Author: RR

Biomarkers for Adjuvant Endocrine and Chemotherapy in Early-Stage Breast Cancer: ASCO Guideline Update

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. Approximately 290,560 new cases of breast cancer will be diagnosed in 2022 and about 43,780 individuals will die of the disease, largely due to metastatic recurrence.

Patients with early stage breast cancer often receive adjuvant therapy. Tumor biomarker assays have become an integral part of the treatment decision making process along with clinical and histologic tumor characteristics, further enabling customized care for patients with early-stage invasive breast cancer. A multitude of biomarker assays are presently available for the practicing Health Care Provider. Choosing the appropriate biomarker assay for a given patient can be a daunting task and the ASCO guidelines set forth herein, were developed by an expert panel based on  a systematic review of evidence published from January 2016 to October 2021, of 24 Phase III randomized clinical trials (RCTs), prospective-retrospective studies, and clinical experience. These guidelines are only applicable for patients with newly diagnosed, non-metastatic, primary breast cancer, to prognosticate and predict outcomes but they do not however comment on the choice of specific treatment or regimens based on recurrence score. Treatment decisions should take into consideration disease stage, comorbidities and patient preferences. Even though several tests are now recommended in the guidelines, only one test should be used to guide therapy for an individual patient.

Three important questions were addressed by this guideline update

  1. For patients with early-stage ER-positive, HER2-negative breast cancer, which biomarkers should be used to guide decisions on adjuvant endocrine and chemotherapy for a newly diagnosed cancer or in the extended setting?
  2. For patients with early-stage HER2-positive breast cancer, which biomarkers should be used to guide decisions on adjuvant endocrine and chemotherapy?
  3. For patients with early-stage triple-negative breast cancer, which biomarkers should be used to guide decisions on adjuvant chemotherapy?

 Newly Diagnosed ER-Positive, HER2-Negative Breast Cancer

Oncotype DX (21-gene recurrence score, 21-gene RS).

Recommendation 1.1. If a patient has node-negative breast cancer, the clinician may use the Oncotype DX test to guide decisions for adjuvant endocrine and chemotherapy

Recommendation 1.2. In the group of patients in Recommendation 1.1 with Oncotype DX recurrence score ≥ 26, the clinician should offer chemoendocrine therapy

Recommendation 1.3. In the group of patients in Recommendation 1.1 who are 50 years of age or younger with Oncotype DX recurrence score 16 to 25, the clinician may offer chemoendocrine therapy

Recommendation 1.4. If a patient is postmenopausal and has node-positive breast cancer with 1-3 positive nodes, the clinician may use the Oncotype DX test to guide decisions for adjuvant endocrine and chemotherapy

Recommendation 1.5. In the group of patients in Recommendation 1.4, the clinician should offer chemoendocrine therapy for those whose Oncotype DX recurrence score is ≥ 26

Recommendation 1.6. If a patient is premenopausal and has node-positive breast cancer with 1-3 positive nodes, the Oncotype DX test should not be offered to guide decisions for adjuvant systemic chemotherapy

Recommendation 1.7. If a patient has node-positive breast cancer with ≥ 4 positive nodes, the evidence on the clinical utility of routine Oncotype DX test to guide decisions for adjuvant endocrine and chemotherapy is insufficient to recommend its use

Qualifying statement: The genomic assay is prognostic and may be used for shared patient-physician treatment decision making.

MammaPrint (70-gene signature).

Recommendation 1.8. If a patient is older than 50 and has high clinical risk breast cancer that is node-negative or node-positive with 1-3 positive nodes, the clinician may use the MammaPrint test to guide decisions for adjuvant endocrine and chemotherapy

Recommendation 1.9. If a patient is 50 years of age or younger and has high clinical risk, node-negative or node-positive with 1-3 positive nodes breast cancer, the clinician should not use the MammaPrint test to guide decisions for adjuvant endocrine and chemotherapy

Recommendation 1.10. If a patient has low clinical risk, regardless of age, the evidence on clinical utility of routine MammaPrint test is insufficient to recommend its use

Recommendation 1.11. If a patient has node-positive breast cancer with ≥ 4 positive nodes, the evidence on the clinical utility of routine MammaPrint test to guide decisions for adjuvant endocrine and chemotherapy is insufficient to recommend its use

Qualifying statement: The genomic assay is prognostic and may be used for shared patient-physician treatment decision making.

EndoPredict (12-gene risk score).

Recommendation 1.12. If a patient is postmenopausal and has breast cancer that is node-negative or node-positive with 1-3 positive nodes, the clinician may use the EndoPredict test to guide decisions for adjuvant endocrine and chemotherapy

Recommendation 1.13. If a patient is premenopausal and has breast cancer that is node-negative or node-positive with 1-3 positive nodes, the clinician should not use the EndoPredict test to guide decisions for adjuvant endocrine and chemotherapy

Recommendation 1.14. If a patient has breast cancer with ≥ 4 positive nodes, evidence on the clinical utility of routine use of the EndoPredict test to guide decisions for adjuvant endocrine and chemotherapy is insufficient

Prosigna (PAM50).

Recommendation 1.15. If a patient is postmenopausal and has breast cancer that is node-negative, the clinician may use the Prosigna test to guide decisions for adjuvant systemic chemotherapy

Recommendation 1.16. If a patient is premenopausal and has node-negative or node-positive breast cancer, the clinician should not use the Prosigna test to guide decisions for adjuvant systemic chemotherapy

Recommendation 1.17. If a patient is postmenopausal and has node-positive breast cancer with 1-3 positive nodes, the evidence is inconclusive to recommend the use of the Prosigna test to guide decisions for adjuvant endocrine and chemotherapy

Recommendation 1.18. If a patient has node-positive breast cancer with ≥ 4 positive nodes, evidence on the clinical utility of routine use of the Prosigna test to guide decisions for adjuvant endocrine and chemotherapy is insufficient to recommend its use

Ki67.

Recommendation 1.19. If a patient is postmenopausal and has stage I-II breast cancer, the clinician may use Ki67 expression in conjunction with other clinical and pathologic parameters to guide decisions on adjuvant endocrine and chemotherapy when multigene assays are not available. Ki67 expression levels are most informative for prognosis when the level is < 5% (low proliferation) or > 30% (high proliferation) because technical reliability of distinguishing values within this range is limited

Recommendation 1.20. If a patient is postmenopausal and has breast cancer, there is insufficient evidence to use baseline Ki67 expression or Ki67 level after 2 weeks of neoadjuvant aromatase inhibitor (AI) therapy to guide decisions on adjuvant endocrine and chemotherapy

Recommendation 1.21. Despite the limitations associated with Ki67 testing, a patient with node-positive breast cancer with a high risk of recurrence and a Ki67 score of ≥ 20% as determined by a US Food and Drug Administration (FDA)–approved test may be offered 2 years of abemaciclib plus endocrine therapy

Immunohistochemistry 4.

