung cancer will be diagnosed and 127,070 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. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

Approximately 10-15% of Caucasian patients and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR (Epidermal Growth Factor Receptor) mutations and 90% of these mutations are either Exon 19 deletions or L858R substitution mutation in Exon 21. Approximately 25% of patients with EGFR mutated NSCLC have brain metastases at diagnosis, increasing to approximately 40% within two years of diagnosis. The presence of brain metastases often reduces median survival to less than eight months. EGFR-Tyrosine Kinase Inhibitors (TKIs) such as TARCEVA® (Erlotinib), IRESSA® (Gefitinib) and GILOTRIF® (Afatinib), have demonstrated a 60-70% response rate as monotherapy when administered as first line treatment, in patients with metastatic NSCLC, who harbor the sensitizing EGFR mutations. However, majority of these patients experience disease progression within 9-14 months. This resistance to frontline EGFR TKI therapy has been attributed to the most common, acquired T790M “gatekeeper” point mutation in EGFR, identified in 50-60% of patients.

TAGRISSO® (Osimertinib) is a highly selective third-generation Epidermal Growth Factor Receptor (EGFR) 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. Further, TAGRISSO® has higher CNS penetration and is therefore able to induce responses in 70-90% of patients with brain metastases. Among patients with metastatic, EGFR-mutant NSCLC, first-line treatment with TAGRISSO® significantly improved median Overall Survival, compared with TARCEVA® and IRESSA®, and should therefore be considered the preferred regimen.

Surgical resection is the primary treatment for approximately 30% of patients with NSCLC who present with early Stage (I–IIIA) disease. These patients are often treated with platinum-based adjuvant chemotherapy to decrease the risk of recurrence. Nonetheless, 45-75% of these patients develop recurrent disease. There is therefore an unmet need for this patient population.

ADAURA is a global, double-blind, randomized Phase III study, which assessed the efficacy and safety of TAGRISSO® versus placebo in patients with Stage IB–IIIA EGFR mutated NSCLC, after complete tumor resection and adjuvant chemotherapy, when indicated. In this study, 682 patients with completely resected Stage IB, II, IIIA NSCLC, with or without postoperative adjuvant chemotherapy, were randomly assigned 1:1 to receive either TAGRISSO® 80 mg orally once daily (N=339) or placebo (N=343) once daily, for up to 3 years. Eligible patients had an ECOG Performance Status of 0 or 1, with confirmed EGFR mutations (Exon 19del or L858R). Treatment groups were well balanced and patients were stratified by Stage (IB/II/IIIA), mutation type (Exon 19del/L858R), and race (Asian/non-Asian). Most patients with Stage II to IIIA disease (76%) and approximately a quarter of the patients with Stage IB disease (26%) received adjuvant platinum-based chemotherapy. The Primary endpoint was Disease Free Survival (DFS) in Stage II–IIIA patients. Secondary endpoints included DFS in the overall population of patients with Stage IB to IIIA disease, Overall Survival (OS) and Safety. Following Independent Data Monitoring Committee recommendation, the trial was unblinded early, due to efficacy.

The FDA approved TAGRISSO® for use as adjuvant treatment in late 2020 based on the primary analysis data demonstrating that in the patients with Stage II/IIIA disease, the DFS had not been reached with TAGRISSO® versus 19.6 months with placebo (HR=0.17; P<0.001). This was equal to an 83% reduction in the risk of recurrence or death, indicating a significantly longer DFS among patients in the TAGRISSO® group, compared to those in the placebo group. The 2-year DFS rate in this patient group with TAGRISSO® was 90% versus 44% with placebo. In the overall population, which included Stage IB to IIIA disease, the median DFS was not reached with TAGRISSO® versus 27.5 months with placebo (HR=0.20; P<0.001). This Hazard Ratio equaled to an 80% reduction in the risk of disease recurrence or death among patients in the TAGRISSO® group compared to those in the placebo group. The 2-year DFS rate in the overall population was 89% with TAGRISSO® versus 52% with placebo. Updated data presented at the 2022 ESMO Congress showed that at a median follow up of 44.2 months, the DFS with TAGRISSO® was still robust at 77% in patients with Stage II/IIIA disease and 73% in the overall Stage IB-IIIA population.

The researchers herein reported the planned final Overall Survival (OS) analysis from ADAURA. Adjuvant TAGRISSO® significantly improved OS compared to placebo and reduced the risk of death by 51% compared to placebo in both Stages II-IIIA (HR for OS=0.49; P=0.0004), and in the overall Stages IB-IIIA trial population (HR=0.49; P<0.0001). This survival benefits with TAGRISSO® was seen, regardless of whether prior adjuvant chemotherapy was received. The 5-year OS rate was 88% in the TAGRISSO® group and 78% in the placebo group. Median OS was not reached in either population or treatment group. The safety profile with adjuvant TAGRISSO® was consistent with that in the primary analysis.

