Tag: Lung Cancer: Non-Small Cell

ENHERTU® in HER2-Mutant Non Small Cell Lung Cancer

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.

The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. HER2 is a Tyrosine Kinase Receptor expressed on the surface of several tumor types including Breast, Gastric, Lung and Colorectal cancers. It is a growth-promoting protein and HER2 overexpression/HER2 gene amplification is often associated with aggressive disease and poor prognosis in certain tumor types. However, HER2 overexpression and gene amplification are associated with distinct molecular entities and have limited therapeutic value in lung cancer.

HER2 mutations unlike HER2 overexpression and gene amplification are oncogenic drivers, and have been detected in 2 to 3% of NSCLCs. They are more often detected in female patients and never-smokers, and almost exclusively in Adenocarcinomas. Majority of of HER2 mutations (80-90%) occur in exon 20, as either a duplication or an insertion of 12 nucleotides, resulting in the addition of four amino acids (YVMA) at codon 775 in the kinase domain. This distinct molecular entity is characterized by specific pathological and clinical behavior. These acquired HER2 gene mutations have been independently associated with cancer cell growth and poor prognosis. There are currently no therapies approved specifically for the treatment HER2 mutant NSCLC, and is therefore an unmet need.

ENHERTU® (Trastuzumab Deruxtecan) is an Antibody-Drug Conjugate (ADC) composed of a humanized monoclonal antibody specifically targeting HER2, with the amino acid sequence similar to HERCEPTIN® (Trastuzumab), attached to a potent cytotoxic Topoisomerase I inhibitor payload by a cleavable tetrapeptide-based linker. ENHERTU® has a favorable pharmacokinetic profile and the tetrapeptide-based linker is stable in the plasma and is selectively cleaved by cathepsins that are up-regulated in tumor cells. Unlike KADCYLA® (ado-Trastuzumab emtansine), which is also an Antibody-Drug Conjugate, ENHERTU® has a higher drug-to-antibody ratio (8 versus 4), the released payload easily crosses the cell membrane with resulting potent cytotoxic effect on neighboring tumor cells regardless of target expression, and the released cytotoxic agent (payload) has a short half-life, minimizing systemic exposure. ENHERTU® is approved in the US for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who received two or more prior anti-HER2 based regimens, and locally advanced or metastatic HER2-positive Gastric or GastroEsophageal Junction adenocarcinoma who have received a prior Trastuzumab based regimen. Translational research demonstrated that HER2-mutant NSCLC may preferentially internalize the HER2 receptor Antibody-Drug Conjugate complex regardless of HER2 protein expression, and overcome resistance to other HER2-targeted agents.
Mechanism-of-Action-ENHERTU
DESTINY-Lung01 is a global, multicenter, open-label, two-cohort, Phase II study, conducted to evaluate the efficacy and safety of ENHERTU® in patients with HER2 mutant or HER2 overexpressing (defined as ImmunoHistoChemistry-IHC 3+ or IHC 2+), unresectable and metastatic non-squamous NSCLC. A total of 91 patients with HER2-mutant NSCLC were enrolled between May 30, 2018, and July 21, 2020 and treated with ENHERTU®. Patients who had previously been treated with a HER2 antibody or an Antibody-Drug Conjugate were ineligible for participation, but those who had previously received a HER2 Tyrosine Kinase Inhibitor such as Afatinib, Pyrotinib, or Poziotinib were eligible. The median patient age was 60 yrs and enrolled patients had a median of two prior lines of therapy, with majority of patients having received platinum-based chemotherapy (95%) and anti-PD-1 or PD-L1 treatment (66%). About 20% of patients received Docetaxel and 14% received HER TKIs. For the majority of patients (93%), HER2 mutations were located in the kinase domain. Patients received ENHERTU® 6.4 mg/kg every 3 weeks by intravenous infusion. The Primary endpoint was Objective Response Rate (ORR) as assessed by Independent Central Review. Secondary endpoints included Disease Control Rate (DCR), Duration of Response (DoR), Progression Free Survival (PFS), Overall Survival (OS) and Safety. At the time of data cutoff, the median duration of treatment was 6.9 months and treatment was ongoing for 16% of patients.