Recommendation 1.22. If a patient has node-negative or node-positive breast cancer with 1-3 positive nodes, the clinician may use immunohistochemistry 4 (IHC4) score to guide decisions for adjuvant endocrine and chemotherapy if the score has been validated in the performing laboratory and if multigene assays are not available

Extended Endocrine Therapy for ER-Positive HER2-Negative Breast Cancer

Oncotype DX, EndoPredict, Prosigna, Ki67, or IHC4.

Recommendation 1.23. If a patient has node-negative breast cancer and has had 5 years of endocrine therapy without evidence of recurrence, there is insufficient evidence to use Oncotype DX, EndoPredict, Prosigna, Ki67, or IHC4 scores to guide decisions about extended endocrine therapy

Breast Cancer Index.

Recommendation 1.24. If a patient has node-negative or node-positive breast cancer with 1-3 positive nodes and has been treated with 5 years of primary endocrine therapy without evidence of recurrence, the clinician may offer the BCI test to guide decisions about extended endocrine therapy with either tamoxifen, an AI, or a sequence of tamoxifen followed by AI

Recommendation 1.25. If a patient has node-positive breast cancer with ≥ 4 positive nodes and has been treated with 5 years of primary endocrine therapy without evidence of recurrence, there is insufficient evidence to use the BCI test to guide decisions about extended endocrine therapy with either tamoxifen, an AI, or a sequence of tamoxifen followed by AI

Clinical treatment score post-5 years.

Recommendation 1.26. If a patient is postmenopausal and had invasive breast cancer and is recurrence-free after 5 years of adjuvant endocrine therapy, the clinical treatment score post-5 years (CTS5) web tool may be used to calculate the estimated risk of late recurrence (recurrence between years 5-10), which could assist in decisions about extended endocrine therapy

HER2-Positive Breast Cancer or Triple-Negative Breast Cancer

Oncotype DX, EndoPredict, MammaPrint, BCI, Prosigna, Ki67, or IHC4.

Recommendation 1.27. If a patient has HER2-positive breast cancer or TNBC, the clinician should not use multiparameter gene expression or protein assays (Oncotype DX, EndoPredict, MammaPrint, BCI, Prosigna, Ki67, or IHC4) to guide decisions for adjuvant endocrine and chemotherapy

Emerging Biomarkers

Tumor-infiltrating lymphocytes.

Recommendation 1.28. If a patient has node-negative or node-positive ER-positive, HER2-positive, or TNBC, the clinician should not use TILs to guide decisions for (neo)adjuvant endocrine and chemotherapy

PD-L1 testing.

Recommendation 1.29. If a patient has node-negative or node-positive ER-positive, HER2-positive, or TNBC, the clinician should not use PD-L1 testing to guide decisions for (neo)adjuvant endocrine and chemotherapy

Circulating tumor cells.

Recommendation 1.30. If a patient has node-negative or node-positive ER-positive, HER2-positive, or TNBC, the clinician should not use circulating tumor cells (CTC) to guide decisions for adjuvant endocrine and chemotherapy

Circulating tumor DNA.

Recommendation 1.31. If a patient has node-negative or node-positive ER-positive, HER2-positive, or TNBC, the clinician should not use ctDNA to guide decisions for adjuvant endocrine and chemotherapy

ASCO additionally recommended that all patients should be given the opportunity to participate in cancer clinical trials.

Biomarkers for Adjuvant Endocrine and Chemotherapy in Early-Stage Breast Cancer: ASCO Guideline Update. Andre F, Ismaila N, Allison KH, et al. DOI: 10.1200/JCO.22.00069 Journal of Clinical Oncology 40, no. 16 (June 01, 2022) 1816-1837.

Landmark Five Year Overall Survival Rates for OPDIVO® and YERVOY® Combination in Advanced NSCLC

RR

SUMMARY: The American Cancer Society estimates that for 2022, about 236,740 new cases of lung cancer will be diagnosed and 135,360 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.

Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions by switching off the immune system T cells. Immune checkpoint proteins/receptors include CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152) and PD-1(Programmed cell Death 1). Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response. OPDIVO® (Nivolumab) 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. YERVOY® is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4.

CheckMate-227 is an open-label, multi-part, global, Phase III trial in which OPDIVO® based regimens were compared with Platinum-doublet chemotherapy in patients with first line advanced NSCLC, across non-squamous and squamous tumor histologies. This study consisted of Part 1a/Part 1b and Part 2. In Part 2 of this trial, OPDIVO® plus chemotherapy was compared with chemotherapy alone, regardless of PD-L1 expression. Part 2 did not meet its Primary endpoint for Overall Survival for OPDIVO® plus chemotherapy versus chemotherapy alone, in patients with non-squamous NSCLC, and is published elsewhere.

Part 1a: Patients received OPDIVO® 3 mg/kg IV every 2 weeks plus YERVOY® 1 mg/kg IV every 6 weeks (N=396), OPDIVO® monotherapy 240 mg IV every 2 weeks (N=396) or chemotherapy alone given every 3 weeks for up to four cycles (N=397), in patients whose tumors had PD-L1 expression of 1% or more.
Part 1b: Patients received OPDIVO® plus YERVOY® (N=187), OPDIVO® 360 mg IV every 3 weeks plus chemotherapy IV every 3 weeks for up to four cycles (N=177), or chemotherapy alone IV every 3 weeks for up to four cycles (N=186), in patients whose tumors did not express PD-L1 (less than 1%)

Patients were stratified by histology, and treatment was administered until disease progression, unacceptable toxicity, or administered for 2 years for immunotherapy. It should be noted that when this trial was launched, chemotherapy along with immunotherapy or immunotherapy alone was not approved for the front-line treatment of NSCLC. Therefore, dual immunotherapy combination was not compared with current standards of care such as chemotherapy plus immunotherapy.

There were two independent Primary endpoints in Part 1 for OPDIVO® plus YERVOY® versus chemotherapy: Overall survival (OS) in patients whose tumors express PD-L1 (assessed in patients enrolled in Part 1a) and Progression Free Survival (PFS) in patients with TMB of 10 mut/Mb or more, across the PD-L1 spectrum (assessed in patients enrolled across Part 1a and Part 1b). Other assessments included Objective Response Rate (ORR), Duration of Response (DOR), and treatment-free interval. Treatment-free interval was measured in patients who discontinued study therapy and was defined as the time from last study dose to start of subsequent systemic therapy.

