The FDA on January 19, 2023, granted accelerated approval to TUKYSA® in combination with Trastuzumab for RAS wild-type HER2-positive unresectable or metastatic colorectal cancer that has progressed following Fluoropyrimidine, Oxaliplatin, and Irinotecan-based chemotherapy. TUKYSA® is a product of Seagen Inc.
Author: RR
LUNSUMIO® (Mosunetuzumab-axgb)
The FDA on December 22, 2022 granted accelerated approval to LUNSUMIO®, a bispecific CD20-directed CD3 T-cell engager for adult patients with Relapsed or Refractory Follicular Lymphoma (FL) after two or more lines of systemic therapy. LUNSUMIO® is a product of Genentech, Inc.
Breast-Conserving Surgery with or without Irradiation in Early Breast Cancer
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. 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, adjuvant chemotherapy, and hormone therapy. However approximately 20% of patients will experience local recurrence or distant relapse during the first 10 years of treatment.
The median age at the time of breast cancer diagnosis in the US is 62 years and approximately 26% of breast cancer diagnoses are in women 65 to 74 years of age. Patient undergoing breast conserving surgery, often receive adjuvant breast radiation therapy to reduce the risk of local recurrence. Radiation therapy however is inconvenient, expensive and is associated with acute and late toxicities. Avoidance of radiation in elderly patients with low risk disease has remained controversial due to the lack of long term Level 1 evidence. In the LUMINA trial and PRIME II study of women over 55 years of age with low risk breast cancer, after a median follow up of 5 years, 5-year rate of ipsilateral breast tumor recurrence was low at 2-4% among those women who did not receive adjuvant whole-breast radiotherapy after breast-conserving surgery. The researchers herein reported the 10-year outcomes of the PRIME II trial.
PRIME II is a Phase III randomized clinical trial of the omission of breast irradiation, designed by the Scottish Cancer Trials Breast Group (SCTBG). This study included women 65 years of age or older, who had Hormone Receptor (HR)-positive, node-negative, T1 or T2 primary breast cancer (with tumors 3 cm or less in the largest dimension), treated with breast-conserving surgery with clear excision margins and adjuvant endocrine therapy. Patients were eligible if they had either cancer with Grade 3 histologic features or lymphovascular invasion but not both. A total of 1326 women were randomly assigned to receive 40-50 Gy whole-breast irradiation (N=658) or no radiation therapy (N=668). Both treatment groups were well balanced. The median patient age was 70 years and less than 10% of patients had ER-low tumors. The Primary end point was local breast cancer recurrence. Regional recurrence, breast cancer–specific survival, distant recurrence as the first event, and Overall Survival were also assessed. The median follow up was 9.1 years.
The cumulative incidence of local breast cancer recurrence after 10 years of follow up was 9.5% in the no-radiotherapy group and 0.9% in the radiotherapy group (HR=10.4; P<0.001). Even though local recurrence was more common in the group that did not receive radiotherapy, there was no substantial difference in the 10-year incidence of distant recurrence as the first event between the two treatment groups (1.6% without radiotherapy and 3.0% with radiotherapy). Overall Survival at 10 years was almost identical in the two groups, at 80.8% with no radiotherapy and 80.7% with radiotherapy. The incidence of regional recurrence and breast cancer–specific survival also did not differ substantially between the two groups.
The authors concluded that omission of radiotherapy was associated with an increased incidence of local recurrence but had no detrimental effect on distant recurrence as the first event, or Overall Survival, among women 65 years of age or older, with Grade 1 or 2, Estrogen Receptor-high breast cancers, treated with breast-conserving surgery and 5 years of adjuvant endocrine therapy.
Breast-Conserving Surgery with or without Irradiation in Early Breast Cancer. Kunkler IH, Williams LJ, Jack WJL, et al. N Engl J Med 2023; 388:585-594.
Lobar or Sublobar Resection for Peripheral Stage IA Non Small Cell Lung Cancer
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.
Low Dose CT (LDCT) screening for lung cancer resulted in a 20% reduction in mortality In the National Lung Screening Trial (NLST). The USPSTF expanded the criteria for lung cancer screening in 2021 and recommended annual screening with Low-Dose CT for adults aged 50-80 years who have a 20 pack-year smoking history and currently smoke or have quit within the past 15 years. Approximately 15% of patients present with early stage (T1-2 N0) disease, and these numbers are likely to increase with the more rigorous implementation of lung cancer screening programs.
Surgical resection is the primary treatment for approximately 30% of patients with NSCLC who present with early Stage (I–IIIA) disease. Pneumonectomy is rarely performed due to unacceptably high mortality rate. Lobectomy has been the standard of surgical care for patients with clinical T1N0 NSCLC since the mid 1990s. This was based on the results of a randomized trial comparing Lobectomy with Sublobar resection in patients with clinical T1N0 NSCLC. In this trial, the frequency of local recurrence was three times higher with Sublobar resection compared with Lobectomy, and lung cancer-related mortality was 50% higher with Sublobar resection.
Sublobar resection includes Wedge resection and Segmentectomy. In Wedge resection, the lung tumor is removed with a surrounding margin of normal lung tissue, and is not an anatomical resection. Segmentectomy, unlike Wedge resection, is an anatomical resection that usually includes one or more pulmonary parenchymal segments with the dissection of intraparenchymal and hilar lymph nodes. Advances in imaging as well as staging by means of mediastinoscopy, and routine intraoperative lymphadenectomy has enabled the identification of small, peripheral NSCLCs for which Sublobar resection was potentially appropriate. Sublobar resection was considered a “compromise operation” in selected high risk patients with early stage lung cancer. With the approval of lung cancer screening in high risk individuals and subsequent detection of small tumors, Sublobar resections have been on the rise and may be the preferred surgical option, even in good-risk patients, in many institutions. Sublobar resection preserves pulmonary function and leaves open more treatment options for NSCLC patients, who remain at high risk for metachronous primary NSCLC, following curative intervention for their first NSCLC.