At a median follow up 13.1 months, the ORR was 55% and the median Duration of Response was 9.3 months. Responses were observed across different HER2 mutation subtypes. The median PFS was 8.2 months and the median OS was 17.8 months. The most common Grade 3 or higher drug-related Adverse Event was neutropenia noted in 19% of patients and adjudicated drug-related Interstitial Lung Disease occurred in 26% of patients and resulted in 2 deaths.

It was concluded that ENHERTU® demonstrated promising clinical activity, with a high Objective Response Rate and durable responses, in a heavily pretreated population of patients with HER2-mutated NSCLC.

Trastuzumab Deruxtecan in HER2-Mutant Non–Small-Cell Lung Cancer. Li BT, Smit EF, Goto Y, et al., for the DESTINY-Lung01 Trial Investigators. N Engl J Med 2022; 386:241-251

Blood Test Plus Risk Model May Predict Who May Benefit From Lung Cancer Screening

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 and Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

In the National Lung Screening Trial (NLST) with Low Dose CT (LDCT) screening for lung cancer, there was a 20% reduction in mortality. Following the publication of the results of NLST, and NCCN issued guideline in 2011, the United States Preventive Services Task Force (USPSTF) recommended Lung Cancer screening with Low Dose CT scan in high risk patients. CMS in 2015 determined that there was sufficient evidence to reimburse for this preventive service. The USPSTF expanded the criteria for Lung Cancer screening in 2021 and recommended annual screening with Low-Dose CT for adults aged 50 to 80 years who have a 20 pack-year smoking history and currently smoke or have quit within the past 15 years. The new USPSTF 2021 criteria were given a B recommendation, as there was additional research needed, to improve uptake of LDCT screening and to develop biomarkers to more accurately identify individuals, who would benefit from screening.

The authors in a previously published study identified the precursor form of Surfactant Protein B (Pro-SFTPB) as predictive of Lung Cancer risk. They were also able to, in a proof-of-principle study, demonstrate that a four Marker Protein panel (4MP) consisting of Pro-SFTPB, Cancer Antigen 125, CarcinoEmbryonic Antigen, and Cytokeratin-19 fragment, has the potential to identify individuals at risk for developing Lung Cancer, better than Pro-SFTPB alone.

The purpose of this study was to determine whether a blood-based four Marker Protein biomarker panel together with the PLCOm2012 Lung Cancer prediction model would better identify individuals for Lung Cancer screening, compared with current US Preventive Services Task Force (USPSTF) criteria.

The PLCO Cancer Screening Trial was a randomized multicenter trial which evaluated the impact of screening for Prostate, Lung, Colorectal, and Ovarian cancer, on disease-specific mortality. In this study, a biorepository was created for blood specimens that were annually collected, after obtaining consent from the intervention group participants. In this study there were 42,450 individuals in the intervention group who have ever smoked, and 85% of the participants in this intervention arm had at least one blood specimen collection. Individuals with histologically-confirmed lung cancers from the ever-smoked participants in the intervention group, who were diagnosed within 6 years of study entry, and with pre-diagnostic blood specimen available (N= 552), were included in the current study.

Non cancer participants who have ever smoked (N=2193) were randomized 4:1 with lung cancer diagnosed cases and were followed for an additional 13 years during which time they remained cancer-free. For each selected participant, all blood samples collected within 6 years of study entry, or up to the time of diagnosis for lung cancer cases, were included in the study specimen set (N=10,008 blood specimens). The mean age of the study population was 65 years, and 64% were male, 60% were former smokers and 40% were current smokers. The baseline information for the PLCOm2012 model included age, race or ethnic group, education, Body Mass Index, Chronic Obstructive Pulmonary Disease, personal history of cancer, family history of lung cancer and smoking status (current versus former), intensity, duration, and quit time. Levels of the 4 marker proteins in the serum were determined using bead-based immunoassays and biomarker scores were calculated for the combined 4 marker proteins. The researchers assessed the performance of the 4 marker protein panel in combination with the PLCOm2012 lung cancer prediction model, and compared the combination with current USPSTF lung cancer screening criteria, among pre-diagnosis lung cancer, and non-lung cancer serum samples, from the PLCO Cancer Screening Trial.