The Overall Survival (OS) data was previously reported at a minimum follow up of 29 months, and the median OS was of 17.1 months for the OPDIVO® plus YERVOY® group, compared to 14.9 months in the chemotherapy group (HR=0.79; P=0.007), with a 2-year OS rate of 40.0% and 32.8%, respectively. The researchers here in presented data after a minimum follow up of 61.3 months (5 years).

Patients whose tumors had PD-L1 expression of 1% or more continued to have sustained long term OS benefit with OPDIVO® plus YERVOY® when compared to chemotherapy (HR=0.77), and the 5-year OS rates were 24% with OPDIVO® plus YERVOY® compared to 14% with chemotherapy alone.

Patients with a PD-L1 expression of less than 1% also demonstrated continued long term OS benefit with OPDIVO® plus YERVOY® when compared to chemotherapy (HR = 0.65), and the 5-year OS rates were 19% for OPDIVO® plus YERVOY&reg compared to 7% for chemotherapy alone.

Among patients who survived for 5 years, median PFS was 59.1 months for PD-L1–positive patients and 60.7 months for PD-L1–negative patients who received OPDIVO® plus YERVOY®, compared to 9.5 months and 24.9 months respectively, for those who received chemotherapy.

Among those who responded to treatment, more patients who received OPDIVO® plus YERVOY® remained in response at five years, compared to chemotherapy, in both PD-L1 expression of 1% or more group (28% versus 3%) and PD-L1 expression of less than 1% group (21% versus 0%), respectively.

Among patients treated with OPDIVO® plus YERVOY® who were alive at five years, approximately two-thirds of patients did not receive any subsequent therapy for more than three years after stopping treatment, regardless of PD-L1 expression.

It was concluded that in this longest reported follow up of a Phase III trial of first line, chemotherapy free, combination immunotherapy, in metastatic Non Small cell Lung Cancer, a combination of OPDIVO® plus YERVOY® continued to provide long term durable clinical benefit and increased 5-year survivorship, when compared to chemotherapy, in previously untreated patients with metastatic NSCLC, regardless of PD-L1 expression.

Five-year survival outcomes with nivolumab (NIVO) plus ipilimumab (IPI) versus chemotherapy (chemo) as first-line (1L) treatment for metastatic non–small cell lung cancer (NSCLC): Results from CheckMate 227. Brahmer JR, Lee J-S, Ciuleanu T-E, et al. DOI: 10.1200/JCO.22.01503 Journal of Clinical Oncology. Published online October 12, 2022.

Clinical considerations in 1L advanced renal cell carcinoma (aRCC)

RR

Written by Manojkumar Bupathi, MD, MS
Sponsored by Exelixis

The treatment of patients with aRCC is evolving rapidly, with new regimens being developed and approved for 1L therapy. When choosing a regimen for patients, there are a number of treatment components to assess, including but not limited to the patient’s clinical presentation, their ability to tolerate treatment, and potential impact on quality of life. In my practice, I look at the location of metastases in the patient, whether they have symptomatic disease, and whether treatment‐related adverse reactions can be managed with supportive care.

A 1L aRCC treatment I consider is the FDA‐approved combination of CABOMETYX® (cabozantinib) + OPDIVO® (nivolumab). I believe CABOMETYX + OPDIVO offers a balance of data including superior OS, safety and tolerability, and patient‐ reported QoL data.1‐3*

CheckMate‐9ER was a randomized (1:1), open‐label, Phase 3 trial vs sunitinib in 651 patients with previously untreated aRCC with a clear‐cell component.1,2,4

  • Dosing: CABOMETYX 40 mg (starting dose) PO once daily in combination with OPDIVO 240 mg flat dose IV every 2 weeks vs sunitinib 50 mg (starting dose) PO once daily for 4 weeks,      followed by 2 weeks off, per cycle.1
  • Starting dose: unlike the 60‐mg recommended starting dose for single‐ agent therapy, the starting dose of CABOMETYX is 40 mg when used in combination with OPDIVO1
  • Primary endpoint: PFS1
  • Secondary endpoints: OS, ORR, and safety1,4
  • Quality of life: evaluated as an exploratory endpoint using the FKSI‐19 scale, and the clinical significance of the results is unknown2,3
  • Additional exploratory endpoints: biomarkers, pharmacokinetics, immunogenicity, and PFS‐22,5
  • Updated efficacy analysis: conducted when 271 events were observed based on the pre‐specified number of events for the pre‐planned final analysis of OS1,6

Primary analysis results (median follow‐up time of 18.1 months; range: 10.6‐30.6 months)2:

Updated analysis of OS (median follow‐up: 32.9 months; range: 25.4‐45.4 months):

  • Median OS was 37.7 months for CABOMETYX + OPDIVO (95% CI: 35.5‐NR; n=323) compared with 34.3 months for sunitinib (95% CI: 29.0‐NR; n=328); HR=0.70 (95% CI: 0.55‐0.90).1,6,7

When selecting a 1L treatment for my patients with aRCC, I review all the efficacy endpoints along with tolerability and safety data, as well as dosing. In Checkmate 9ER, serious adverse reactions occurred in 48% of patients receiving CABOMETYX+ OPDIVO (n=320).1 Serious adverse reactions reported in ≥2% of patients were diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract infection, and hyponatremia.1 Fatal intestinal perforations occurred in 3 (0.9%) patients.1 The most common adverse reactions (≥20%) in patients receiving CABOMETYX + OPDIVO were diarrhea (64%), fatigue (51%), hepatotoxicity (44%), palmar‐plantar erythrodysesthesia syndrome (40%), stomatitis (37%), rash (36%), hypertension (36%), hypothyroidism (34%), musculoskeletal pain (33%), decreased appetite (28%), nausea (27%), dysgeusia (24%), abdominal pain (22%), upper respiratory tract infection (20%), and cough (20%).1

  • CABOMETYX may be interrupted or reduced due to adverse events to 20 mg daily or 20 mg every other day.1
    • If previously receiving 20 mg once every other day, resume at same dosage. If not tolerated, discontinue CABOMETYX.1
    • Adverse reactions leading to discontinuation of either CABOMETYX or OPDIVO occurred in 20% of patients, which included 8% (CABOMETYX only) and 7% (OPDIVO only). It is important to note that 6% of patients in the CheckMate‐9ER trial discontinued both CABOMETYX and OPDIVO due to adverse events, compared with 16.9% of patients in the sunitinib arm who permanently discontinued their treatment.1,8
  • CABOMETYX should be permanently discontinued for Grade 3 or 4 hemorrhage, development of a GI perforation or Grade 4 fistula, acute myocardial infarction or Grade 2 or higher cerebral infarction, Grade 3 or 4 arterial thromboembolic events or Grade 4 venous thromboembolic events, Grade 4 hypertension/hypertensive crisis or Grade 3 hypertension/hypertensive crisis that cannot be controlled, nephrotic syndrome, or reversible posterior leukoencephalopathy syndrome1
  • For patients being treated with CABOMETYX in combination with OPDIVO, if ALT or AST >10x ULN or >3x ULN with concurrent total bilirubin ≥2x ULN, both CABOMETYX and OPDIVO should be permanently discontinued1