With the implementation of CT-based lung cancer screening recently, lung cancers are likely detected at a very early stage (T1a-bN0; 2 cm or less, node negative tumors). Further, Adenocarcinoma now is the most frequent histologic subtype of lung cancer and present as peripherally located tumors. Advances in preoperative staging such as endobronchial ultrasonography, have improved patient selection for treatment. Majority of surgical resections are now performed by means of video or robotic-assisted thoracic surgery. This has improved postoperative outcomes, with significant reduction in perioperative morbidity, mortality and median length of hospital stay after either Sublobar resection or Lobectomy.
The authors in this study reported the results of a randomized international trial comparing Sublobar resection (wedge resection or segmentectomy) with Lobectomy, in patients with clinical Stage IA NSCLC, with a tumor size of 2 cm or less. Cancer and Leukemia Group B (CALGB) 140503 was a multicenter, international, randomized, noninferiority, Phase III trial, involving patients with NSCLC clinically staged as T1aN0. In this study, a total of 697 patients, after intraoperative confirmation of node-negative disease, were randomly assigned to undergo either Sublobar resection (N=340) or Lobar resection (N=357). Of the 340 patients assigned to Sublobar resection, 201 (59.1%) underwent wedge resection and 129 (37.9%) underwent an anatomical segmental resection. Wedge resection was allowed in the current trial as it is the most frequently practiced method of Sublobar resection in North America and Europe and its inclusion would make the trial more representative of a “real world” setting. The median patient age was 68 years. Approximately 50% of patients had tumor size 1.0-1.5 cm, 40% had tumor size 1.5-2.0 cm, and two thirds of the patients had Adenocarcinoma histology. Over 90% of the patients were current or former smokers. The Primary end point was Disease-Free Survival (DFS), defined as the time between randomization and disease recurrence or death from any cause. Secondary end points included Overall Survival (OS), locoregional and systemic recurrence, and pulmonary functions.
After a median follow up of 7 years, Sublobar resection was noninferior to Lobar resection for DFS (HR for disease recurrence or death=1.01). The 5-year DFS was 63.6% after Sublobar resection and 64.1% after Lobar resection. The Overall Survival after Sublobar resection was similar to that after Lobar resection (HR for death, 0.95). The 5-year OS was 80.3% after Sublobar resection and 78.9% after Lobar resection. No substantial difference was seen between the two groups in the incidence of locoregional or distant recurrence. At 6 months postoperatively, pulmonary functions favored the Sublobar resection group.
It was concluded that Sublobar resection by either anatomical segmentectomy or wedge resection, for patients with peripheral NSCLC with a tumor size of 2 cm or less and pathologically confirmed node-negative disease in the hilar and mediastinal lymph nodes, was non inferior to Lobectomy, with respect to Disease Free Survival and with similar Overall Survival, and is an effective management approach for this subgroup of patients with NSCLC.
Lobar or Sublobar Resection for Peripheral Stage IA Non–Small-Cell Lung Cancer. Altorki N, Wang X, Kozono D, et al. N Engl J Med 2023; 388:489-498
A POSITIVE Trial for Hormone Receptor Positive Breast Cancer Survivors Desiring Pregnancy
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. 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, adjuvant chemotherapy, and hormone therapy. However approximately 20% of patients will experience local recurrence or distant relapse during the first 10 years of treatment.
The median age at the time of breast cancer diagnosis in the US is 62 years. However approximately 5% of new diagnoses each year occur in those who are under 40 years. These young patients with Hormone Receptor (HR)-positive breast cancer receiving modern adjuvant endocrine therapy have excellent long-term outcomes. Nonetheless, 40-60% of patients who are diagnosed with breast cancer at age 40 or younger are concerned about their future fertility and pregnancy, as many have not completed their family planning at diagnosis due to delay in childbearing.
The POSITIVE (Pregnancy Outcome and Safety of Interrupting Therapy for Women with Endocrine Responsive Breast Cancer) trial is a multicenter, global, single-arm prospective study, designed to evaluate whether temporary interruption of adjuvant endocrine therapy to attempt pregnancy is associated with a higher risk of breast cancer recurrence. This study included 517 women with Stage I-III Hormone Receptor (HR)-positive early breast cancer, 42 years or less, who had received 18-30 months of adjuvant endocrine therapy and wished to interrupt endocrine therapy for pregnancy. The study permitted treatment interruption for up to 2 years (after a 3 month endocrine therapy washout period) to allow pregnancy, delivery and breastfeeding, followed by endocrine therapy resumption to complete the planned duration of 5-10 of adjuvant endocrine therapy. The median age was 37 years, 75% were nulliparous, fertility preservation was used by 51% of women, 93% had Stage I/II disease, 66% were node negative and 62% had received neo/adjuvant chemotherapy. Tamoxifen alone was the most prescribed endocrine therapy (42%), followed by Tamoxifen plus Ovarian Function Suppression (OFS) (35%).
The Primary endpoint of the study was Breast Cancer-Free Interval (BCFI), defined as the time from study enrollment to the first invasive breast cancer event (local/regional/distant recurrence or contralateral breast cancer). Three interim safety analyses were conducted by a Data Safety Monitoring Committee, and determined that the trial would be suspended if there were more than 46 breast cancer recurrences within approximately 3 years of average follow-up. This threshold however was not reached.