It was concluded that adjuvant TAGRISSO® demonstrated an unprecedented, highly statistically significant and clinically meaningful Overall Survival benefit in patients with EGFR mutated Stage IB–IIIA NSCLC after complete tumor resection, with or without adjuvant chemotherapy. The authors added that ADAURA is the first global Phase III study to demonstrate a statistically significant Disease Free Survival and Overall Survival benefit with targeted treatment for this patient group, reinforcing the importance of testing for biomarkers at the time of diagnosis and before starting therapy.

Overall Survival with Osimertinib in Resected EGFR-Mutated NSCLC. Tsuboi M, Herbst RS, John T, et al., for the ADAURA Investigators. June 4, 2023. DOI: 10.1056/NEJMoa2304594

Significant Survival Benefit with NALIRIFOX in Previously Untreated Metastatic Pancreatic Cancer

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SUMMARY: The American Cancer Society estimates that in 2023, about 64,050 people will be diagnosed with Pancreatic cancer and 50,550 people will die of the disease. Pancreatic cancer is the fourth most common cause of cancer-related deaths in the United States and Western Europe. Unfortunately, unlike other malignancies, very little progress has been made and outcome for patients with advanced Pancreatic cancer has been dismal, with a 5-year survival rate for metastatic Pancreatic cancer of approximately 10%. Pancreatic cancer has surpassed breast cancer as the third leading cause of cancer death in the United States and is on track to surpass colorectal cancer, to move to the second leading cause of cancer related deaths in the United States. Majority of patients with Pancreatic cancer (80% of cases) are diagnosed at an advanced stage, and are not amenable to curative surgical resection, at the time of diagnosis. The current treatment regimens for advanced disease have proved ineffective, conferring a median Overall Survival (OS) of 6-8 months.

ONIVYDE® is a novel nanoliposomal encapsulation of Irinotecan, a topoisomerase 1 inhibitor. It is designed to optimize the delivery of Irinotecan, by extending the duration of circulation of the drug in the body and preferentially activating the drug within the tumor tissues, to achieve higher levels of the active cytotoxic drug metabolite, SN-38. This approach reduces the toxicity of Irinotecan to normal tissues while maintaining or increasing its anti-tumor efficacy.

In the NAPOLI-1 open-label Phase III study, a combination of ONIVYDE®, 5-FU and Leucovorin improved Overall Survival, Progression Free Survival, CA19-9 response and Disease Control Rate following Gemcitabine-based therapy, in patients with metastatic Pancreatic adenocarcinoma. ONIVYDE® in combination with Fluorouracil (5-FU) and Leucovorin was approved for this indication in 2015. In a Phase I/II study, ONIVYDE® in combination with 5-FU, Leucovorin and Oxaliplatin (NALIRIFOX) demonstrated promising anti-tumor activity in patients with metastatic Pancreatic ductal adenocarcinoma.

NAPOLI 3 is a global, randomized, open-label Phase III trial which tested the safety and efficacy of NALIRIFOX regimen in treatment naïve patients with metastatic Pancreatic ductal adenocarcinoma. In this study, 770 patients with histopathologically/cytologically confirmed untreated metastatic Pancreatic ductal adenocarcinoma were randomized in a 1:1 ratio to receive NALIRIFOX (N=383) or Gemcitabine plus nab-Paclitaxel (N=387). The NALIRIFOX regimen consisted of ONIVYDE® 50 mg/m2 IV, given along with 5-FU 2400 mg/m2 IV, Leucovorin 400 mg/m2 IV and Oxaliplatin 60 mg/m2 IV on days 1 and 15 of a 28-day cycle. Patients in the Gemcitabine/nab-Paclitaxel group received Gemcitabine 1000 mg/m2 IV along with nab-Paclitaxel 125 mg/m2 IV, on days 1, 8 and 15 of a 28-day cycle. Both treatment groups were well balanced with similar baseline characteristics, including median age of 64.5 years and number of metastatic sites (three or greater in 37% of patients). Approximately 80% of patients had liver metastases. Patients were stratified by ECOG performance status, geographic region, and presence or absence of liver metastases. The Primary endpoint was Overall Survival (OS) and Secondary endpoints included were Progression Free Survival (PFS), Overall Response Rate (ORR) and Safety.

At a median follow-up of 16.1 months, the median OS was 11.1 months in the NALIRIFOX group versus 9.2 months in the Gemcitabine plus nab-Paclitaxel arm (HR=0.83; P=0.04). The 12 months OS rate was 45.6% versus 39.5%, and 18 months OS rate was 26.2% versus 19.3% respectively. There was also a significant improvement in the PFS at 7.4 months versus 5.6 months respectively (HR=0.69; P=0.0001). The 12 months PFS rate was 27.4% versus 13.9%, and 18 months PFS rate was 11.4% versus 3.6% respectively. This OS and PFS benefit was observed across subgroups.

