Author: RR

Late Breaking Abstract – ASCO 2023: First Line versus Second Line Use of CDK4/6 Inhibitors in Advanced HR-Positive/HER-Negative 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 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 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. Factors associated with high risk of recurrence in HR-positive, HER2-negative early breast cancer include positive nodal status, the number of positive nodes, large tumor size (5 cm or more), and high tumor grade (Grade 3).

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. CDK 4 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.

It has been shown that CDK4/6 inhibitors in combination with endocrine therapy improves Progression Free Survival (PFS) as well as Overall Survival (OS) when given as initial treatment (first-line) and after prior endocrine monotherapy (second-line), in patients with HR-positive, HER2-negative advanced breast cancer. Treatment guidelines recommend first-line use of CDK4/6 inhibitors along with endocrine therapy, but evidence of superiority of first-line use over second-line based on a head-to-head comparison is lacking.

SONIA is a real-world, randomized, investigator-initiated, nationwide, Phase III trial, conducted to evaluate the efficacy, safety and cost-effectiveness of CDK4/6 inhibitors added to either first or second-line endocrine therapy, in patients with HR-positive, HER2-negative advanced breast cancer, who have received no prior therapy for their advanced disease. In this study, 1050 pre and postmenopausal women (N=1050) with measurable or evaluable disease, who received no prior therapy for advanced breast cancer, were randomized 1:1 to receive first-line treatment with a non-steroidal Aromatase Inhibitor and a CDK4/6 inhibitor, followed upon progression by Fulvestrant (strategy A) or first-line treatment with a non-steroidal Aromatase Inhibitor, followed upon progression by Fulvestrant and CDK4/6 inhibitor (strategy B). Both treatment groups were well balanced. Neoadjuvant/adjuvant therapy was allowed if the disease-free interval after non-steroidal Aromatase Inhibitor therapy was more than 12 months. The choice of CDK4/6 inhibitor was a stratification factor and was left to the discretion of the treating physician. The Primary endpoint was time from randomization to second objective disease progression, as assessed by local investigators, or death (PFS2). Secondary endpoints include Overall Survival (OS), Safety, Quality of Life, and cost-effectiveness.

At a median follow-up was 37.7 months, the median duration of CDK4/6 inhibitor treatment/usage was 24.6 months in the first-line group and 8.1 months in the second-line group. The median PFS with strategy A as expected was significantly longer in the CDK4/6 inhibitor group than in the non-steroidal Aromatase Inhibitor group (24.7 months and 16.1 months respectively, HR=0.59; P<0.0001).  However, with regards to PFS2, there was no significant difference between the two treatment groups. The median PFS2 was 31.0 months with strategy A versus 27.8 months with strategy B (HR=0.89; P=0.14) and this similar PFS2 treatment effect was consistent across pre-defined subgroups. There was no significant difference in Overall Survival between the two treatment groups (HR=0.98; P=0.83).

There were more grade 3 or 4 adverse events when CDK4/6 inhibitors were used in the first-line setting and the use of strategy A increased the cost of treatment by an average of $200,000 per patient. Quality of life, as measured by Functional Assessment of Cancer Therapy – Breast (FACT-B) total score, was not different between the 2 arms.

It was concluded that first-line use of CDK4/6 inhibitor along with endocrine therapy does not provide statistically significant and clinically meaningful Progression Free Survival benefit compared to second-line use in women with HR-positive and HER2-negative advanced breast cancer. The authors added that second-line use may thus be a preferred option for the majority of these patients, as the use in first-line prolongs the time on CDK4/6 inhibitors by over 16 months and increases toxicity and cost of treatment. It should however be noted that in this study, patients received single-agent Fulvestrant as second-line treatment which may not be the standard treatment intervention, given the approval of Alpelisib for patients with PIK3CA mutations. Treatment selection based on biomarkers testing therefore is important. Based on the SONIA trial data, offering endocrine therapy alone in the first line setting may not be inappropriate for favorable risk patients without high visceral tumor burden.