At a median follow up of 41 months, of the 497 patients evaluated for pregnancy status, 74% (N=368) had at least one pregnancy, with 70% of the pregnancies occurring within 2 years. Additionally, 63.8% (N=317) had at least one live birth, with a total of 365 babies born. Birth defects were low at 2% and the rates of conception and childbirth were similar to rates in the general public. The 3-year breast cancer recurrence rate among patients who halted therapy was 8.9%, similar to the 9.2% rate in an external control cohort from the SOFT/TEXT trials, which examined adjuvant endocrine therapy in premenopausal patients. Long term follow up is ongoing to assess recurrence risk over time, and trial participants were strongly recommended to resume endocrine therapy following their pregnancy attempts or success.
The authors concluded that these data provide guidance to younger patients diagnosed with early breast cancer on endocrine therapy, who may be hoping to have children. They added that such decisions should be made in close consultation with health professionals.
Pregnancy outcome and safety of interrupting therapy for women with endocrine responsive breast cancer: primary results from the POSITIVE trial (IBCSG 48-14 / BIG 8-13). Partridge A, Niman SM, Ruggeri M, et al. Presented at 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX.
FDA Approves JAYPIRCA® for Relapsed or Refractory Mantle Cell Lymphoma
SUMMARY: The FDA on January 27, 2023, granted accelerated approval to JAYPIRCA® (Pirtobrutinib) for Relapsed or Refractory Mantle Cell Lymphoma (MCL) after at least two lines of systemic therapy, including a BTK inhibitor.
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. In the US, approximately 3,300 new cases of MCL are diagnosed each year. Mantle Cell Lymphoma is an aggressive B-cell lymphoma and accounts for approximately 6% of all Non Hodgkin Lymphomas in adults, and is associated with a high relapse rate, following dose-intensive therapies. Early and late relapses in patients with MCL have been attributed to persistence of residual disease. Majority of patients with MCL are elderly and are not candidates for aggressive treatment or Autologous Stem Cell Transplantation.
Bruton’s Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor, and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. BTK inhibitors inhibit cell proliferation and promotes programmed cell death (Apoptosis) by blocking B-cell activation and signaling. BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas including Chronic Lymphocytic Leukemia (CLL), Mantle Cell Lymphoma (MCL), and Waldenstrom Macroglobulinemia (WM). The 3 covalent BTK inhibitors presently approved by the FDA for MCL include IMBRUVICA® (Ibrutinib) approved in 2013, CALQUENCE® (Acalabrutinib) approved in 2017, and BRUKINSA® (Zanubrutinib) approved in 2019. Covalent BTK inhibitors have transformed the treatment landscape of Mantle Cell Lymphoma. Despite the efficacy of covalent BTK inhibitors, treatment failure often occurs through development of resistance or intolerance.
JAYPIRCA® is a highly selective, reversible (non-covalent) Bruton’s Tyrosine Kinase (BTK) inhibitor, developed to reversibly bind BTK, deliver consistently high target coverage regardless of BTK turnover rate, and preserve activity in the presence of the C481 acquired resistance mutations. JAYPIRCA® is 300 times more selective in BTK inhibition versus 98% of other kinases tested in preclinical studies and inhibits both wildtype and C481-mutant BTK with equal low nM potency, and has favorable oral pharmacology. JAYPIRCA® is well tolerated and demonstrated promising efficacy in patients with poor-prognosis B-cell malignancies following prior therapy, including prior covalent BTK inhibitors (Mato et al. Lancet, 2021).
The BRUIN Phase I/II clinical trial is the ongoing first-in-human, global, open-label, multicenter single armstudy, which evaluated the efficacy of JAYPIRCA® in previously treated patients with Mantle Cell Lymphoma (MCL), Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL), or other Non-Hodgkin Lymphomas (NHL). The trial included a Phase I dose-escalation component in which the daily dosing of JAYPIRCA® between 25 mg and 300 mg was evaluated, a Phase Ib drug combination safety arm, and a Phase II dose-expansion component, in which JAYPIRCA® 200 mg daily, as a part of 28-day cycles, is being evaluated.
The present FDA approval is based on data from a subset of patients with Mantle Cell Lymphoma (N=120) in the BRUIN Phase I/II trial, treated with JAYPIRCA® 200 mg once daily until disease progression or unacceptable toxicity. Patients had received a median of three prior lines of therapy with 93% having two or more prior lines, and all patients received one or more prior lines of therapy containing a covalent BTK inhibitor. The most common prior BTK inhibitors received were Ibrutinib (67%), Acalabrutinib (30%), and Zanubrutinib (8%), and 83% had discontinued their last BTK inhibitor due to refractory or progressive disease. Patients with active Central Nervous System Lymphoma or allogeneic Hematopoietic Stem Cell Transplantation or CAR T-cell therapy within 60 days were excluded. The main efficacy measures were Overall Response Rate (ORR) and Duration of Response (DOR), as assessed by an Independent Review Committee, using 2014 Lugano criteria.
The ORR was 50%, with a Complete Response rate of 13%, and the Partial Response rate was 38%. The Time to Response was 1.8 months. The estimated median Duration of Response was 8.3 months, and the estimated Duration of Response rate at 6 months was 65.3%. The most common adverse reactions in 15% or more of MCL patients were fatigue, musculoskeletal pain, diarrhea, edema, dyspnea, pneumonia, and bruising. Grade 3 or 4 laboratory abnormalities in 10% or more of patients were cytopenias.