The NALIRIFOX group also had a higher Objective Response Rate at 41.8% versus 36.2% for patients treated with Gemcitabine and nab-Paclitaxel group, and the median Duration of Response was 7.3 months versus 5.0 months respectively. A lower percentage of patients who received NALIRIFOX went on to receive subsequent anticancer therapy (50.5% versus 54.4%). Treatment related toxicities associated with NALIRIFOX regimen were manageable and included a higher incidence of diarrhea, nausea and hypokalemia.

It was concluded that first-line treatment with NALIRIFOX regimen demonstrated clinically meaningful and statistically significant improvement in Overall Survival and Progression Free Survival, compared with Gemcitabine and nab-Paclitaxel, in treatment-naïve patients with metastatic Pancreatic ductal adenocarcinoma.

Liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin (NALIRIFOX) versus nab-paclitaxel + gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): 12- and 18-month survival rates from the phase 3 NAPOLI 3 trial. O’Reilly EM, Melisi D, Macarulla T, et al. J Clin Oncol. 2023;41(suppl 16):4006. doi:10.1200/JCO.2023.41.16_suppl.4006

Late Breaking Abstract – ASCO 2023: Adjuvant Treatment with Ribociclib in Early 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. It is estimated that approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 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 that blocks 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 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 Safety, Quality of Life, and Overall Survival.

At a median follow up of 34 months, as of data cutoff, 74.7% of patients remained on study treatment, with 1,984 patients on Ribociclib and 1,826 patients on Endocrine Therapy alone. 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 3-year invasive DFS rates were 90.4% in the Ribociclib group, compared with 87.1% in the Endocrine Therapy alone. This invasive DFS benefit was generally consistent across stratification factors and other subgroups. There was a trend towards improvement in Overall Survival with the addition of Ribociclib, although further follow up is needed. This regimen had a favorable safety profile with no new safety signals.

It was concluded from this study that the addition of Ribociclib to Endocrine Therapy demonstrated a statistically significant, clinically meaningful improvement in invasive Disease Free Survival, with a well-tolerated safety profile. The authors added that this study results support the addition of Ribociclib to Endocrine Therapy as the treatment of choice in a broad group of patients with Stage II or III HR+/HER2-negative early breast cancer, including those with high risk node negative disease. The lower dose of Ribociclib chosen in this study and given over an extended 3-year period may be important to prolong cell cycle arrest and drive more tumor cells into senescence or death.

Ribociclib and endocrine therapy as adjuvant treatment in patients with HR+/HER2- early breast cancer: Primary results from the phase III NATALEE trial. Slamon DJ, Stroyakovskiy D, Yardley DA, et al. DOI: 10.1200/JCO.2023.41.17_suppl.LBA500 Journal of Clinical Oncology 41, no. 17_suppl (June 10, 2023) LBA500-LBA500.

Pembrolizumab Plus Chemotherapy Improves Overall Survival in Advanced Biliary Tract Cancer

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SUMMARY: Bile Tract cancer (Cholangiocarcinoma) is a rare and highly aggressive heterogenous cancer, and is the second most common type of primary liver cancer after Hepatocellular carcinoma. It comprises about 30% of all primary liver tumors and includes both intrahepatic and extrahepatic bile duct cancers. It is estimated that approximately 211,000 patients are diagnosed with Biliary Tract cancer and 174,000 patients will die of the disease each year globally. Biliary Tract cancer is most frequently diagnosed in patients between 50 to 70 years old, and 75% of patients are diagnosed at an advanced stage. Klatskin tumor is a type of Cholangiocarcinoma that begins in the hilum, at the junction of the left and right bile ducts. It is the most common type of Cholangiocarcinoma, accounting for more than half of all cases. About 8,000 people in the US are diagnosed with Cholangiocarcinoma each year and approximately 20% of the cases are suitable for surgical resection. Patients diagnosed with Biliary Tract cancer have a very poor prognosis, and the 5-year survival among those with advanced stage disease is less than 10%, with limited progress made over the past two decades. There is therefore an urgent unmet need for new effective therapies.

Patients with advanced Biliary Tract cancers often receive chemotherapy in the first and second line settings, with limited benefit. Gemcitabine and Cisplatin combination is currently the first line standard-of-care treatment. With the recognition of immunogenic features displayed by Biliary Tract cancers, the role of immune checkpoint inhibitors for improving disease control and prolonging survival has been increasingly explored.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. By doing so, it unleashes the tumor-specific effector T cells, and is thereby able to undo PD-1 pathway-mediated inhibition of the immune response.