Primary outcome analysis of the phase 3 SONIA trial (BOOG 2017-03) on selecting the optimal position of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors for patients with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC). Sonke GS, Van Ommen-Nijhof A, Wortelboer N, et al. DOI: 10.1200/JCO.2023.41.17_suppl. LBA1000 Journal of Clinical Oncology 41, no. 17_suppl (June 10, 2023) LBA1000

Late Breaking Abstract – ASCO 2023: Superior Outcomes with First Line Nivolumab versus Brentuximab Vedotin in Advanced Classical Hodgkin Lymphoma

RR

SUMMARY: The American Cancer Society estimates that in the United States for 2023, about 8830 new cases of Hodgkin Lymphoma will be diagnosed and about 900 patients will die of the disease. Hodgkin Lymphoma is classified into two main groups – Classical Hodgkin Lymphomas and Nodular Lymphocyte Predominant type, by the World Health Organization. The Classical Hodgkin Lymphomas include Nodular sclerosing, Mixed cellularity, Lymphocyte rich, Lymphocyte depleted, subtypes and accounts for approximately 10% of all malignant lymphomas. Nodular sclerosis Hodgkin lymphoma histology, accounts for approximately 80% of Hodgkin Lymphoma cases in older children and adolescents in the United States. Classical Hodgkin Lymphoma is a malignancy of primarily B lymphocytes and is characterized by the presence of large mononucleated Hodgkin and giant multinucleated Reed-Sternberg (RS) cells collectively known as Hodgkin and Reed-Sternberg cells (HRS).

For patients with Hodgkin Lymphoma, the goal of first-line chemotherapy is cure. A positive PET scan following first-line chemotherapy is indicative of incomplete response with residual disease and warrants subsequent chemotherapy or radiation. Advanced stage (Stage III-IV) Classical Hodgkin lymphoma has a cure rate of approximately 70-80% when treated in the first-line setting with a combination of Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine (ABVD). This regimen which was developed more than 40 years ago is less expensive, easy to administer, is generally well tolerated and is often used in first line setting. Nonetheless, this regimen which contains Bleomycin can cause pulmonary toxicity, the incidence of which is higher in older patients and in those who receive consolidation radiotherapy to the thorax.

Brentuximab Vedotin (ADCETRIS®) is an Antibody-Drug Conjugate (ADC) that targets CD30, which is a surface antigen, expressed on Reed-Sternberg cells, in patients with Classical Hodgkin lymphoma. This ADC consists of an anti-CD30 monoclonal antibody linked to MonoMethyl Auristatin E (MMAE), an antimicrotubule agent. Upon binding to the CD30 molecule on the cancer cells, MMAE is released into the cancer cell, resulting in cell death. In the ECHELON-1 study, frontline treatment with Brentuximab Vedotin (BV) in combination with Doxorubicin, Vinblastine and Dacarbazine (AVD) resulted in a significant improvement both in Progression Free Survival as well as Overall Survival, after a median follow up of 6 years. However, frontline BV adds toxicity, and 7-20% of patients still develop Relapsed/Refractory Hodgkin Lymphoma.

Preclinical studies suggest that HRS cells evade immune detection by exploiting the pathways associated with immune checkpoint, Programmed Death-1 (PD-1) and its ligands PD-L. Classical Hodgkin Lymphoma is an excellent example of how the tumor microenvironment influences cancer cells to proliferate and survive. The most common genetic abnormality in Nodular sclerosis subtype of Hodgkin lymphoma is the selective amplification of genes on the short arm of chromosome 9 (9p24.1) which includes JAK-2, with resulting increased expression of PD-1 ligands such as PDL1 and PDL2 on HRS cells, as well as increased JAK-STAT activity, essential for the proliferation and survival of Hodgkin Reed-Sternberg (HRS) cells. Infection with Epstein–Barr virus (EBV) similarly can increase the expression of PDL1 and PDL2 in EBV-positive Hodgkin lymphomas. It would therefore seem logical to block or inhibit immune check point PD-1 rather than both its ligands, PDL1 and PDL2.