It was concluded that JAYPIRCA® offers a new approach to targeting the BTK pathway for Relapsed and Refractory Mantle Cell Lymphoma patients, previously treated with a covalent BTK inhibitor. The researchers added that this approval of JAYPIRCA® represents an important advance for this group of patients who currently have limited treatment options and have a poor prognosis.
Efficacy of Pirtobrutinib in Covalent BTK-Inhibitor Pre-Treated Relapsed / Refractory Mantle Cell Lymphoma: Additional Patients and Extended Follow-up from the Phase 1/2 BRUIN Study. Wang ML, Shah NN, Jurczak W. Presented at the 64th ASH Annual Meeting and Exposition, December 10-13, 2022, New Orleans, Louisiana. Abstract # 4218.
FDA Approves Adjuvant KEYTRUDA® in NSCLC Irrespective of PD-L1 Expression
SUMMARY: The FDA on January 26, 2023, approved KEYTRUDA® (Pembrolizumab) for adjuvant treatment following resection and platinum-based chemotherapy for Stage IB (T2a ≥4 cm), II, or IIIA Non-Small Cell Lung Cancer (NSCLC). 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.
The 5-year survival rate for patients diagnosed with lung cancer in the US is about 25%, which is a significant improvement over the past 5 years, in part due to earlier detection from lung cancer screening, reduction in smoking, advances in diagnostic and surgical procedures, as well as the introduction of new therapies. However, the 5-year survival rate remains significantly lower among communities of color at 20%. Early detection and screening remain an important unmet need, as 44% of lung cancer cases are not found until they are advanced. In the US, only 5.8% of those individuals at high risk were screened in 2021.
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.
KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. By doing so, it unleashes the tumor-specific effector T cells, and is thereby able to undo PD-1 pathway-mediated inhibition of the immune response.
KEYNOTE-091/EORTC-1416-LCG/ETOP-8-15 – PEARLS trial is a multicenter, randomized, triple-blind, placebo-controlled Phase III trial, which compared the efficacy of KEYTRUDA® with placebo, among patients with resected NSCLC. In this study, 1,177 patients with completely resected Stage IB (T2a ≥4 cm), II, or IIIA NSCLC with negative margins, and with tumor tissue available for PD-L1 testing were included. Systematic complete or lobe-specific mediastinal lymph node dissection was recommended. In the least, the subcarinal and 1 lobe-specific lymph node must have been examined. Eligible patients had not received neoadjuvant radiotherapy or chemotherapy, had ECOG PS of 0-1, and adjuvant chemotherapy for up to four cycles was optional. Adjuvant chemotherapy could be considered for those with Stage IB disease and was strongly recommended for those with Stage II and IIIA disease. Patients were randomized (1:1) to receive KEYTRUDA® 200 mg or placebo IV every three weeks and treatment was continued until disease recurrence, unacceptable toxicity, or up to 1 year. Both treatment groups were well balanced. The median patient age was 65 years, majority of patients (68%) were male, approximately 65% of patients had nonsquamous histology, 56% of patients had Stage II disease and 86% of patients had received adjuvant platinum-based chemotherapy following complete resection. Stratification factors included disease stage, receipt of adjuvant chemotherapy, PD-L1 Tumor Proportion Score and geographic region of the world. The median duration of exposure to KEYTRUDA® was 11.7 months and 68% of patients in the KEYTRUDA® group were exposed to KEYTRUDA® for at least 6 months. The major efficacy outcome measure was investigator-assessed Disease-Free Survival (DFS). An additional efficacy outcome was Overall Survival (OS).
The trial met its Primary endpoint, demonstrating a statistically significant improvement in DFS in the overall population. In patients who received adjuvant platinum-based chemotherapy following surgical resection, KEYTRUDA® reduced the risk of disease recurrence or death by 27% (HR=0.73) versus placebo, regardless of PD-L1 expression. For patients who received adjuvant chemotherapy, median DFS regardless of PD-L1 expression was 58.7 months in the KEYTRUDA® group versus 34.9 months in the placebo group. In an exploratory subgroup analysis of the 167 patients who did not receive adjuvant chemotherapy, the DFS Hazard Ratio was 1.25. Overall survival Data were not mature.
It was concluded that these data support the benefit of KEYTRUDA® as a new adjuvant immunotherapy treatment option, for early-stage NSCLC following complete resection, and if indicated, adjuvant chemotherapy, regardless of PD-L1 expression.
EORTC-1416-LCG/ETOP 8-15 – PEARLS/KEYNOTE-091 study of pembrolizumab versus placebo for completely resected early-stage non-small cell lung cancer (NSCLC): Outcomes in subgroups related to surgery, disease burden, and adjuvant chemotherapy use.O’Brien M, Paz-Ares L, Jha N, et al. DOI: 10.1200/JCO.2022.40.16_suppl.8512 Journal of Clinical Oncology 40, no. 16_suppl (June 01, 2022) 8512-8512.Published online June 02, 2022.
Low Dose Dasatinib as Frontline Therapy in Newly Diagnosed Chronic Myeloid Leukemia
SUMMARY: Chronic Myeloid Leukemia (CML) constitutes approximately 10% of all new cases of leukemia. The American Cancer Society estimates that 6,660 new CML cases will be diagnosed in the United States in 2015 and about 1,140 people will die of the disease. Chronic Myeloid Leukemia in Chronic Phase (CML-CP) is a clonal myeloproliferative disorder and the hallmark of CML, the Philadelphia Chromosome (Chromosome 22), is a result of a reciprocal translocation between chromosomes 9 and 22, wherein the ABL gene from chromosome 9, fuses with the BCR gene on chromosome 22. As a result, the auto inhibitory function of the ABL gene is lost and the BCR-ABL fusion gene is activated resulting in cell proliferation and leukemic transformation of hematopoietic stem cells. With the development of small molecule tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1, the 10-year survival rate in CML in Chronic phase is 80-90%. There are presently four TKIs (First Generation-Imatinib; Second Generation- Nilotinib, Dasatinib and Bosutinib) approved by the FDA for frontline therapy of patients with newly diagnosed CML-CP. Treatment with second generation TKIs has demonstrated significantly deeper and faster cytogenetic and Major MolecularResponses, but without any impact on long-term survival.