KEYNOTE-966 is a multinational, randomized, double-blind, Phase III trial, conducted to determine whether adding the immune checkpoint inhibitor Pembrolizumab to first line standard chemotherapy, would impact survival outcomes in patients with metastatic or unresectable Biliary Tract cancers. In this study, 1069 patients (N=1069) with advanced and/or unresectable Biliary Tract cancers were randomly assigned to receive Pembrolizumab 200 mg IV every 3 weeks for up to 35 cycles (N=533) or placebo (N=536). Both treatment groups received Gemcitabine 1000 mg/m2 IV on days 1 and 8 every 3 weeks without preset maximum number of cycles, and Cisplatin 25 mg/m2 IV on days 1 and 8 every 3 weeks for up to 8 cycles. The median age was 63.5 years, majority of patients had metastatic disease (88%) and more than half had intrahepatic disease. The Primary endpoint was Overall Survival (OS). Secondary endpoints included Progression Free Survival (PFS), Objective Response Rate (ORR), Duration of Response and Safety. The median follow up was 25.6 months.

The median OS was 12.7 months in the Pembrolizumab group and 10.9 months in the placebo group (HR=0.83; P=0.0034). This represented a 17% reduction in the risk of death in the Pembrolizumab group compared to the placebo group. The 12-month OS rate was 52% with the Pembrolizumab regimen versus 44% for chemotherapy alone and the 24-month OS rates were 24.9% versus 18.1%, respectively. The OS results were generally consistent across subgroups.

There was no significant difference in PFS between the treatment groups but there was a trend toward improved PFS with Pembrolizumab. The median PFS was 6.5 months in the Pembrolizumab arm and 5.6 months in the placebo group (HR=0.87; P=0.23). The estimated 12-month PFS was 25% and 20% respectively.The Objective Response Rates were similar between the two treatment groups – 28.7% in the Pembrolizumab group and 28.5% in the placebo arm.The safety profile of Pembrolizumab was consistent with that observed in previously reported studies and Grade 3-4 adverse events were similar between treatment groups.

The authors concluded that KEYNOTE-966 is the largest randomized Phase III trial in advanced Biliary Tract cancers to date, with more patients enrolled from non-Asian countries. First line treatment with Pembrolizumab plus chemotherapy significantly improved Overall Survival, when compared with chemotherapy alone. The researchers added that one of the limitations of this study is that patients with intrahepatic bile duct cancers were overrepresented in the study population compared with the incidence of the disease in the general population, resulting in smaller sample sizes of patients with extrahepatic and gall bladder sites of origin.

Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): A randomised, double-blind, placebo-controlled, phase 3 trial. Kelley RK, Ueno M, Yoo C, et al. Lancet. Published online April 16, 2023. https://doi.org/10.1016/S0140-6736(23)00727-4.

Personalized mRNA Cancer Vaccine in Combination with KEYTRUDA® Improves Relapse Free Survival in Resected High Risk Melanoma

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SUMMARY: The American Cancer Society’s estimates that for 2023, about 97,610 new cases of melanoma of the skin will be diagnosed in the United States and 7,990 people are expected to die of the disease. The rates of melanoma have been rising rapidly over the past few decades, but this has varied by age. Surgical resection with a curative intent is the standard of care for patients with early stage melanoma.
Immune Checkpoint Inhibitors are the standard of care adjuvant treatment for high-risk resected melanoma. In the KEYNOTE-054 trial, the 5-year Relapse Free Survival (RFS) with adjuvant Pembrolizumab was 55.4% versus 38.3% with placebo. In the CHECKMATE-238 trial, the 4-year RFS rate was of 51.7% for Nivolumab versus 41.2% for ipilimumab. Given the high relapse rates with the present adjuvant melanoma therapies, there is an unmet clinical need.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. By doing so, it unleashes the tumor-specific effector T cells, and is thereby able to undo PD-1 pathway-mediated inhibition of the immune response.

mRNA-4157 (V940) is a novel messenger RiboNucleic Acid (mRNA)-based individualized neoantigen therapy consisting of a single synthetic mRNA coding for up to 34 neoantigens, that is designed and produced based on the unique mutational signature of the DNA sequence of the patients tumor. Individualized neoantigen therapies are designed to prime the immune system so that a patient can generate a tailored antitumor response specific to their tumor mutation signature. mRNA-4157 (V940) was designed to stimulate an immune response by generating specific T cell responses based on the unique mutational signature of a patient’s tumor. Early clinical studies demonstrated that combining mRNA-4157 (V940) with Pembrolizumab may potentially provide an additive benefit and enhance T cell-mediated destruction of tumor cells.