With these data, I feel comfortable using CABOMETYX + OPDIVO as a first‐line treatment for appropriate aRCC patients. I’d like to add that, according to the NCCN guidelines, CABOMETYX + OPDIVO is a category 1 preferred regimen in clear cell aRCC, which gives me additional confidence to prescribe this regimen for appropriate patients.9‡

Dr Bupathi received a fee for participating in this program, and his comments reflect his opinions and are not intended to constitute medical advice for individual patients.

[Footnotes]
*Superior OS vs sunitinib in patients with previously untreated aRCC. Primary analysis OS results: 40% reduction in risk of death with CABOMETYX + OPDIVO vs sunitinib (HR=0.60 [98.89% CI: 0.40‐0.89]; P=0.001); median OS was not reached in either arm. The primary endpoint was PFS, and secondary endpoints included OS, ORR, and safety. Quality of life was evaluated as an exploratory endpoint using the FKSI‐19 scale, and the clinical significance is unknown.1-3
†PFS and ORR were assessed by BICR.1
‡The trial population size of CheckMate‐9ER was 651 patients.1

1L=first‐line; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BICR=blinded independent central review; CI=confidence interval; FDA=Food and Drug Administration; FKSI‐19=Functional Assessment of Cancer Therapy‐Kidney Symptom Index 19; HR=hazard ratio; IO=immunotherapy; IV=intravenous; NR=not reached; ORR=objective response rate; OS=overall survival; PFS=progression‐free survival; PFS‐2=PFS after subsequent therapy; PO=by mouth; QoL=quality of life; TKI=tyrosine kinase inhibitor; ULN=upper limit of normal.

INDICATIONS
CABOMETYX® (cabozantinib), in combination with nivolumab, is indicated for the first‐line treatment of patients with advanced renal cell carcinoma (RCC).
CABOMETYX is indicated for the treatment of patients with advanced RCC.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS
Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX patients in RCC, HCC, and DTC studies. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage and prior to surgery as recommended. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.
Perforations and Fistulas: Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a Grade 4 fistula or a GI perforation.
Thrombotic Events: CABOMETYX increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX patients. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention.
Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension was reported in 37% (16% Grade 3 and <1% Grade 4) of CABOMETYX patients. Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume at a reduced dose. Permanently discontinue CABOMETYX for severe hypertension that cannot be controlled with anti‐hypertensive therapy or for hypertensive crisis.
Diarrhea: Diarrhea occurred in 62% of CABOMETYX patients. Grade 3 diarrhea occurred in 10% of CABOMETYX patients. Monitor and manage patients using antidiarrheals as indicated. Withhold CABOMETYX until improvement to ≤ Grade 1, resume at a reduced dose.
Palmar‐Plantar Erythrodysesthesia (PPE): PPE occurred in 45% of CABOMETYX patients. Grade 3 PPE occurred in 13% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.
Hepatotoxicity: CABOMETYX in combination with nivolumab can cause hepatic toxicity with higher frequencies of Grades 3 and 4 ALT and AST elevations compared to CABOMETYX alone.
Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes than when the drugs are administered as single agents. For elevated liver enzymes, interrupt CABOMETYX and nivolumab and consider administering corticosteroids.
With the combination of CABOMETYX and nivolumab, Grades 3 and 4 increased ALT or AST were seen in 11% of patients. ALT or AST >3 times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0‐1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT or AST who were rechallenged with either CABOMETYX (n=9) or nivolumab (n=11) as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST was observed in 2 patients receiving CABOMETYX, 2 patients receiving nivolumab, and 7 patients receiving both CABOMETYX and nivolumab.
Withhold and resume at a reduced dose based on severity.
Adrenal Insufficiency: CABOMETYX in combination with nivolumab can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold CABOMETYX and/or nivolumab and resume CABOMETYX at a reduced dose depending on severity.
Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received CABOMETYX with nivolumab, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of CABOMETYX and nivolumab in 0.9% and withholding of CABOMETYX and nivolumab in 2.8% of patients with RCC.
Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom CABOMETYX with nivolumab was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.
Proteinuria: Proteinuria was observed in 8% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. For Grade 2 or 3 proteinuria, withhold CABOMETYX until improvement to ≤ Grade 1 proteinuria, resume CABOMETYX at a reduced dose. Discontinue CABOMETYX in patients who develop nephrotic syndrome.
Osteonecrosis of the Jaw (ONJ): ONJ occurred in <1% of CABOMETYX patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain, or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to CABOMETYX initiation and periodically during treatment. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold CABOMETYX for development of ONJ until complete resolution, resume at a reduced dose.
Impaired Wound Healing: Wound complications occurred with CABOMETYX. Withhold CABOMETYX for at least 3 weeks prior to elective surgery. Do not administer CABOMETYX for at least 2 weeks after major surgery and until adequate wound healing. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic findings on MRI, can occur with CABOMETYX. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.
Thyroid Dysfunction: Thyroid dysfunction, primarily hypothyroidism, has been observed with CABOMETYX. Based on the safety population, thyroid dysfunction occurred in 19% of patients treated with CABOMETYX, including Grade 3 in 0.4% of patients.
Patients should be assessed for signs of thyroid dysfunction prior to the initiation of CABOMETYX and monitored for signs and symptoms of thyroid dysfunction during CABOMETYX treatment. Thyroid function testing and management of dysfunction should be performed as clinically indicated.
Hypocalcemia: CABOMETYX can cause hypocalcemia. Based on the safety population, hypocalcemia occurred in 13% of patients treated with CABOMETYX, including Grade 3 in 2% and Grade 4 in 1% of patients. Laboratory abnormality data were not collected in CABOSUN.
In COSMIC‐311, hypocalcemia occurred in 36% of patients treated with CABOMETYX, including Grade 3 in 6% and Grade 4 in 3% of patients.
Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue CABOMETYX depending on severity.
Embryo‐Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiating CABOMETYX and advise them to use effective contraception during treatment and for 4 months after the last dose.