Dasatinib (SPRYCEL®) is an oral second generation TKI and is 325 times more potent than imatinib in inhibiting unmutated BCR-ABL1 kinase in vitro. It additionally inhibits the Src family of kinases, which are key regulators of signal transduction. Dasatinib 100mg once daily was approved by the FDA in 2010 for the treatment of patients with newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase, based on the Pivotal DASISION Study. In this trial, Dasatinib demonstrated Superior Efficacy with Higher and Faster Molecular and Confirmed Complete Cytogenetic Response Rates, compared to Imatinib by 12 months. In this trial drug-related pleural effusions occurred more frequently with Dasatinib than with Imatinib (28% versus <1%), as well as myelosuppression (20%), and, occasionally, pulmonary hypertension (5%).
Dasatinib in early clinical trials demonstrated activity at lower doses with better safety profile. Further in the DASISION trial, the efficacy of Dasatinib was maintained among patients who had their dose reduced, while improving its safety profile. Low-dose Dasatinib appears to be safe and effective in patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP). However there are no randomized trials comparing the outcome with standard-dose Dasatinib.
This present study was conducted to compare the outcome of patients with newly diagnosed CML-CP treated with Dasatinib 50 versus 100 mg/day. The researchers analyzed 233 patients with newly diagnosed CML-CP treated with low-dose Dasatinib (N = 83) or standard-dose Dasatinib (N = 150). Using Propensity score analysis with 1:1 matching, 77 patients in each cohort were identified without significant baseline differences.
Response rates were reported as the cumulative incidences of Complete Cytogenetic Response (CCyR), Major Molecular Response (MMR), Molecular Response with 4.0 (MR4.0) and 4.5 (MR4.5) log reduction. MMR was defined as BCR-ABL1/ABL1 (IS) ≤0.1%, MR4.0 defined as BCR-ABL1/ABL1 (IS) ≤0.01% and MR4.5 defined as BCR-ABL1/ABL1 (IS) ≤0.0032%. Additional comparisons between the two groups included Overall Survival (OS) calculated from the start date of the therapy to the date of death from any cause at any time or date of last follow-up, Event-Free Survival (EFS) to the date of any of the events while on study as defined in the IRIS study, Failure-Free Survival (FFS) was calculated from the start date of therapy to the dates of treatment discontinuation for any reason except of treatment-free remission, Transformation-Free Survival (TFS), to the date of transformation to accelerated or blast phases during study. Patients on low-dose Dasatinib with suboptimal response by European LeukemiaNet (ELN) 2013 criteria had the option to increase the dose to 100 mg/day. The median age was 47 years. By Sokal risk score, 66% patients had low-risk, 25% had intermediate-risk, and 9% had high-risk disease. The median follow-up time was 60 months.
The 3-year MMR rates were 92% and 84% for low-dose and standard-dose Dasatinib, respectively (P=0.23). Dasatinib 50 mg/day induced higher cumulative incidence of MR4.0 (77% versus 66%; P=0.04) and MR4.5 (77% vs. 62%; P=0.02) at 3 years. The 4-year FFS, EFS and OS rates were 89% versus 77% (P=0.04), 95% versus 92% (P=0.06), and 97% versus 96% (P=0.78) with low-dose and standard-dose Dasatinib, respectively. The incidence of any grade pleural effusion was 5% with Dasatinib 50 mg/day compared to 21% with Dasatinib 100 mg/day.
It was concluded that Dasatinib 50mg daily is a new, cost-effective therapeutic option for frontline therapy in CML-CP and is at least as effective as Dasatinib 100 mg/day, with a better safety profile.
Low-dose dasatinib 50 mg/day versus standard-dose dasatinib 100 mg/day as frontline therapy in chronic myeloid leukemia in chronic phase: A propensity score analysis. Jabbour E, Sasaki K, Haddad FG, et al. Am J Hematol. 2022;97:1413-1418.
EGFR Exon 20 Insertion Mutations – These Are NOT Your Common EGFR Mutations
Written By: David M. Waterhouse, MD, MPH & Anita Koshy, MD
This promotional educational activity is brought to you by Janssen Biotech, Inc., and is not certified for continuing medical education.
Dr. Waterhouse is a paid consultant writing on behalf of Janssen Biotech, Inc., and must present this information in compliance with FDA requirements applicable to Janssen Biotech, Inc.