Using prediagnostic case, and non-case serum samples from the PLCO Cancer Screening Trial data, a combined four-marker protein panel along with PLCO m2012 model showed statistically significant improvement in sensitivity by 11.9% and 9.9% and specificity by 12.9% and 6.9% ,compared with USPSTF 2013 and the recent USPSTF 2021 criteria, respectively. If the 4MP along with PLCOm2012 model was applied to individuals with 10 or more pack-year smoking history, the improved performance of this combination would have resulted in referral to screening of 12.6% more lung cancer cases among the 119 cases who would otherwise receive a lung cancer diagnosis within a year, as well as nonreferral of 29.6% of the 14,061 non-cases. When compared with the USPSTF 2021 criteria, the 4MP plus PLCOm2012 model would have identified for annual screening 9.2% more lung cancer cases and would have reduced referral by 13.7% among non-cases, compared with USPSTF 2021 criteria.

It was concluded that the 4MP plus PLCOm2012 model yielded superior predictive performance and sensitivity and specificity for ruling individuals into LDCT screening, compared with USPSTF 2013 or USPSTF 2021 eligibility criteria, and with the PLCOm2012 model alone. The authors added that the public health benefit is significant, as it better identifies individuals at high risk of lung cancer and expands upon the number of individuals who would be considered eligible for lung cancer screening, thereby addressing some of the limitations of current screening eligibility criteria. These findings have important implications for improving lung cancer screening programs and reducing the burden of lung cancer through personalized risk assessment.

Blood-Based Biomarker Panel for Personalized Lung Cancer Risk Assessment. Fahrmann JF, Marsh T, Irajizad E, et al. J Clin Oncol. Published online January 7, 2022. doi:10.1200/JCO.21.01460.

KRAS Variant Status and Outcomes with Immune Checkpoint Inhibitor-Based Therapy in Advanced Non Small Cell Lung Cancer

RR

SUMMARY: The American Cancer Society estimates that for 2021, about 235,760 new cases of lung cancer will be diagnosed and 131,880 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.

Patients with advanced NSCLC without a driver mutation and with Programmed cell Death Ligand 1 (PD-L1) expression of 50% or greater, are often treated first line with Immune Checkpoint Inhibition (ICI) monotherapy or ICI in combination with chemotherapy. The choice between these two treatment regimens is usually based on tumor burden and patient comorbidities, as there are presently no biomarkers available to predict the risk and benefit of these treatment interventions. The KEYNOTE-042 study demonstrated that single agent Pembrolizumab given as first line therapy demonstrated Overall Survival (OS) benefit over chemotherapy, in patients with previously untreated advanced NSCLC, with PD-L1 expression of 1% or greater. In an exploratory analysis, this benefit was seen regardless of KRAS status, but was more pronounced in patients with KRAS variants than those without KRAS variants.

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. When mutated, KRAS oncogene has 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 12-15% of 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.

The authors conducted this study to evaluate the association of KRAS status with outcomes following ICI monotherapy versus chemoimmunotherapy in patients with PD-L1 of 50% or greater. The researchers used the Flatiron Health database, comprising 280 cancer clinics across the US and analyzed 1127 patients with advanced non-squamous NSCLC with PD-L1 expression of 50% or greater, known KRAS variant status, and no alteration in EGFR, ALK, or ROS1, who were treated with first line ICI monotherapy or chemoimmunotherapy between January 2016 and May 2020. Of the patients analyzed, 50.8% had KRAS variant status and 49.2% had KRAS wild type status. Patients with KRAS variant status were more likely to be female (58.7% versus 47.1%; P =0.002) and had smoking history (96.4% versus 87.7%; P < .001). Other patient demographics and patient characteristics, including age, race, ethnicity, Performance Status, and stage at diagnosis, were well balanced among the groups analyzed. Patient groups were stratified by treatment type and KRAS status (variant or wild type), and Overall Survival (OS) was compared between the treatment groups. Adjusted Hazard ratios for death associated with KRAS status and treatment regimen was estimated, using Cox proportional hazards models.

It was noted that among patients treated with ICI monotherapy, KRAS variant status was associated with superior median survival compared with KRAS wild type (21.1 months versus 13.6 months; HR=0.77; P=0.03), and this was statistically significant. However, among patients treated with chemoimmunotherapy, there was no significant median survival difference between patients with KRAS variant and KRAS wild type status (20.0 months versus 19.3 months; HR=0.99; P=0.93).