KEYNOTE-942 is a randomized Phase IIb trial, which assessed the efficacy of mRNA-4157/V940 in prolonging RFS in patients with resected, Stages IIIB/IIIC/IIID and IV melanoma, when given in combination with Pembrolizumab, the standard of care adjuvant therapy in this patient population. This study included 157 patients who were randomly assigned (2:1) to receive mRNA-4157/V940 in combination with Pembrolizumab (107 patients) or Pembrolizumab alone (50 patients). The vaccine was administered every three weeks for a total of nine doses, and Pembrolizumab was given at 200 mg IV every three weeks for up to 18 cycles (approximately one year). All patients had tumor sample (Formalin Fixed Paraffin Embedded-FFPE) available for Next Generation Sequencing and patients were stratified by disease stage. mRNA-4157/V940 was successfully prepared for more than 99% of patients in the combination arm. The median patient age was 62 years and 84% of patient had Stage IIIC disease. Approximately 64% of patients were PD-L1 positive and 74% had high Tumor Mutational Burden-TMB (10 or more mutations/Mb) in the combination treatment group, and 54% were PD-L1 positive and 60% had high TMB in the single agent Pembrolizumab group, respectively. The Primary endpoint was Relapse Free Survival (RFS), defined as the time from first dose of Pembrolizumab until the date of first recurrence (local, regional, or distant metastasis), a new primary melanoma, or death from any cause. Secondary endpoints included distant Metastasis-Free Survival and Safety. Exploratory endpoints included distribution of TMB expression in baseline tumor samples across study arms and their association with the primary RFS endpoint. The median follow up was 23 months for the mRNA-4157/V940 plus Pembrolizumab group and 24 months for Pembrolizumab alone group.

The Relapse Free Survival at 18 months was 78.6% for the immunotherapy combination versus 62.2% for Pembrolizumab alone (HR=0.56; P=0.0266), and this equated to a 44% reduction in the risk of recurrence or death with 2 years of follow up. mRNA-4157/V940 and Pembrolizumab combination treatment demonstrated an improvement in RFS, irrespective of PD-L1 status and TMB status. The immunotherapy combination was well tolerated without increased Grade 3-4 immune mediated or serious toxicities. The most common adverse events of any grade attributed to the combination immunotherapy were fatigue, injection site pain and chills.

The researchers concluded that this is the first randomized trial to demonstrate Relapse Free Survival improvement with an individualized neoantigen approach, compared to standard of care treatment with Pembrolizumab, among patients with high-risk resected melanoma.

A personalized cancer vaccine, mRNA-4157, combined with pembrolizumab versus pembrolizumab in patients with resected high-risk melanoma: Efficacy and safety results from the randomized, open-label Phase 2 mRNA-4157-P201/Keynote-942 trial. Khattak A, Carlino M, Meniawy T, et al. Presented at: 2023 AACR Annual Meeting; April 14-19, 2023; Orlando, FL. Abstract CT001.

Zolbetuximab Plus Chemotherapy Improves Survival in CLDN18.2 Positive Metastatic Gastric and Gastroesophageal Junction Cancer

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SUMMARY: The American Cancer Society estimates that in the US about 26,500 new gastric cancer cases will be diagnosed in 2023 and about 11,130 people will die of the disease. It is one of the leading causes of cancer-related deaths in the world. Several hereditary syndromes such as Hereditary Diffuse Gastric Cancer (HDGC), Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer) and Familial Adenomatous Polyposis (FAP) have been associated with a predisposition for Gastric cancer. Additionally, one of the strongest risk factor for Gastric adenocarcinoma is infection with Helicobacter pylori (H.pylori), which is a gram-negative, spiral-shaped microaerophilic bacterium.
Patients with localized disease (Stage II and Stage III) are often treated with multimodality therapy and 40% of the patients may survive for 5 years or more. However, majority of the patients with Gastric and GastroEsophageal junction Adenocarcinoma have advanced disease at the time of initial presentation and have limited therapeutic options with little or no chance for cure. The five-year relative survival rate for patients at the metastatic stage is approximately 6%.

These patients frequently are treated with platinum containing chemotherapy along with a Fluoropyrimidine such as modified FOLFOX6. Patients with HER2-positive disease are usually treated with chemotherapy plus trastuzumab, and for those patients with HER2-negative disease, patients receive chemotherapy along with a checkpoint inhibitor or checkpoint inhibitor alone if the tumors express PD-L1.

Zolbetuximab is a first-in-class chimeric IgG1 monoclonal antibody that targets and binds to CLDN18.2, a transmembrane protein. CLDN18.2 protein found in normal gastric cells, and is a major component of epithelial and endothelial tight junctions controlling the flow of molecules between cells. Pre-clinical studies have shown that CLDN18.2 expression which can also be present in gastric tumors, increases as cancer progresses, and may become more exposed and accessible to targeted therapies with antibodies as gastric tumors develop. The binding interaction of Zolbetuximab to CLDN18.2 activates Antibody-Dependent Cellular Cytotoxicity (ADCC) and Complement Dependent Cytotoxicity (CDC) resulting in cancer cell death. About 30-40% of patients with gastric cancer have CLDN18.2 expression.