Nivolumab (OPDIVO®) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells.

SWOG S1826 was an open-label, randomized Phase III trial conducted to compare the combination of Nivolumab plus AVD to Brentuximab Vedotin plus AVD, in patients with advanced-stage classical Hodgkin Lymphoma (cHL). In this study, 976 newly diagnosed Stage III or IV cHL patients (N=976) were randomly assigned 1:1 to receive either 6 cycles of Nivolumab at 240 mg IV on days 1 and 15 (N=489) or Brentuximab Vedotin 1.2 mg/kg IV on days 1 and 15 (N=487). Both treatment groups also received AVD IV (Doxorubicin, Vinblastine, Dacarbazine ) on days 1 and 15, and treatment was repeated every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Granulocyte-Colony Stimulating Factor (G-CSF) Pegfilgrastim SC on days 2 and 16, or Filgrastim SC on days 6-10 and 21-25 was optional in the Nivolumab group (N-AVD) but was required in the Brentuximab Vedotin group (BV-AVD). Approximately 54% in the N-AVD group received G-CSF compared to 95% in the BV-AVD group. After completion of cycle 6, patients could receive radiation therapy at the discretion of the treating physician, to metabolically active residual lesions noted on the end of treatment PET. Less than 1% of patients had received radiotherapy. Patients were stratified by age, International Prognostic Score (IPS) and intent to use radiation therapy. The median age was 27 years, 76% were Caucasian, 55% were men, 64% had Stage IV disease and 32% had IPS of 4-7. The Primary endpoint was Progression Free Survival (PFS). Secondary endpoints included Overall Survival (OS), Event-Free Survival (EFS), Patient-Reported Outcomes (PROs), and Safety.

At the planned 2nd interim analysis, upon recommendation from the SWOG Data and Safety Monitoring Committee, the primary results were reported. With a median follow up of 12.1 months, PFS was superior in the N-AVD group compared to the BV-AVD group. The estimated 1 year PFS was 94% in the N-AVD group compared with 86% among patients treated with BV-AVD (HR=0.48; P=0.0005). The PFS benefit was consistent across treatment subgroups. This benefit was most pronounced among patients over 60 years of age, those with an IPS of 4-7 and those with Stage IV disease. The estimated 1 year EFS was 91% with N-AVD versus 84% with BV-AVD (HR=0.56; P=0.0019). The 1 year OS data were not mature and the OS rates were 99% versus 98% respectively. The rate of Grade 3 or more hematologic AEs were 48.4% after N-AVD, compared to 30.5% after BV-AVD. There was however no increase in infectious complications even though there was a higher rate of neutropenia in the N-AVD group. Hypo/Hyperthyroidism was more frequent after N-AVD whereas peripheral neuropathy was more common after BV-AVD.

The researchers concluded that in this largest Hodgkin Lymphoma study in National Clinical Trials Network (NCTN) history, Nivolumab in combination with AVD significantly improved Progression Free Survival, compared to Brentuximab Vedotin in combination with AVD, in patients with advanced stage Hodgkin Lymphoma, and may be the new standard therapy for this group of patients. Follow-up is ongoing to confirm the durability of PFS benefit, assess Overall Survival and Patient Reported Outcomes.

SWOG S1826, a randomized study of nivolumab(N)-AVD versus brentuximab vedotin(BV)-AVD in advanced stage (AS) classic Hodgkin lymphoma (HL). Herrer AF, LeBlanc ML, Castellino SM, et al. J Clin Oncol. 2023;41(suppl 17): DOI: 10.1200/JCO.2023.41.17_suppl.LBA4

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

RR

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

RR

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

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 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

RR

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.