Among patients with KRAS variant status, the median OS did not differ between those treated with ICI monotherapy and chemoimmunotherapy (21.1 months versus 20.0 months; P =0.78), whereas among patients with KRAS wild type status, those treated with ICI monotherapy had numerically worse median survival than those treated with chemoimmunotherapy, although this difference was not statistically significant (13.6 months versus 19.3 months; HR=1.19; P =0.06).

In conclusion, this data suggests that chemoimmunotherapy might be favored over ICI monotherapy for patients with KRAS wild type tumors associated with high PD-L1 expression. The authors caution that in this analysis KRAS variant subtype and co-mutation status including TP53 and STK11 was unknown, and further investigation is needed to selection appropriate therapies for patients with PD-L1 High NSCLC.

Association Between KRAS Variant Status and Outcomes With First-line Immune Checkpoint Inhibitor–Based Therapy in Patients With Advanced Non–Small-Cell Lung Cancer. Sun L, Hsu M, Cohen RB, et al. JAMA Oncol. 2021;7:937-939.

Stereotactic Ablative Radiotherapy Non-Inferior to Surgery in Operable Stage I Non Small Cell Lung Cancer

RR

SUMMARY: The American Cancer Society estimates that for 2021, about 235,760 new cases of lung cancer will be diagnosed and 131,880 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer. Approximately 15% of patients present with early stage (T1-2 N0) disease, and these numbers are likely to increase with the implementation of Lung Cancer screening programs. Patients with early stage disease unless medically unfit, undergo surgical resection with a curative intent. Those who are not surgical candidates are often treated with conventional Radiation Therapy, over a period of 4 to 6 weeks.

Dating back to the 1930’s, the only hope for curing lung cancer has been surgery. However, important advances in the field of medical physics, computer science, and engineering have enabled significant progress in the field of Radiation Oncology, by better targeting the tumor and escalating the daily treatment doses. Surgery for Stage I NSCLC is now being challenged by these new Radiation Therapy techniques.

Stereotactic Ablative Radiotherapy (SABR) is a non-surgical procedure that allows delivery of significantly higher doses of precisely focused radiation to the tumor, compared to conventional Radiation Therapy, with less collateral damage to the surrounding normal tissue. The technologies used for SABR include GAMMA KNIFE® which uses highly focused gamma rays, Proton Beam therapy which uses ionized Hydrogen or Protons, Linear Accelerator (LINAC) and CYBER KNIFE® which use Photons, to target the tumor tissue. Because SABR is fractionated and delivered over 1-5 days, the short-and long-term side effects of radiation therapy are decreased and may allow higher total dosage to be given.

In a previously published pooled analysis of two independent, randomized, Phase III trials of SABR in patients with operable, clinical T1–2a (<4 cm), N0M0, Stage I NSCLC (STARS and ROSEL), Overall Survival (OS) was higher after Stereotactic Ablative Radiotherapy (SABR) than with surgery. This analysis had notable limitations and was closed early due to slow accrual. In the present study, the SABR group in the STARS trial was re-accrued with a larger sample size and the authors reported long-term results of the revised STARS trial, along with a protocol-specified propensity-matched comparison with a prospectively registered, contemporary institutional cohort of patients, who underwent Video-Assisted Thoracoscopic Surgical Lobectomy with Mediastinal Lymph Node Dissection (VATS L-MLND).

This single-arm prospective trial done at the University of Texas MD Anderson Cancer Center did not include patients from the previous pooled analysis and enrolled 80 patients (N=80) with newly diagnosed and histologically confirmed NSCLC with N0M0 disease (squamous cell, adenocarcinoma, large cell, or NSCLC not otherwise specified), and a tumor diameter of 3 cm or less. SABR dosing for peripheral lesions was 54 Gy in three fractions and 50 Gy in four fractions for central tumors, with simultaneous integrated boost to gross tumor totaling 60 Gy.