ADVERSE REACTIONS
The most common (≥20%) adverse reactions are:
CABOMETYX as a single agent: diarrhea, fatigue, PPE, decreased appetite, hypertension, nausea, vomiting, weight decreased, constipation.
CABOMETYX in combination with nivolumab: diarrhea, fatigue, hepatotoxicity, PPE, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.

DRUG INTERACTIONS
Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit juice.
Strong CYP3A4 Inducers: If coadministration with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage. Avoid St. John’s wort.

USE IN SPECIFIC POPULATIONS
Lactation: Advise women not to breastfeed during CABOMETYX treatment and for 4 months after the final dose.
Hepatic Impairment: In patients with moderate hepatic impairment, reduce the CABOMETYX dosage. Avoid CABOMETYX in patients with severe hepatic impairment.

Please see accompanying full Prescribing Information by clicking here.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1‐800‐FDA‐1088.

References
1. CABOMETYX® (cabozantinib) Prescribing Information. Exelixis, Inc, 2022.
2. Choueiri TK, Powles T, Burotto M, et al; CheckMate 9ER Investigators. Nivolumab plus cabozantinib versus sunitinib for advanced renal‐cell carcinoma. N Engl J Med. 2021;384(9):829‐841.
3. Choueiri TK, Powles T, Burotto M, et al; CheckMate 9ER Investigators. Nivolumab plus cabozantinib versus sunitinib for advanced renal‐cell carcinoma [supplementary appendix]. N Engl J Med. 2021;384(9):829‐841.
4. Motzer RJ, Choueiri TK, Powles T, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal cell carcinoma: outcomes by sarcomatoid histology and updated trial results with extended follow‐up of CheckMate 9ER. Poster presented at Genitourinary Cancers Symposium; February 11‐ 13, 2021.
5. Choueiri TK, Powles T, Burotto M, et al; CheckMate 9ER Investigators. Nivolumab plus cabozantinib versus sunitinib for advanced renal‐cell carcinoma [protocol]. N Engl J Med. 2021;384(9):829‐841.
6. Powles T, Choueiri TK, Burotto M, et al. Final overall survival analysis and organ‐specific target lesion assessments with 2‐year follow‐up in CheckMate 9ER: nivolumab plus cabozantinib versus sunitinib for patients with advanced renal cell carcinoma. Poster presented at the American Society of Clinical Oncology Genitourinary Cancers Symposium; February 17‐19, 2022.
7. Motzer RJ, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib in first‐line treatment for advanced renal cell carcinoma (CheckMate 9ER): long‐term follow‐up results from an open‐label, randomized, phase 3 trial. Lancet Oncol. 2022;23(7):888‐898.
8. Data on file. Final Clinical Study Report for Study CA2099ER. Bristol Myers Squibb.
9. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Kidney Cancer V.3.2023. © National Comprehensive Cancer Network, Inc. 2022.

All rights reserved. Accessed September 29, 2022. To view the most recent and complete version of the guideline, go online to NCCN.org.

©2022 Exelixis, Inc. CA‐2644 12/22
OPDIVO® and the related logo are registered trademarks of Bristol‐Myers Squibb Company.

TUKYSA® Combination in HER2-Positive Metastatic Breast Cancer Patients with Brain Metastases

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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. Approximately 290,560 new cases of breast cancer will be diagnosed in 2022 and about 43,780 individuals will die of the disease, largely due to metastatic recurrence.

The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. Patients with HER2-positive metastatic breast cancer are often treated with anti-HER2 targeted therapy along with chemotherapy, irrespective of hormone receptor status, and this has resulted in significantly improved treatment outcomes. HER2-targeted therapies include HERCEPTIN® (Trastuzumab), TYKERB® (Lapatinib), PERJETA® (Pertuzumab), KADCYLA® (ado-Trastuzumab emtansine), ENHERTU® (Trastuzumab deruxtecan) and MARGENZA® (Margetuximab). Dual HER2 blockade with HERCEPTIN® and PERJETA®, given along with chemotherapy (with or without endocrine therapy), as first line treatment, in HER2-positive metastatic breast cancer patients, was shown to significantly improve Progression Free Survival (PFS) as well as Overall Survival (OS). The superior benefit with dual HER2 blockade has been attributed to differing mechanisms of action and synergistic interaction between HER2 targeted therapies. Patients progressing on Dual HER2 blockade often receive KADCYLA® which results in an Objective Response Rate (ORR) of 44% and a median PFS of 9.6 months, when administered after HERCEPTIN® and a taxane. There is however no standard treatment option for this patient population following progression on KADCYLA®.

With advances in systemic therapies for this patient population, the incidence of brain metastases as a sanctuary site has increased. Approximately 50% of patients with HER2-positive metastatic breast cancer develop brain metastases. However, systemic HER2-targeted agents, including Tyrosine Kinase Inhibitors, as well as chemotherapy have limited antitumor activity in the brain. Local therapeutic interventions for brain metastases include neurosurgical resection and Stereotactic or Whole-Brain Radiation Therapy. There is a high unmet need for systemic treatment options to treat established brain metastases and reduce the risk for progression in the Central Nervous System (CNS).

TUKYSA® (Tucatinib) is an oral Tyrosine Kinase Inhibitor that is highly selective for the kinase domain of HER2 with minimal inhibition of Epidermal Growth Factor Receptor. In a Phase 1b dose-escalation trial, TUKYSA® in combination with HERCEPTIN® and XELODA® (Capecitabine) showed encouraging antitumor activity in patients with HER2-positive metastatic breast cancer, including those with brain metastases.

HER2CLIMB is an international, randomized, double-blind, placebo-controlled trial in which the combination of TUKYSA® plus HERCEPTIN® and XELODA® was compared with placebo plus HERCEPTIN® and XELODA®. A total of 612 patients with unresectable locally advanced or metastatic HER2-positive breast cancer, who were previously treated with HERCEPTIN®, PERJETA® (Pertuzumab) and KADCYLA® (ado-Trastuzumab emtansine) were enrolled. Patients were randomly assigned in a 2:1 ratio to receive either TUKYSA® 300 mg orally twice daily throughout the treatment period (N=410) or placebo orally twice daily (N=201), in combination with HERCEPTIN® 6 mg/kg IV once every 21 days, following an initial loading dose of 8 mg/kg, and XELODA® 1000 mg/m2 orally twice daily on days 1 to 14 of each 21-day cycle. Stratification factors included presence or absence of brain metastases, ECOG Performance Status and geographic region. The median patient age was 52 years and patient demographics as well as disease characteristics at baseline were well balanced between the two treatment groups. In the total treatment population, 47.5% had brain metastases at baseline, 48.3% in the TUKYSA® combination group and 46% in the placebo combination group. The Primary endpoint was Progression Free Survival (PFS). Secondary end points included Overall Survival (OS), PFS among patients with brain metastases, confirmed Objective Response Rate (ORR), and Safety.