FDA Approves Glofitamab for Relapsed or Refractory Large B-Cell Lymphomas

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SUMMARY: The FDA on June 15, 2023, granted accelerated approval to Glofitamab-gxbm (COLUMVI®) for Relapsed or Refractory Diffuse Large B-Cell Lymphoma, Not Otherwise Specified (DLBCL, NOS) or Large B-Cell Lymphoma (LBCL) arising from Follicular Lymphoma, after two or more lines of systemic therapy.

The American Cancer Society estimates that in 2023, about 80,550 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,180 individuals will die of this disease. Diffuse Large B-Cell Lymphoma (DLBCL) is the most common of the aggressive Non-Hodgkin lymphomas in the United States, and the incidence has steadily increased 3-4% each year. More than half of patients are 65 or older at the time of diagnosis and the incidence is likely to increase with aging of the American population. The etiology of Diffuse Large B-Cell Lymphoma is unknown. Contributing risk factors include immunosuppression (AIDS, transplantation setting, autoimmune diseases), UltraViolet radiation, pesticides, hair dyes, and diet.

DLBCL is a neoplasm of large B cells and the most common chromosome abnormality involves alterations of the BCL-6 gene at the 3q27 locus, which is critical for germinal center formation. Two major molecular subtypes of DLBCL arising from different genetic mechanisms have been identified, using Gene Expression Profiling: Germinal Center B-cell-like (GCB) and Activated B-Cell-like (ABC). Patients in the GCB subgroup have a higher 5-year survival rate, independent of clinical IPI (International Prognostic Index) risk score, whereas patients in the ABC subgroup have a significantly worse outcome. Regardless, R-CHOP regimen (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone), given every 21 days, for 6 cycles, delivered with curative intent, is the current standard of care for patients of all ages, with newly diagnosed DLBCL, regardless of molecular subtype. Approximately 30-40% of patients experience disease progression or relapse, during the first 2 years and attempts to improve on R-CHOP regimen have not been successful. Maintenance treatment strategy following R-CHOP, to better control the disease, delay disease progression and improve long term survival, have included Autologous Stem Cell Transplantation, CAR T-cell therapy, maintenance treatment with agents such as oral protein kinase inhibitor Enzastaurin and Everolimus. Outcomes for transplant-ineligible patients with Relapsed/Refractory DLBCL patients remain poor. There is a critical unmet need for this patient group.

Glofitamab is a CD20-directed CD3 T-cell engager bispecific antibody, designed to target CD20 on the surface of B cells and CD3 on the surface of T cells. This dual targeting activates and redirects a patient’s existing T cells to engage and eliminate target B cells by releasing cytotoxic proteins into the B cells. Glofitamab differs from other CD20-directed CD3 T-cell engager bispecific antibodies in that it has two anti-CD20 binding domains. It is therefore bivalent for the tumor antigen and monovalent for the T-cell CD3 protein. Further, it is a time-limited therapy.

The present FDA approval was based on positive data from the NP30179 study, which is a Phase I/II, multicenter, open-label, dose-escalation and expansion study, evaluating the safety, efficacy and pharmacokinetics of Glofitamab in patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL). Once the recommended Phase II dose of Glofitamab was established, patients with DLBCL who had previously received at least two lines of therapy were enrolled in the expansion cohorts. This expansion cohort included 154 patients (N=154), who had Relapsed or Refractory disease, and had received at least two previous lines of therapy including at least one anti-CD20 antibody-containing regimen and at least one anthracycline-containing regimen.