For the propensity-matching analysis, the researchers used a surgical cohort from the MD Anderson Department of Thoracic and Cardiovascular Surgery’s prospectively registered, institutional review board-approved database of all patients with clinical Stage I NSCLC who underwent VATS L-MLND during the period of enrolment in this trial. Propensity matching consisted of determining a propensity score using a several covariates such as age, tumor size, histology, Performance Status, and the interaction of age and sex. The Primary endpoint was the 3-year Overall Survival. Non-inferiority could be claimed if the 3-year Overall Survival rate after SABR was lower than that after VATS L-MLND by 12% or less and the upper bound of the 95% CI of the Hazard Ratio (HR) was less than 1.965.

At a median follow-up time was 5.1 years, the OS with SABR was 91% at 3 years and 87% at 5 years. The OS in the propensity-matched VATS L-MLND cohort was 91% at 3 years and 84% at 5 years. Non-inferiority was claimed since the 3-year OS after SABR was not lower than that observed in the VATS L-MLND group. There was no significant difference in OS between the two patient cohorts from a multivariable analysis (HR=0.86; P=0•65). SABR was well tolerated with no Grade 4-5 toxicities.

It was concluded from this study that long term survival after SABR is non-inferior to VATS L-MLND for operable Stage IA Non Small Cell Lung Cancer. SABR remains promising for this patient group and the authors strongly recommend a multidisciplinary management approach .

Stereotactic ablative radiotherapy for operable stage I non-small-cell lung cancer (revised STARS): long-term results of a single-arm, prospective trial with prespecified comparison to surgery. Chang JY, Mehran RJ, Feng L, et al. Lancet Oncol. 2021;22:1448-1457.

Sintilimab for Patients with Pretreated EGFR-Mutated Non Small Cell Lung Cancer

RR

SUMMARY: The American Cancer Society estimates that for 2021, about 235,760 new cases of lung cancer will be diagnosed and 131,880 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

Approximately 10-15% of Caucasian patients and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR mutations and 90% of these mutations are either exon 19 deletions or L858R substitution mutation in exon 21. Patients with advanced EGFR-mutated NSCLC, following initial clinical response to first, second and third generation EGFR-TKIs therapies, will inevitably advance to a progressive disease course. These patients often receive platinum-based chemotherapy, with limited clinical benefit. Immune checkpoint inhibitors given alone have low efficacy in the treatment of patients with metastatic NSCLC with oncogenic-driven tumors. There is a highly unmet medical need for these patients with resistant disease.

Sintilimab is an immunoglobulin G4, anti-PD-1 monoclonal antibody, which 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.

ORIENT-31 is a prospective, randomized, double-blind, multi-center Phase III study, which evaluated Sintilimab, with or without a Bevacizumab biosimilar injection (IBI305), in combination with chemotherapy (Pemetrexed and Cisplatin), in patients with EGFR-mutated locally advanced or metastatic non-squamous NSCLC, who have progressed following EGFR TKI treatment. Patients were randomized in a 1:1:1 ratio to receive Sintilimab 200 mg IV plus Bevacizumab biosimilar 15 mg/kg IV combined with Pemetrexed 500 mg/m2 IV and Cisplatin 75 mg/m2 IV (Arm A), Sintilimab combined with Pemetrexed and Cisplatin (Arm B), or chemotherapy alone with Pemetrexed and Cisplatin (Arm C), all agents administered every 3 weeks for 4 cycles followed by maintenance treatment with Sintilimab plus Bevacizumab and Pemetrexed in Arm A, Sintilimab and Pemetrexed in Arm B, and Pemetrexed alone in Arm C. Treatment was continued until radiographic disease progression or unacceptable toxicity. Eligible patients included patients with disease progression following first or second generation EGFR TKI and confirmed as T790M negative, or T790M positive but further progressed on third generation EGFR TKI, or patients with disease progression following third generation EGFR TKI as first line treatment. The median age was 57 years, 36% of patients had brain metastasis, 64% of patients had received First or Second generation TKIs without T790M mutation, 28% had received First or Second generation TKIs and then a Third generation TKI for T790M mutation, and 8% patients received first line Third generation TKI. The target accrual was 480 patients and by the data cutoff date of the first interim analysis, 444 patients were enrolled. The Primary endpoint was Progression Free Survival (PFS) as assessed by an Independent Radiographic Review Committee (IRRC). Secondary endpoints included Overall Survival (OS), PFS as assessed by investigators, Objective Response Rate (ORR) and Safety. The median follow up at first interim analysis was 9.8 months.