At median follow-up of 29.6 months, median OS in all patients with brain metastases at baseline was 9.1 months longer in the TUKYSA® combination group compared to the placebo combination group (21.6 versus 12.5 months, HR=0.60; P<0.001), with a 40% reduction in the risk of death with the TUKYSA® combination. The estimated 1-year OS was 70.0% for the TUKYSA® combination group and 50.6% for the placebo combination group and the estimated 2-year OS was 48.5% and 25.1% respectively.

The researchers in this exploratory subgroup analyses reported efficacy outcomes for patients with brain metastases, as well as time to new brain lesion(s) as the site of first progression or death, in all patients enrolled in HER2CLIMB trial, at a median follow up of 29.6 months.

There was greater CNS Progression Free Survival in the TUKYSA® combination group compared with the placebo combination group and was 5.7 months longer (9.9 versus 4.2 months, HR=0.39; P<0.001), with a 61% reduction in the risk of CNS progression with the TUKYSA® combination. The estimated 1 and 2-year CNS Progression Free Survivals were 38.4% versus 7.9% and 19.3% versus 0%, respectively.

Among those with active brain metastases and measurable disease at baseline, the intracranial Objective Response Rates for the TUKYSA® combination group were 47.3% versus 20.0% for the placebo combination group, with a median duration of intra cranial response of 8.6 versus 3.0 months, respectively.

The risk of developing new brain lesions as the site of first progression or death was reduced by 45% in the TUKYSA® combination group versus the placebo-combination group (HR=0.55; P =0.006).

The authors concluded that in this exploratory subgroup analysis, TUKYSA® in combination with HERCEPTIN® and XELODA® provided a clinically meaningful survival benefit, while reducing the risk of developing new brain lesions. The authors added that HER2CLIMB is currently the only double-blind, randomized, controlled clinical trial for patients with HER2-positive metastatic breast cancer, that prospectively included patients with both active and stable brain metastases.

Tucatinib vs Placebo, Both in Combination with Trastuzumab and Capecitabine, for Previously Treated ERBB2 (HER2)-Positive Metastatic Breast Cancer in Patients With Brain Metastases: Updated Exploratory Analysis of the HER2CLIMB Randomized Clinical Trial. Lin NU, Murthy RK, Abramson V, et al. JAMA Oncol. Published online December 1, 2022. doi:10.1001/jamaoncol.2022.5610

FDA Grants Accelerated Approval to KRAZATI® for KRAS G12C-mutated NSCLC

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SUMMARY: The FDA on December 12, 2022, granted accelerated approval to KRAZATI® (Adagrasib), a RAS GTPase family inhibitor, for adult patients with KRAS G12C-mutated locally advanced or metastatic Non-Small Cell Lung Cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy. FDA also approved the QIAGEN therascreen KRAS RGQ PCR kit (tissue) and the Agilent Resolution ctDx FIRST Assay (plasma) as companion diagnostics for KRAZATI®. If no mutation is detected in a plasma specimen, the tumor tissue should be tested.

The American Cancer Society estimates that for 2022, about 236,740 new cases of lung cancer will be diagnosed and 135,360 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.

The KRAS (kirsten rat sarcoma viral oncogene homologue) proto-oncogene encodes a protein that is a member of the small GTPase super family. The KRAS gene provides instructions for making the KRAS protein, which is a part of a signaling pathway known as the RAS/MAPK pathway. By relaying signals from outside the cell to the cell nucleus, the protein instructs the cell to grow, divide and differentiate. The KRAS protein is a GTPase and converts GTP into GDP. To transmit signals, the KRAS protein must be turned on by binding to a molecule of GTP. When GTP is converted to GDP, the KRAS protein is turned off or inactivated, and when the KRAS protein is bound to GDP, it does not relay signals to the cell nucleus. The KRAS gene is in the Ras family of oncogenes, which also includes two other genes, HRAS and NRAS. When mutated, oncogenes have the potential to change normal cells cancerous.

KRAS is the most frequently mutated oncogene in human cancers and are often associated with resistance to targeted therapies and poor outcomes. The KRAS G12C mutation occurs in approximately 25% of Non-Small Cell Lung Cancers (NSCLC) and in 3-5% of colorectal cancers and other solid cancers. KRAS G12C is one of the most prevalent driver mutations in NSCLC and accounts for a greater number of patients than those with ALK, ROS1, RET, and TRK 1/2/3 mutations combined. KRAS G12C cancers are genomically more heterogeneous and occur more frequently in current or former smokers and are likely to be more complex genomically than EGFR mutant or ALK rearranged cancers. G12C is a single point mutation with a Glycine-to-Cysteine substitution at codon 12. This substitution favors the activated state of KRAS, resulting in a predominantly GTP-bound KRAS oncoprotein, amplifying signaling pathways that lead to oncogenesis.

KRAZATI® (Adagrasib) is a potent, orally available, small molecule covalent inhibitor of KRAS G12C. This drug irreversibly and selectively binds KRAS G12C in its inactive, GDP-bound state. Unlike LUMAKRAS® (Sotorasib), which is also a selective covalent inhibitor of KRAS G12C, KRAZATI® has a longer drug half-life of 23 hours, as compared to 5 hours for LUMAKRAS®, has dose-dependent extended exposure, and can penetrate the CNS. Approximately, 27-42% of patients with NSCLC harboring KRAS G12C mutations have CNS metastases, with poor outcomes. KRYSTAL-1 is a Phase I/II multiple expansion cohort trial involving patients with advanced solid tumors harboring a KRAS G12C mutation. KRAZATI® demonstrated clinical activity in patients with KRAS G12C-mutated solid tumors, including colorectal, pancreatic, and biliary tract cancers. Further, preliminary data from two patients with untreated CNS metastases from a Phase 1b cohort showed antitumor activity against CNS metastases, with satisfactory concentrations of KRAZATI® in the CSF.