Eighty percent of patients had Relapsed or Refractory DLBCL, and 20% had LBCL arising from Follicular Lymphoma. Approximately 85% of patients were refractory to their most recent therapy and 33% had received prior CAR T-cell therapy. This study excluded patients with active or previous Central Nervous System lymphoma or disease. Treatment consisted of a single dose of Obinutuzumab 1,000 mg IV on Cycle 1 Day 1, to deplete circulating and lymphoid tissue B cells and to mitigate Cytokine Release Syndrome, followed by fixed-duration Glofitamab monotherapy administered by IV infusion according to a step-up dosing schedule (2.5 mg on Day 8 of Cycle 1 and 10 mg on Day 15 of Cycle 1), then 30 mg on Day 1 of each subsequent cycle for a maximum of 12 cycles. The cycle length was 21 days. Patients were hospitalized for the first dose of Glofitamab and subsequent doses were administered in the outpatient setting unless Cytokine Release Syndrome of Grade 2 or higher was reported after the first dose. The Primary end point was Complete Response (CR) rate according to assessment by an Independent Review Committee. Key Secondary end points included Duration of Response, Progression Free Survival, and Safety. The efficacy analysis included 132 patients.

The Overall Response Rate (ORR) was 56% with a Complete Response rate of 43%. With an estimated median follow up of 11.6 months among responders, the estimated median Duration of Response was 18.4 months. Further, 68.5% of patients who achieved a response continued to respond for 9 months or longer. The median Time to Response was 42 days. The most common adverse reactions, excluding laboratory abnormalities were Cytokine Release Syndrome (CRS), musculoskeletal pain, rash, and fatigue. CRS occurred in 70% (with 4.1% Grade 3 or higher CRS), Immune Effector Cell-Associated Neurotoxicity (ICANS) in 4.8%, serious infections in 16%, and tumor flare in 12%. The most common Grade 3 to 4 laboratory abnormalities were lymphopenia and neutropenia, decrease in serum phosphate and fibrinogen levels, and increase in serum uric acid.

It was concluded that a fixed duration treatment of off-the-shelf therapy with Glofitamab induced durable Complete Responses, among patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma.

Glofitamab for Relapsed or Refractory Diffuse Large B-Cell Lymphoma. Dickinson MJ, Carlo-Stella C, Morschauser F, et al. N Eng J Med. 2022;387:2220-2231.

Capivasertib 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-positive, 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. A therapy overcoming endocrine resistance is an area of active research in the breast cancer space.

The P13K/Akt pathway is a growth-regulating cellular signaling pathway, which in many human cancers is overactivated. Inhibition of the PI3K/Akt signaling pathway leads to inhibition of cell proliferation and induction of apoptosis in tumor cells. A wide range of solid and hematological malignancies show dysregulated PI3K/AKT/mTOR/PTEN signaling due to mutations in the genes involved. Overactivation of the PI3K-AKT-PTEN signaling pathway occurs in approximately 50% of HR-positive, HER2-negative breast cancers by means of activating mutations in PIK3CA and AKT1 and inactivating alterations in PTEN. These alterations may be present at the time of cancer recurrence, and can also be acquired following previous treatment including with CDK4/6 inhibitors. Further, AKT signaling may also be activated in the absence of genetic alterations in patients with endocrine resistance.

Capivasertib is a novel, first-in-class, orally bioavailable small molecule 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). 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. In the Phase II FAKTION trial, Capivasertib in combination with Fulvestrant significantly improved Progression Free and Overall Survival as compared with Fulvestrant alone, among postmenopausal women with HR-positive advanced breast cancer, who had previously received endocrine therapy. 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 and CDK4/6 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 have become resistant to endocrine therapies and CDK4/6 inhibitors.

Capivasertib in Hormone Receptor–Positive Advanced Breast Cancer. Turner N, Oliveria M, Howell SJ, et al., for the CAPItello-291 Study Group. N Engl J Med 2023; 388:2058-2070.

Platelet Transfusion before Central Venous Catheter Placement in Patients with Thrombocytopenia

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SUMMARY: Thrombocytopenia is a frequent finding in hospitalized patients and is one of the most common reasons for inpatient hematology consultations. Thrombocytopenia is usually defined as a platelet count of less than 150,000 per cubic millimeter, whereas severe thrombocytopenia is considered as platelet counts less than 50,000 per cubic millimeter. It is estimated that the prevalence of thrombocytopenia at admission to ICU is around 20-30% of patients, and a similar number of patients develop thrombocytopenia (from a normal platelet count) while being treated in the ICU.