Sintilimab plus Bevacizumab biosimilar in combination with chemotherapy (Arm A), demonstrated a statistically significant and clinically meaningful improvement in PFS, compared with Arm C (chemotherapy alone group). The median PFS was 6.9 months in Arm A, and 4.3 months in Arm C (HR=0.46; P<0.0001). Additionally, the key Secondary endpoints of ORR and Duration of Response (DOR) were improved in Arm A compared with Arm C, and the results of PFS, ORR and DOR assessed by the investigator were consistent with the results assessed by IRRC. The prespecified PFS futility analysis that compares Arm A to Arm B (Sintilimab and chemotherapy group) did not cross futility stopping boundary. The PFS data of Arm B versus Arm C were immature.

The authors concluded that in this first prospective, double-blind, Phase III study among patients with EGFR mutated NSCLC who had progressed after EGFR TKIs, this quadruple regimen of Sintilimab plus Bevacizumab biosimilar in combination with chemotherapy, significantly improved Progression Free Survival, compared with chemotherapy alone.

VP9-2021: ORIENT-31: Phase III study of sintilimab with or without IBI305 plus chemotherapy in patients with EGFR mutated nonsquamous NSCLC who progressed after EGFR-TKI therapy. Lu S, Wu L, Jian H, et al. Published:November 19, 2021DOI:https://doi.org/10.1016/j.annonc.2021.10.007.

FDA Approves TECENTRIQ® as Adjuvant Treatment for Non Small Cell Lung Cancer

RR

SUMMARY: The FDA on October 15, 2021, approved TECENTRIQ® (Atezolizumab) for adjuvant treatment, following resection and Platinum-based chemotherapy, in patients with Stage II to IIIA Non-Small Cell Lung Cancer (NSCLC) whose tumors have PD-L1 expression on 1% or more of tumor cells, as determined by an FDA-approved test. Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2021, about 235,760 new cases of lung cancer will be diagnosed and 131,880 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.

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.

TECENTRIQ® is an anti PD-L1 monoclonal antibody, designed to directly bind to PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, thereby blocking its interactions with PD-1 and B7.1 receptors expressed on activated T cells. PD-L1 inhibition may prevent T-cell deactivation and further enable the activation of T cells.

IMpower 010 is a global, multicentre, open-label, randomized Phase III study evaluating the efficacy and safety of TECENTRIQ® compared with Best Supportive Care (BSC), in patients with Stage IB-IIIA NSCLC, following surgical resection and up to 4 cycles of adjuvant Cisplatin-based chemotherapy. In this study, 1005 patients were randomized 1:1 to receive TECENTRIQ® 1200 mg IV every 3 weeks for 16 cycles, or BSC. Both study groups were well balanced and eligible patients had an ECOG PS of 0-1. The Primary endpoint was Disease Free Survival (DFS) in the PD-L1-positive Stage II-IIIA patients, all randomized Stage II-IIIA patients and Intent to Treat (ITT) Stage IB-IIIA populations. Key Secondary endpoints included Overall Survival (OS) in the overall study population and ITT Stage IB-IIIA NSCLC patients. At data cutoff on January 21, 2021, median follow up was 32.2 months in the ITT population.

Treatment with TECENTRIQ® following surgery and chemotherapy reduced the risk of disease recurrence or death (DFS-Disease Free Survival) by 34% (HR=0.66; P=0.0039), in patients with Stage II-IIIA NSCLC, whose tumor PD-L1 expression was 1% or more, compared with BSC. In this patient population, median DFS was Not Reached for TECENTRIQ®, compared with 35.3 months for BSC. This benefit was even more so among Stage II-IIIA NSCLC patients with PD-L1 expression 50% or more. Adjuvant TECENTRIQ® following surgery and chemotherapy in this patient group reduced the risk of disease recurrence or death (DFS) by 57% (HR=0.43). In the larger population of all randomized Stage II-IIIA study patients, TECENTRIQ® reduced the risk of disease recurrence or death by 21% (HR=0.79, P=0.02). In this patient population, TECENTRIQ® increased DFS by a median of seven months, compared with BSC (42.3 months versus 35.3 months). The significance boundary was not crossed for DFS in the ITT patient population. Overall Survival data were immature and not formally tested. Safety data for TECENTRIQ® were consistent with its known safety profile and no new safety signals were identified.