It is estimated that approximately 237,000 people in the US will be diagnosed with lung cancer in 2022. Despite advancements in standard-of-care treatments for lung cancer, this disease remains the leading cause of cancer death in both males and females.1 Nonetheless, the burgeoning number of targeted therapies for some types of lung cancer, particularly non-small cell lung cancer (NSCLC), have allowed for improvements in mortality and survival.2 As of 2022, there are ~20 targeted therapies for ~9 actionable driver mutations in stage IV NSCLC.3,4 In order to determine optimal targeted therapies, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend comprehensive biomarker testing, like next-generation sequencing (NGS), for all eligible patients at diagnosis of advanced NSCLC.5
Common EGFR Mutations (Exon 19 deletion and Exon 21 [L858R] mutations)
Epidermal growth factor receptor (EGFR) is a potent oncogene commonly altered in NSCLC, and EGFR driver mutations may be found in as many as 28% of metastatic NSCLC patients.6 Tyrosine kinase inhibitors (TKIs) directed against EGFR were among the first molecular targeted agents used for treatment of advanced NSCLC.7 Initial studies of EGFR TKIs showed that patient characteristics associated with EGFR mutations, such as non-smoking status, female gender, East Asian origin, and adenocarcinoma histology suggested a greater benefit from EGFR TKIs compared with first-line chemotherapy.8 Later studies identified gene mutations that could target the kinase domain of EGFR and predicted response to such inhibitors. The variable deletions of at least 3 amino acid residues in exon 19, as well as the single point mutation leucine-858 to arginine (L858R) in exon 21, are often referred to as “common” activating EGFR mutations and represent the vast majority (90%) of all observed EGFR kinase domain mutations in NSCLC.8 (Figure 1)
EGFR Exon 20 Insertion Mutations
Exon 20 insertion mutations are the third most prevalent type of activating EGFR mutations in NSCLC and are associated with a poor prognosis.9-11 These mutations are also enriched in women, non-smokers, Asian populations, and those with adenocarcinoma. Exon 20 insertion mutations, however, lack the key structural features that confer sensitivity of L858R and exon19 deletion mutations to first-and second-generation EGFR inhibitors. In-frame base pair insertions in exon 20 result in activation of EGFR, but, unlike the common activating EGFR mutations, they are associated with reduced affinity to most clinically available EGFR TKIs indicated for common EGFR mutations. Data are limited and variable, but multiple studies found that patients with EGFR exon 20 insertion mutations had an overall response rate of 0% to 8.7% when treated with first-, second-, or third-generation EGFR TKIs.12-16 (Figure 2)
*These data were taken from a retrospective observational study.16
†Common mutations include L858R, L861Q, and exon 19 deletions.16
‡These data were taken from multiple sources: a cohort study, a prospective post hoc analysis of phase 2 and phase 3 trials, a single-center retrospective analysis, and a systematic literature review and meta-analysis.12-14
HR, hazard ratio; ORR, overall response rate; PFS, progression-free survival.
Study results also demonstrate limited efficacy of immuno-oncology (IO) monotherapy in this patient population compared to patients with wild-type EGFR. In a retrospective study using real-world data, patients with EGFR exon 20 insertion mutation-positive NSCLC were associated with a 58% increased risk of shorter time to next-line therapy after first-line IO monotherapy compared to patients with wild-type NSCLC.17
The NCCN Guidelines® do not recommend most TKIs or IO monotherapy for treating patients with mNSCLC and EGFR exon 20 insertion mutations in the first- or second-line setting. Instead, the Guidelines recommend platinum-based chemotherapy as the standard first-line treatment for NSCLC with EGFR exon 20 insertion mutations.5§
§Exceptions include p.A763_Y764insFQEA and p.A763_Y764insLQEA.5
EGFR Testing
The NCCN Guidelines recommend comprehensive biomarker testing, like NGS, prior to the initiation of first-line therapy, if clinically feasible.5 Despite that recommendation, rates of broad biomarker testing remain low, according to real-world evidence.18,19 In a retrospective observational chart review study among 3,474 patients with advanced NSCLC receiving first-line therapy in the US Oncology Network, the EGFR testing rate was found to be 70%, but comprehensive NGS testing was completed in only 42% of patients.20 Failure to order comprehensive NGS testing is particularly problematic when it comes to identifying EGFR exon 20 insertions. There are over 100 unique EGFR exon 20 insertion variants, and polymerase chain reaction (PCR) testing can miss approximately 50% of the insertions identified by NGS.21 (Figure 3)
||Analysis from mutation profiles of 36,465 lung adenocarcinomas from Foundation Medicine (Cambridge, MA) FoundationInsights database, which is a database of 315,688 patient genomic profiles across 150 cancer types.
¶Commercially available qPCR methods were Roche cobas® EGFR mutation test v2 and Qiagen therascreen EGFR RGQ PCR kit.
Another notable issue is the accurate application of NGS data to clinical care. In multiple retrospective, observational cohort studies, approximately 17% to 24% of treatment-naive and 14% to 22% of second-line patients with EGFR exon 20 insertions received EGFR TKIs.11,17,22** Studies also found that approximately 7% to 40% of treatment-naive and 26% to 41% of second-line patients received IO monotherapy.17,22,23 These therapies (ie, most TKIs indicated for common mutations†† and IO monotherapies) are not recommended for first- or second-line therapy for EGFR exon 20 insertion mutations.5
**EGFR TKIs included first-, second- and third-generations.
††Exceptions include p.A763_Y764insFQEA and p.A763_Y764insLQEA.