Approximately 18% of hospitalized patients undergo Central Venous Catheter (CVC) placement, an invasive procedure, during admission. Central Venous Catheter facilitates simultaneous infusion of multiple medications, administration of vasoactive drugs, irritating or hypertonic solutions such as TPN, as well as hemodialysis and hemodynamic monitoring. The routine use of ultrasound guided CVC placement has greatly reduced the risk of bleeding complication. In clinical practice, platelet-transfusion thresholds range from 20,000 to 50,000 per cubic millimeter, as there is lack of good-quality evidence. It is however unclear whether the use of prophylactically transfused platelet concentrates is necessary to prevent CVC-related bleeding complications, in patients with severe thrombocytopenia.

The PACER trial is a multicenter, randomized, controlled, noninferiority study of Prophylactic Platelet Transfusion Prior to Central Venous Catheter Placement in Patients with Thrombocytopenia. This trial was conducted on hematology wards and in ICUs at 10 hospitals in the Netherlands, to evaluate whether the omission of prophylactic platelet transfusion before CVC placement in patients with a platelet count of 10,000 to 50,000 per cubic millimeter increased the risk of catheter-related bleeding. This study included 373 patients (N=373) randomized in a 1:1 ratio to receive either one unit of platelet concentrate (N=188) or no platelet transfusion (N=185) before CVC placement. CVC placement was ultrasound guided, performed by an experienced operator, could be of any diameter, could be either tunneled or nontunneled, and could be placed in the internal jugular vein, subclavian vein, or femoral vein. Randomization was stratified according to the trial center and catheter type (large-bore dialysis catheter or regular catheter). Patient characteristics at the time of CVC placement were well balanced between the two trial groups. Exclusion criteria included therapeutically administered anticoagulant, a history of congenital or acquired coagulation factor deficiency or bleeding risk, or a spontaneously prolonged INR of 1.5 or more.

The Primary outcome was the occurrence of catheter-related bleeding of Grade 2-4 within 24 hours after CVC placement. Bleeding was assessed according to the Common Terminology Criteria for Adverse Events. The occurrence of bleeding and any related treatments were recorded by trained staff members at each site immediately after CVC placement, and at 1 hour and 24 hours thereafter. A key Secondary outcome was major bleeding (Grade 3-4).

Grade 2-4 catheter-related bleeding occurred in 4.8% of patients in the platelet transfusion group and in 11.9% of patients in the no-transfusion group. The absolute risk difference was 7.1%, Relative Risk was 2.45, and noninferiority of withholding platelet transfusion was not shown. The risk of Grade 3 or 4 catheter-related bleeding was lower in the platelet transfusion group compared to the no-transfusion group (2.1% versus 4.9%), with Relative Risks consistent with the Primary outcome.

The bleeding risk in the prespecified exploratory subgroup analysis, were similar to the findings of the Primary analysis. The bleeding risk among the patients being treated on the hematology ward was higher than that among patients in the ICU, and the same was true with the use of tunneled catheters as compared with nontunneled catheters. The differences in CVC-related bleeding risk was attributed to patients in the ICU more often having consumptive thrombocytopenia, whereas patients with hematologic problems in the hematology ward more often have hypoproliferative thrombocytopenia.

It was concluded from this study that in patients with severe thrombocytopenia, withholding prophylactic platelet transfusion before Central Venous Catheter placement in those with a platelet count of 10,000 to 50,000 per cubic millimeter resulted in more catheter-related bleeding events, and prophylactic platelet transfusion was associated with a lower risk of bleeding.

Platelet Transfusion before CVC Placement in Patients with Thrombocytopenia. van Baarle FLF, van de Weerdt EK, van der Velden WJFM, et al. N Engl J Med 2023; 388:1956-1965.