The present FDA approval was based on the results from Cohort A, a Phase 2 cohort of the KRYSTAL-1 study in which KRAZATI® at a dose of 600 mg orally twice daily was evaluated in patients with KRAS G12C-mutated NSCLC, previously treated with chemotherapy and anti-Programmed Death 1 (PD-1) or Programmed Death Ligand 1 (PD-L1) therapy. This registration study included a total of 116 unresectable or metastatic NSCLC patients, with histologically confirmed diagnosis, with KRAS G12C mutation (detected in tumor tissue at a local or central laboratory), who had previously received treatment with at least one platinum-containing chemotherapy regimen and checkpoint inhibitor therapy (in sequence or concurrently), and who had measurable tumor lesions. Enrolled patients received KRAZATI® 600 mg capsule twice daily, and treatment was continued until disease progression or unacceptable toxicities. The median patient age was 64 years, 97% had adenocarcinoma histology, 98% had both platinum-based therapy and checkpoint inhibitor therapy, and 21% of patients had CNS metastases. Key exclusion criteria included active CNS metastases (patients were eligible if CNS metastases were adequately treated and neurologically stable), carcinomatous meningitis, and previous treatment with a KRAS G12C inhibitor. Exploratory Biomarker Analyses included candidate biomarkers (PD-L1 Tumor Proportion Score and mutational status of STK11, KEAP1, TP53, and CDKN2A on tumor-tissue specimens, blood specimens, or both, for their association with tumor response. The Primary end point was Objective Response Rate as assessed by blinded Independent Central Review. Secondary end points included the Duration of Response, Progression Free Survival, Overall Survival, and safety. The median follow up was 12.9 months and the median duration of treatment was 5.7 months.

Of 112 patients with measurable disease at baseline, the confirmed Objective Response Rate was 42.9% and the median Duration of Response was 8.5 months. The median Progression Free Survival was 6.5 months, and the median Overall Survival was 12.6 months, at a median follow up of 15.6 months. Among 33 patients with previously treated, stable CNS metastases, the intracranial confirmed Objective Response Rate was 33.3%. Treatment-related adverse events occurred in 97.4% of the patients and 53% were Grade 1 or 2 toxicities. KRAZATI® was discontinued in 6.9% of patients due to adverse events.

It was concluded that among patients with previously treated KRAS G12C-mutated NSCLC, KRAZATI® showed significant clinical efficacy without new safety signals and encouraging intracranial activity. The researchers added that these are the first clinical data demonstrating CNS-specific activity of a KRAS G12C inhibitor in this patient population.

Adagrasib in Non–Small-Cell Lung Cancer Harboring a KRASG12C Mutation. Jänne PA, Riely GJ, Gadgeel SM, et al. N Engl J Med 2022; 387:1238-1239

Sustained Benefit with Adjuvant VERZENIO® in High-Risk 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. Approximately 290,560 new cases of breast cancer will be diagnosed in 2022 and about 43,780 individuals will die of the disease, largely due to metastatic recurrence. 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. Majority of these patients are diagnosed with early stage disease and 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. 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, 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.

VERZENIO® (Abemaciclib) is an oral, selective inhibitor of CDK4 and CDK6 kinase activity, and prevents the phosphorylation and subsequent inactivation of the Rb tumor suppressor protein, thereby inducing G1 cell cycle arrest and inhibition of cell proliferation. VERZENIO® is structurally distinct from other CDK 4 and 6 inhibitors (such as Ribociclib and Palbociclib) and is 14 times more potent against Cyclin D1/CDK 4 and Cyclin D3/CDK 6, in enzymatic assays, but potentially less toxic than earlier pan-CDK inhibitors. At higher doses, only VERZENIO® causes significant cancer cell death, compared with other CDK4/6 inhibitors, suggesting that this drug may be affecting proteins, other than CDK4/6. Additionally, preclinical studies have demonstrated that VERZENIO® may have additional therapeutic benefits for a subset of tumors that are unresponsive to treatment or have grown resistant to other CDK4/6 inhibitors. It has also been shown to cross the blood-brain barrier.

The International monarchE trial, is an open-label, randomized, Phase III study, which included 5637 patients, who were pre- and postmenopausal, with HR-positive, HER2-negative early breast cancer, and with clinical and/or pathologic risk factors that rendered them at high risk for relapse. The goal of monarchE was to evaluate the additional benefit of adding a CDK4/6 inhibitor to endocrine therapy in the adjuvant setting, for patients with HR-positive, HER2-negative, high risk, early breast cancer. The researchers defined high risk as the presence of four or more positive axillary lymph nodes, or 1-3 three positive axillary lymph nodes, with either a tumor size of 5 cm or more, or histologic Grade 3 disease (Cohort 1). A smaller group of patients with 1-3 positive axillary lymph nodes and centrally determined Ki-67 score of 20% or more were enrolled in Cohort 2. Ki-67 score was also determined centrally in Cohort 1 patients, but Ki-67 determination was not required for enrollment in this cohort. Following completion of primary therapy which included both adjuvant and neoadjuvant chemotherapy and radiotherapy, patients were randomly assigned (1:1) to VERZENIO® 150 mg orally twice daily for 2 years plus 5-10 years of physician’s choice of endocrine therapy as clinically indicated (N=2808), or endocrine therapy alone (N=2829). The median patient age was 51 years, about 43% of the patients were premenopausal, and 95% of patients had prior chemotherapy. Approximately 60% of patients had 4 or more positive lymph nodes. The Primary endpoint was Invasive Disease-Free Survival (IDFS) in the Intent to Treat (ITT) population (Cohorts 1 and 2). Secondary end points included IDFS in patients with high Ki-67 score (in the ITT population and in the Cohort 1 population), Distant Relapse-Free Survival (DRFS), Overall Survival (OS), and Safety. The researchers reported updated results from an interim analysis to assess overall survival, as well as Invasive Disease-Free Survival and Distant Relapse-Free Survival, with additional follow-up.

At a median follow-up of 42 months (3.5 years), the median Invasive Disease-Free Survival (IDFS) was not reached in either group, and the IDFS benefit previously reported was sustained. The risk of developing invasive disease was reduced by 33.6% (HR=0.664; nominal P<0.0001). The 4-year IDFS rate was 85.8% for patients treated with VERZENIO® plus endocrine therapy, compared to 79.4% for patients treated with endocrine therapy alone, reflecting an absolute difference of 6.4% (compared to 2.8% at two years). The majority of the IDFS events were distant metastatic disease. Adjuvant VERZENIO® also reduced the risk of developing metastatic disease by 34.1% (HR=0.659; nominal P<0.0001). The 4-year DRFS rate was 88.4% for patients treated with VERZENIO® plus endocrine therapy, compared to 82.5% for patients treated with endocrine therapy alone, an absolute difference of 5.9% (compared to 2.5% at two years). As was noted in the previous analyses, a high Ki-67 score correlated with increased risk of recurrence, but this IDFS and DRFS benefit was seen across all prespecified subgroups, regardless of Ki-67 score. Overall Survival (OS) data were immature at the time of this analyses. However, fewer deaths were observed in the VERZENIO® plus endocrine therapy group, compared to endocrine therapy alone. There were no new safety findings, and overall results were consistent with the safety profile for VERZENIO®.