Current Treatment Strategies for Patients With Exon 20 Insertion Mutations
Chemotherapy with a platinum doublet remains the recommended treatment option for the first-line treatment of patients with an EGFR exon 20 insertion mutation.5 When many of these patients progress, subsequent treatment options are needed. The NCCN Guidelines recommend amivantamab-vmjw or mobocertinib as subsequent therapy options for patients with EGFR exon 20 insertion mutations who have progressed on or after initial systemic therapy.5
Conclusion:
- Advances made in the treatment of NSCLC have improved patient mortality and survival,2 and these advancements are due in part to the discovery of actionable mutations, like common EGFR mutations, and targeted therapies3,4,7,8
- Multiple studies have found, however, that patients with EGFR exon 20 insertion mutations had a poor overall response when treated with first-, second-, or third-generation EGFR TKIs,11-15,17 and that IO monotherapies provide little benefit as a first-line treatment in patients with EGFR mutations, including exon 20 insertions17
- The NCCN Guidelines recommend:
- Testing eligible patients with mNSCLC for targetable genetic alterations to both identify potentially appropriate targeted therapies and avoid therapies unlikely to provide clinical benefit5
- Treating patients who harbor a common EGFR mutation (exon 19 deletion and exon 21 [L858R] mutations) with an EGFR TKI in the first line of treatment, whereas those with an EGFR exon 20 insertion mutation are best treated with a regimen containing a platinum doublet5
- Amivantamab-vmjw or mobocertinib as subsequent therapy options for patients with EGFR+ mNSCLC with exon 20 insertion mutations who have progressed on or after initial systemic therapy per the NCCN Guidelines5
References
1. National Cancer Institute. Cancer stat facts: common cancer sites. Accessed September 30, 2022. https://seer.cancer.gov/statfacts/html/common.html
2. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021.CA Cancer J Clin. 2021;71:7-33.
3. Benjamin DJ, Haslam A, Gill J, Prasad V. Targeted therapy in lung cancer: Are we closing the gap in years of life lost? Cancer Med. 2022;11(18):3417-3424.
4. Targeted Therapy in Metastatic Non–Small Cell Lung Cancer: Recent Updates and Controversies. Angel Qin. ASCO Daily News. Published January 19, 2022. Accessed November 14, 2022. https://dailynews.ascopubs.org/do/10.1200/ADN.22.200810/
5. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.6.2022. © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed December 2, 2022. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in anyway.
6. Jordan EJ, Kim HR, Arcila ME, et al. Prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies. Cancer Discov. 2017;7(6):596-609.
7. Luo SY, Lam DC. Oncogenic driver mutations in lung cancer. Transl Respir Med. 2013;1(1):6.
8. Gazdar AF. Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene. 2009;28 (Suppl 1):S24-S31.
9. Arcila ME, Nafa K, Chaft JE, et al. EGFR exon20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics. Mol Cancer Ther. 2013;12(2):220-229.
10. Leal JL, Alexander M, Itchins M, et al. EGFR exon 20 insertion mutations: clinicopathological characteristics and treatment outcomes in advanced non-small cell lung cancer. Clin Lung Cancer. 2021;22(6):e859-e869.
11. Bazhenova L, Minchom A, Viteri S, et al. Comparative clinical outcomes for patients with advanced NSCLC harboring EGFR exon 20 insertion mutations and common EGFR mutations. Lung Cancer. 2021;162:154-161.
12. Wu JY, Yu CJ, Shih JY. Effectiveness of treatments for advanced non-small-cell lung cancer with exon 20 insertion epidermal growth factor receptor mutations. Clin Lung Cancer. 2019;20:e620-e630.
13. Yang JC, Sequist LV, Geater SL, et al. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6.Lancet Oncol. 2015;16(7):830-838.
14. Kate S, Chougule A, JoshiA, et al. Outcome of uncommon EGFR mutation positive newly diagnosed advanced non-small cell lung cancer patients: a single center retrospective analysis. Lung Cancer (Auckl). 2019;10:1-10.
15. Kwon CS, Lin HM, Crossland V, et al. Non-small cell lung cancer with EGFR exon 20 insertion mutation: a systematic literature review and meta-analysis of patient outcomes. Curr Med Res Opin. 2022;38(8):1341-1350.
16. Robichaux JP, Elamin YY, Tan Z, et al. Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancer. Nat Med. 2018;24:638-646.
17. Girard N, Minchom A, Ou SI, et al. Comparative clinical outcomes between EGFR ex20 ins and wild type NSCLC treated with immune checkpoint inhibitors. Clin Lung Cancer. 2022;23(7):571-577.
18. Paz-Ares L, Gondos A, Saldana D, et al. Genomic testing among patients with newly diagnosed advanced non-small cell lung cancer in the United States: A contemporary clinical practice patterns study. Lung Cancer. 2022;167:41-48.
19. Waterhouse DM, Tseng WY, Espirito JL, Robert NJ. Understanding contemporary molecular biomarker testing rates and trends for metastatic NSCLC among community oncologists. Clin Lung Cancer. 2021;22(6):e901-e910.
20. Robert N, Chen L, Espirito J, et al. Trends in molecular testing for metastatic non-small cell lung cancer in the US Oncology Network community practices. J Thorac Oncol. 2021;16(10) (suppl):S1169.
21. Bauml J, Viteri S, Minchom A, et al. Underdiagnosis of EGFR exon 20 insertion mutation variants: estimates from NGS-based real-world datasets. Presented at: the IASLC 2020 World Conference on Lung Cancer; January 28-31, 2021;Singapore.
22. He J, Pericone CD, Vanderpoel J. Real-world patient characteristics, treatment patterns, and mutation testing patterns among US patients with advanced non-small cell lung cancer harboring EGFR mutations. Adv Ther. 2022;39(7):3347-3360.
23. Choudhury NJ, Schoenfeld AJ, Flynn J, et al. Response to standard therapies and comprehensive genomic analysis for patients with lung adenocarcinoma with EGFR exon 20 insertions. Clin Cancer Res. 2021;27(10):2920-2927.
© Janssen Biotech, Inc. 2022 12/22 cp-345345v1
FDA Approves ORSERDU® for ESR-1 Mutated Advanced Breast Cancer
SUMMARY: The FDA on January 27, 2023, approved ORSERDU® (Elacestrant) for postmenopausal women or adult men with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer, with disease progression following at least one line of endocrine therapy. FDA also approved the Guardant360 CDx assay as a companion diagnostic device to identify patients with breast cancer for treatment with ORSERDU®.