SPOTLIGHT trial is a Phase III, global, multi-center, double-blind, randomized study, in which the efficacy and safety of Zolbetuximab plus mFOLFOX6 was compared with placebo plus mFOLFOX6, as first-line treatment of patients with CLDN18.2-positive, HER2- negative, locally advanced unresectable or metastatic Gastric or GastroEsophageal Junction cancer. In this study, 565 enrolled patients were randomly assigned 1:1 to receive the combination of Zolbetuximab and mFOLFOX6 (N=283) or placebo and mFOLFOX6 (N=282). Zolbetuximab was given at 800 mg/m2 IV on day 1 of cycle 1 followed by 600 mg/m2 on day 22 of cycle 1, and days 1 and 22 of subsequent cycles, every 3 weeks. mFOLFOX6 (Oxaliplatin, 5-Fluorouracil and Leucovorin) was given IV every 2 weeks in cycles 1 to 4 of 42-day cycles. For cycles 5 and beyond, Zolbetuximab was given at the same dosing schedule in combination with 5-Fluorouracil and Leucovorin IV every 2 weeks. Those in the placebo arm were given placebo at the every 3-week schedule and chemotherapy was administered at the same dosing schedule. Treatment was continued until disease progression or discontinuation criteria were met. Enrolled patients had moderate-to-strong CLDN18 staining intensity in at least 75% of tumor cells based on a validated ImmunoHistoChemistry assay, had HER2-negative disease, and an ECOG performance status of 0 or 1. Patients were stratified by region (Asian versus non-Asian), number of organs with metastases (0-2 versus 3 or more), and prior gastrectomy. The median age was 61 years and 31.4% of patients were from Asia. Majority of patients had 0-2 organs with metastases, 30% had prior gastrectomy. Approximately 13% of patients had tumors with a PD-L1 CPS of at least 5. The primary disease site was stomach in 76% of patients and was GastroEsophageal Junction in 24%. The Primary endpoint was Progression Free Survival (PFS). Secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR), and Safety.

This study met the Primary endpoint and the median PFS was 10.61 months with the Zolbetuximab plus mFOLFOX6 combination versus 8.67 months with placebo plus mFOLFOX6 (HR=0.75; P=0.0066) and this was statistically significant. The OS was also significantly improved (18.23 versus 15.54 months, HR=0.750; P=0.0053), making this one of the longest durations of median OS seen in Phase III trials for this patient population. The most common Adverse Events with Zolbetuximab plus mFOLFOX6 were nausea, vomiting and decreased appetite. The incidences of serious Adverse Events were similar between the two treatment groups.

The authors concluded that Zolbetuximab plus mFOLFOX6 is a new potential Standard-of-Care treatment for a biomarker-based subgroup of patients with CLDN18.2-positive/HER2-negative locally advanced unresectable or metastatic Gastric/GE Junction adenocarcinoma. It is unclear if this regimen is superior to chemotherapy plus a checkpoint inhibitor in patients with PD-L1–positive and CLDN18.2-positive disease.

Zolbetuximab + mFOLFOX6 as first-line (1L) treatment for patients (pts) withclaudin-18.2+ (CLDN18.2+) / HER2− locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: Primary results from phase 3 SPOTLIGHT study. Shitara K, Lordick F, Bang Y-J, et al. J Clin Oncol. 2023;41(suppl; abstr LBA292). doi:10.1200/JCO.2023.41.3_suppl.LBA292

Capivasertib Plus Fulvestrant Improves Progression Free Survival in Advanced Hormone Receptor Positive 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. It is estimated that approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 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-positive (HR-positive), HER2-negative breast cancer is the most frequently diagnosed molecular subtype. The most common subtype of metastatic breast cancer is HR-positive, HER2-negative breast cancer (65% of all metastatic breast tumors), and these patients are often treated with anti-estrogen therapy as first line treatment. However, resistance to hormonal therapy occurs in a majority of the patients, with a median Overall Survival (OS) of 36 months. With the development of Cyclin Dependent Kinases (CDK) 4/6 inhibitors, endocrine therapy plus a CDK4/6 inhibitor is the mainstay, for the management of HR+/HER2-negative metastatic breast cancer, as first line therapy. Even with this therapeutic combination, most patients will eventually experience disease progression due to resistance to endocrine therapy. Therapies overcoming this resistance is an area of active research in the breast cancer space.