It was concluded that adjuvant VERZENIO® combined with endocrine therapy continued to demonstrate statistically significant and clinically meaningful improvement in Invasive Disease Free Survival and Distant Relapse Free Survival, among patients with HR-positive, HER2-negative, node-positive, high risk, early breast cancer, regardless of Ki-67 status. These benefits were sustained after patients completed 2 years of adjuvant treatment with VERZENIO®, with an absolute increase at 4 years. The authors added that further follow-up is needed to establish whether Overall Survival can be improved with VERZENIO® plus endocrine therapy in this patient group.

Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): results from a preplanned interim analysis of a randomised, open-label, phase 3 trial. Johnston SRD, Toi M, O’Shaughnessy J, et al. The Lancet Oncology. Published:December 06, 2022. DOI:https://doi.org/10.1016/S1470-2045(22)00694-5

Unprecedented Progression Free Survival with SARCLISA® plus KYPROLIS® and Dexamethasone in Relapsed Multiple Myeloma

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 34,470 new cases will be diagnosed in 2022 and 12,640 patients will die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, Immunomodulatory agents and CD 38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, multiple myeloma in 2022 remains an incurable disease.

KYPROLIS® (Carfilzomib) is a second generation selective, epoxyketone Proteasome Inhibitor and unlike VELCADE® (Bortezomib), proteasome inhibition with KYPROLIS® is irreversible. CD38 is a transmembrane glycoprotein abundantly expressed on malignant plasma cells and with low levels of expression on normal lymphoid and myeloid cells. DARZALEX® (Daratumumab) is a human IgG1 antibody that targets CD38, and was approved for use in combination with KYPROLIS® and Dexamethasone in 2020, for the treatment of patients with multiple myeloma, who had received 1-3 prior lines of therapy. This was based on the CANDOR open label, Phase III trial, in which the triplet combination of DARZALEX®, KYPROLIS® and Dexamethasone resulted in a 37% reduction in the risk of progression or death, compared with KYPROLIS® and Dexamethasone. DARZALEX® exerts its cytotoxic effect on myeloma cells by multiple mechanisms, including Antibody Dependent Cellular Cytotoxicity (ADCC), Complement Mediated Cytotoxicity and direct apoptosis. Additionally, DARZALEX® may have a role in immunomodulation, by depleting CD38-positive regulator Immune suppressor cells, and thereby expanding T cells, in patients responding to therapy.

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

IKEMA trial is a multicenter, randomized, open label, Phase III study, in which the efficacy and safety of SARCLISA® in combination with KYPROLIS® and Dexamethasone was evaluated among patients with relapsed and/or refractory multiple myeloma, who had received 1-3 prior lines of therapy. In this study, 302 eligible patients were randomized 3:2 to receive SARCLISA® plus KYPROLIS® and Dexamethasone (N=179) or KYPROLIS® and Dexamethasone alone (N=123). SARCLISA® was given at 10 mg/kg IV weekly for 4 weeks and then every 2 weeks. KYPROLIS® was given at 20 mg/m2 IV on days 1 and 2 and then at 56 mg/m2 IV thereafter twice weekly for 3 of 4 weeks and Dexamethasone was given at 20 mg twice weekly. Treatment was continued until disease progression or unacceptable toxicity. The median age was 64 years, 23% had 3 or more prior lines of therapy, 90% of patients had prior treatment with Proteasome Inhibitor, 78% had prior treatment with Immunomodulatory drug (IMiD) and 24% had high-risk cytogenetics. The Primary endpoint was Progression Free Survival (PFS) as determined by an Independent Review Committee (IRC). Key Secondary endpoints included Overall Response Rate (ORR), rate of Very Good Partial Response (VGPR) or better, Complete Response (CR) rate, Minimal Residual Disease (MRD) negativity rate (10-5 by NGS), and Overall Survival (OS). The authors have now reported updated efficacy and safety results from IKEMA trial.

At a median follow-up of 44 months, the median PFS was 35.7 months in the SARCLISA® group and 19.2 months in the KYPROLIS® and Dexamethasone group (HR=0.58; 95.4% CI). The PFS benefit with SARCLISA® group was consistent across subgroups, including among patients with high-risk cytogenetics and those who were refractory to Lenalidomide. SARCLISA® plus KYPROLIS® and Dexamethasone also delayed the time to next treatment and prolonged PFS2. The median time to next treatment was 44.9 months with SARCLISA® combination and 25.0 months with KYPROLIS® and Dexamethasone (HR=0.55; 95% CI). The median PFS2 was 47.2 months and 35.6 months respectively (HR=0.68; 95% CI). The Complete Response (CR) rate or stringent CR rate was 44.1% in the SARCLISA® combination group and 28.5% in the KYPROLIS® and Dexamethasone group. MRD negativity was achieved in 33.5% of patients in the SARCLISA® combination group and 15.4% in the KYPROLIS® and Dexamethasone group. The rate of MRD negativity among patients with a CR or stringent CR was 26.3% in the SARCLISA® combination group and 12.2% in the KYPROLIS® and Dexamethasone group. No new safety signals were identified.

It was concluded that the addition of SARCLISA® to KYPROLIS® and Dexamethasone resulted in unprecedented median Progression Free Survival, Complete Response Rate and MRD negativity with a non-Lenalidomide regimen, and is the longest Progression Free Survival with a Proteasome Inhibitor backbone in the relapsed multiple myeloma setting. The authors added that SARCLISA® combination was well tolerated with manageable safety and a favorable benefit-risk profile, and this updated efficacy data support SARCLISA® in combination with KYPROLIS® and Dexamethasone as a standard of care treatment for patients with relapsed or refractory multiple myeloma.

VP5-2022: Updated progression-free survival (PFS) and depth of response in IKEMA, a randomized phase III trial of isatuximab, carfilzomib and dexamethasone (Isa-Kd) vs Kd in relapsed multiple myeloma (MM). Moreau P, Dimopoulos MA, Mikhael J, et al. ESMO Virtual Plenary. May 19-20, 2022. DOI:https://doi.org/10.1016/j.annonc.2022.04.013

IMBRUVICA® (Ibrutinib)

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The FDA on August 24, 2022, approved IMBRUVICA® (Ibrutinib) for pediatric patients ≥ 1 year of age with chronic Graft Versus Host Disease (cGVHD) after failure of 1 or more lines of systemic therapy. Formulations include capsules, tablets, and oral suspension. IMBRUVICA® is a product of Pharmacyclics LLC.