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. Approximately 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors. The most common subtype of metastatic breast cancer is Hormone Receptor-positive (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 ER+/HER2-negative metastatic breast cancer, as first line therapy. Even with this therapeutic combination, most patients will eventually experience disease progression, including the development of ESR1 (Estrogen Receptor gene alpha) mutations.
ESR1 (Estrogen Receptor 1) gene mutation is the most common acquired mutation noted in breast tumors as they progress from primary to metastatic setting. These mutations promote ligand independent Estrogen Receptor activation and have been shown to promote resistance to estrogen deprivation therapy. It appears that ESR1 mutations are harbored in metastatic ER-positive breast cancers with prior Aromatase Inhibitor (AI) therapy, but not in primary breast cancers, suggesting that ESR1 mutations may be selected by prior therapy with an AI in advanced breast cancer. In a previously published study (JAMA Oncol.2016;2:1310-1315), ESR1 mutations Y537S and D538G mutations detected in baseline plasma samples from ER+/HER- advanced breast cancer patients, was associated with shorter Overall Survival. In this study it was noted that there was a three-fold increase in the prevalence of these mutations in patients who had failed first line hormonal therapy for metastatic disease, compared with those who were initiating first line therapy for advanced breast cancer (33% versus 11%). It is estimated that 40% of ER-positive, HER2-negative advanced or metastatic breast cancer patients have tumors that harbor ESR1 mutations.
Fulvestrant (FASLODEX®) is a parenteral, Selective Estrogen Receptor Degrader (SERD) and is the only SERD approved for the treatment of postmenopausal women with HR-positive metastatic breast cancer. However, acquired ESR1 mutations can also occur following Fulvestrant treatment, possibly because of poor bioavailability and incomplete ER blockade when administered intramuscularly. There is therefore an urgent unmet need for an alternate SERD that has activity in tumors harboring ESR1 mutations, and has improved bioavailability allowing oral administration.
ORSERDU® (Elacestrant) is an oral, nonsteroidal, Selective Estrogen Receptor Degrader (SERD) that degrades the Estrogen Receptor (ER) in a dose-dependent manner and inhibits estradiol-dependent functions of ER target gene transcription induction and breast cancer cell proliferation. Estradiol-stimulated tumor growth was diminished by ORSERDU® in the HR-positive xenograft models derived from heavily pretreated patients, including models resistant to CDK 4/6 inhibitors, Fulvestrant and those harboring ESR1 mutations Y537S and D538G. In an early Phase I trial, ORSERDU® was noted to have an acceptable safety profile and demonstrated single-agent activity with confirmed Partial Responses in heavily pretreated patients with HR-positive metastatic breast cancer.
The present FDA approval was based on the EMERALD trial, which is a multicenter, International, randomized, open-label, Phase III study, designed to evaluate the benefit of ORSERDU® in patients with ER+/HER2- advanced or metastatic breast cancer. In this study, 478 postmenopausal women with ER+/HER2- metastatic breast cancer were randomly assigned 1:1 to receive either ORSERDU® 400 mg orally daily (N=239) or the Standard of Care which included investigator’s choice of Fulvestrant or an Aromatase Inhibitor including Anastrozole, Letrozole, or Exemestane (N=239). Treatment was given until disease progression. Both treatment groups were well balanced. The median patient age was 63 years, and patients must have progressed or relapsed on or after 1 or 2 lines of endocrine therapy for advanced disease, one of which was given in combination with a CDK4/6 inhibitor, had 1 or fewer lines of chemotherapy for advanced disease, and had an ECOG performance status of 0 or 1. ESR1 mutational status was determined by blood circulating tumor deoxyribonucleic acid (ctDNA) using the Guardant360 CDx assay and was limited to ESR1 missense mutations in the ligand binding domain. In the study, 48% (N=228) had tumors with mutated ESR1 and 43% received two prior endocrine therapies. These patients were evenly distributed in both treatment groups. Patients were stratified by ESR1-mutation status, prior treatment with Fulvestrant, and visceral metastases. The co-Primary end points were Progression Free Survival (PFS) in the overall population, and in those with ESR1 mutations. Overall Survival (OS) was a Secondary end point.
This study met both co-Primary endpoints and treatment with ORSERDU® resulted in a statistically significant and clinically meaningful improvement in PFS, compared with Standard of Care treatment. In the group of patients whose tumors had ESR1 mutations, the median PFS was 3.8 months in the ORSERDU® group and 1.9 months in the Standard of Care group (HR=0.55; P=0.0005), reducing the risk of progression or death by 45%. A post-hoc analysis of the PFS results based on the duration of prior CDK4/6 inhibitors usage was presented at San Antonio Breast Cancer Symposium (SABCS) in December 2022. The median PFS was 8.6 months in the ORSERDU® group versus 1.9 months in the Standard of Care group, in those patients whose tumors harbored ESR1 mutations and had been treated with a CDK4/6 inhibitors for at least 12 months.
It can be concluded from this study that ORSERDU® is the first oral Selective Estrogen Receptor Degrader for ER-positive, HER2-negative advanced breast cancer patients with ESR1 mutations, and offers a novel therapeutic option for this patient group.
Elacestrant (oral selective estrogen receptor degrader) Versus Standard Endocrine Therapy for Estrogen Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer: Results From the Randomized Phase III EMERALD Trial. Bidard F-C, Kaklamani VG, Neven P, et al. DOI: 10.1200/JCO.22.00338 Journal of Clinical Oncology. Published online May 18, 2022.