Capivasertib is a novel pyrrolopyrimidine derivative, and is first-in-class orally available inhibitor of the serine/threonine protein kinase AKT (protein kinase B), with potential antineoplastic activity. It is a potent, selective ATP-competitive inhibitor of all three AKT isoforms (AKT1/2/3). Inhibition of AKT prevents the phosphorylation of AKT substrates that mediate cellular processes, such as cell division, apoptosis, and glucose and fatty acid metabolism. A wide range of solid and hematological malignancies show dysregulated PI3K/AKT/mTOR/PTEN signaling due to mutations in the genes involved. By targeting AKT, the key node in the PIK3/AKT signaling network, Capivasertib potentially may be used as monotherapy or combination therapy for a variety of human cancers. The researchers conducted the CAPItello-291 trial to determine whether the addition of Capivasertib to Fulvestrant would improve outcomes in patients with HR-positive breast cancer whose tumors had developed resistance to an Aromatase Inhibitor.

CAPItello-291 is a randomized, double-blind Phase III trial in which 708 adult patients with histologically confirmed HR-positive, HER2-low or negative breast cancer, whose disease has recurred or progressed during or after Aromatase Inhibitor therapy, with or without a CDK4/6 inhibitor, were enrolled. Patients were randomly assigned 1:1 to receive either the Capivasertib plus Fulvestrant (N=355) arm or the placebo plus Fulvestrant arm (N=353). Patients in the study group received Capivasertib 400 mg orally twice daily for 4 days on and 3 days off along with Fulvestrant 500 mg IM on days 1 and 15 during cycle 1, then every 4 weeks thereafter. The present dosing of Capivasertib was chosen based on tolerability and the degree of target inhibition in early phase trials. The control group received matched placebo along with Fulvestrant. In this trial, patients could have received up to one line of chemotherapy for advanced disease and approximately 40% of tumors had PI3K/AKT/PTEN alterations. Both treatment groups were well balanced. Stratification factors included liver metastases and prior CDK 4/6 inhibitor. The dual Primary endpoints were Progression Free Survival (PFS) in the overall patient population and in a subgroup of patients whose tumors have qualifying alterations in the PIK3CA, AKT1 or PTEN genes. Secondary endpoints included Overall Survival (OS) and Objective Response Rate (ORR).

The trial met both Primary endpoints, improving PFS in the overall patient population and in a prespecified biomarker subgroup of patients whose tumors had qualifying alterations in the AKT pathway genes. In the overall trial population, patients treated with Capivasertib plus Fulvestrant had a median PFS of 7.2 months, compared to 3.6 months in patients treated with placebo plus Fulvestrant (HR=0.60; P<0.001). This amounted to a 40% lower risk of disease progression among patients who received Capivasertib plus Fulvestrant.

Among patients with AKT pathway mutations treated with Capivasertib plus Fulvestrant, the median PFS was 7.3 months versus 3.1 months in the placebo group (HR=0.50; P<0.001), reducing the risk of disease progression or death by 50%, versus placebo plus Fulvestrant. In the group without qualifying alterations in the AKT pathway genes, the PFS was 7.2 months in the Capivasertib group versus 3.7 months in the placebo group (HR=0.70). The benefit from Capivasertib was consistent across key clinically relevant subgroups, including patients previously treated with CDK4/6 inhibitor and patients with liver metastases.

The Objective Response Rate in the overall trial population was 22.9% among patients treated with Capivasertib plus Fulvestrant compared with 12.2% for patients treated with placebo plus Fulvestrant and was 28.8% and 9.7% respectively in the biomarker altered population. Although the Overall Survival data were immature at the time of the analysis, early data are encouraging and follow up is ongoing.

The most frequent Grade 3 or higher toxicities occurring in 5% or more of patients were diarrhea (9.3%) and rash (12.1%). Treatment discontinuation due to adverse events was 13% among patients who received Capivasertib plus Fulvestrant versus 2.3% among patients who received placebo plus Fulvestrant.

It was concluded that a combination of Capivasertib plus Fulvestrant is a new treatment option with significantly improved Progression Free Survival, in patients who have Hormone Receptor–positive/HER2-negative advanced breast cancer, who had progressed on, or become resistant to, endocrine therapies and CDK4/6 inhibitors.

Capivasertib and fulvestrant for patients with aromatase inhibitor-resistant hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: results from the Phase III CAPItello-291 trial. Turner N, Oliveria M, Howell SJ, et al. Presented at the 2022 San Antonio Breast Cancer Symposium: December 6-10, 2022; San Antonio, TX. Abstract GS3-04.

BRUKINSA® Superior to IMBRUVICA® in Relapsed/Refractory CLL/SLL

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SUMMARY: The American Cancer Society estimates that for 2022, about 20,160 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4410 patients will die of the disease. CLL accounts for about one-quarter of the new cases of leukemia. The average age of patients diagnosed with CLL is around 70 years, and is rarely seen in people under age 40, and is extremely rare in children.

Bruton’s Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. Ibrutinib (IMBRUVICA®) is an oral, irreversible inhibitor of BTK and inhibits cell proliferation and promotes programmed cell death (Apoptosis) by blocking B-cell activation and signaling. IMBRUVICA® demonstrated survival benefits, when compared to chemoimmunotherapy, both in previously untreated (RESONATE-2), as well as relapsed (RESONATE) CLL patients. However, toxicities leading to IMBRUVICA® discontinuation occurred in a significant number of patients, and Atrial Fibrillation was noted in 11-16% of patients and hypertension rates were between 20-26%.

Zanubrutinib (BRUKINSA®) is an irreversible, potent, next-generation, small molecule inhibitor of Bruton’s Tyrosine Kinase, designed to deliver targeted and sustained inhibition of the BTK protein by optimizing bioavailability, half-life, and selectivity, while minimizing off-target inhibition of TEC- and EGFR-family kinases. It has been hypothesized that the increased selectivity of BRUKINSA® may minimize toxicities, (such as those often associated with IMBRUVICA®) and improve efficacy outcomes. BRUKINSA® demonstrated promising efficacy among patients with CLL/SLL (Small Lymphocytic Lymphoma), in early phase trials.

ALPINE study is a randomized, global, Phase III trial in which BRUKINSA® was compared with IMBRUVICA® in previously treated patients with relapsed or refractory CLL or SLL. In this trial, a total of 652 patients were randomly assigned 1:1 to receive either BRUKINSA® 160 mg orally twice daily or IMBRUVICA® 420 mg orally once daily, until disease progression or unacceptable toxicity. Enrolled patients had at least one prior systemic therapy and were required to have measurable lymphadenopathy by CT scan or MRI. Exclusion criteria included current or past Richter’s transformation and prior treatment with BTK inhibitors. The median age was 67 years, 45% of the patients had bulky disease with a tumor that was 5 cm or more in the greatest dimension, 73% had unmutated IGHV status, and 23% had a chromosome 17p deletion, TP53 mutation, or both and fewer than 15% of patients were on anticoagulants. The median number of previous lines of therapy was 1 and a total of 80% of the patients in the BRUKINSA® group and 76% of those in the IMBRUVICA® group had previously received chemoimmunotherapy. The Primary end point of the trial was Overall Response Rate (ORR) assessed by investigator and Independent Review Committee (IRC), and Secondary end points included Progression Free Survival (PFS), event rate of Atrial Fibrillation or Flutter, Duration of Response, Time to Treatment Failure, Overall Survival (OS), Patient-Reported Outcomes, and Safety.

A prespecified interim analysis showed that BRUKINSA® was superior to IMBRUVICA®, with respect to Overall Response Rate. The authors in this final analysis reported the clinical outcomes of Progression Free Survival, a key Secondary endpoint. Progression Free Survival was assessed with the use of a hierarchical testing strategy to determine whether BRUKINSA® was noninferior to IMBRUVICA®. If noninferiority was established, the superiority of BRUKINSA® was assessed and claimed if the two-sided P value was less than 0.05.

At a median follow up of 29.6 months, BRUKINSA® was found to be superior to IMBRUVICA® with respect to Progression Free Survival, as assessed by the investigators and Independent Review Committee (HR=0.65; P=0.002). The PFS at 24 months was 78.4% in the BRUKINSA® group and 65.9% in the IMBRUVICA® group. Median PFS was not reached in the BRUKINSA® group and was 34.2 months in the IMBRUVICA® group.

Among patients with a 17p deletion, a TP53 mutation, or both, those who received BRUKINSA® had longer PFS than those who received IMBRUVICA® (HR=0.53). The percentage of patients who were alive without disease progression at 24 months in this high-risk population was 72.6% in the BRUKINSA® group, and 54.6% in the IMBRUVICA® group. The PFS benefit was in favor of BRUKINSA® across major prespecified subgroups, including age, previous lines of therapy, disease stage, and IGHV mutational status.

Consistent with the findings at the interim analysis, the Overall Response Rate was higher in the BRUKINSA® group than in the IMBRUVICA® group, and were 86.2% and 75.7%, respectively, as assessed by the Independent Review Committee.

BRUKINSA® had a more favorable safety profile, with a lower incidence of cardiac disorders (21.3%), than in the IMBRUVICA® group (29.6%). Cardiac events leading to treatment discontinuation occurred in 0.3% of patients in the BRUKINSA® group and in 4.3% of patients in the IMBRUVICA® group. The incidence of Atrial fibrillation or flutter of any grade, a key Secondary endpoint, was lower in the BRUKINSA® group than in the IMBRUVICA® group (5.2% versus 13.3%).

It was concluded that in patients with Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma, treatment with BRUKINSA® resulted in a significantly longer Progression Free Survival, compared to those patients who received IMBRUVICA®, and BRUKINSA® was associated with fewer cardiac adverse events.

Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. Brown JR, Eichhorst B, Hillmen P, et al. N Engl J Med 2023; 388:319-332.