It was concluded that this study met its Primary endpoint, and is the first Phase III study to demonstrate that treatment with TECENTRIQ® following surgery and chemotherapy can significantly delay disease recurrence in patients with early stage lung cancer, with a more pronounced benefit noted, in patients with tumor PD-LI expression of 1% or more.

IMpower010: Primary results of a phase III global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB-IIIA non-small cell lung cancer (NSCLC). Wakelee HA, Altorki NK, Zhou C, et al. J Clin Oncol. 2021;39:(suppl 15; abstr 8500). doi:10.1200/JCO.2021.39.15_suppl.8500

Durable Survival Benefit with First Line OPDIVO® plus YERVOY® and a Limited Course of Chemotherapy

RR

SUMMARY: The American Cancer Society estimates that for 2021, about 235,760 new cases of lung cancer will be diagnosed and 131,880 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® 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. In the CheckMate-227, Part 1, Phase III trial, a combination of OPDIVO® plus YERVOY®, significantly improved Overall Survival (OS), Progression Free Survival (PFS), Objective Response Rates (ORR) and Duration of Response, compared to chemotherapy, independent of PD-L1 expression level. The authors in this study hypothesized that a limited course of chemotherapy combined with OPDIVO® plus YERVOY® could provide rapid disease control, while building on the durable Overall Survival benefit seen with dual PD-1 and CTLA-4 inhibition, as well as minimizing the toxicities associated with a full course of chemotherapy.Unleashing-T-Cell-Function-with-Immune-Checkpoint-Inhibitors

CheckMate-9LA is a randomized, open-label, multi-center, Phase III trial which evaluated the benefit of a combination of OPDIVO® plus YERVOY®, and 2 cycles of Platinum-doublet chemotherapy (experimental arm) versus Platinum-doublet chemotherapy (control arm) for 4 cycles, followed by optional Pemetrexed maintenance therapy, as a first-line treatment in patients with metastatic or recurrent NSCLC, regardless of PD-L1 status and histology. In this study, 719 adults treatment naïve patients with histologically confirmed Stage IV/recurrent NSCLC, with ECOG Performance Status 0-1, and no known sensitizing EGFR/ALK alterations, were randomly assigned 1:1 to receive OPDIVO® 360 mg every 3 weeks plus YERVOY® 1 mg/kg every 6 weeks and 2 cycles of platinum-doublet chemotherapy (N=361), or 4 cycles of platinum-doublet chemotherapy alone (N=358). Chemotherapy was based on histology. Patients with non-squamous NSCLC in the chemo-only randomized group could receive optional Pemetrexed maintenance treatment. Patients were treated with immunotherapy until disease progression, unacceptable toxicity, or for 2 years. Patients were stratified by PD-L1 status (less than 1% versus 1% or more), sex, and histology (squamous versus non-squamous). Demographics in treatment groups were well balanced. Crossover between treatment groups was not permitted. However, at physician discretion, patients could receive subsequent immunotherapy upon discontinuation of study treatment in either group.

The Primary end point was Overall Survival (OS). Secondary endpoints included Progression Free Survival (PFS), Objective Response Rate (ORR) and efficacy by PD-L1 subgroups. PFS2 was a pre-specified exploratory endpoint and was defined as time from randomization, to objectively documented progression after the next line of therapy, or to death from any cause, whichever occurred first. At a preplanned interim analysis after a minimum follow up 8.1 months, this trial met its primary and secondary endpoints, showing statistically significant improvements in OS, PFS, and Objective Response Rate (ORR), when compared to chemotherapy alone. This clinical benefit was noted across tumor PD-L1 expression levels and histologies.

The authors in this publication reported updated efficacy and safety outcomes, along with Progression-Free Survival (PFS) after next line of treatment (PFS2), Treatment-Related Adverse Events (TRAEs) by treatment cycle, and efficacy outcomes in patients who discontinued all treatment components in the experimental treatment group due to TRAEs, from the CheckMate 9LA Phase III trial. The minimum follow up for OS was 24.4 months. The majority of patients (93%) received two cycles of chemotherapy and 13% completed the maximum 2 years of immunotherapy treatment. The median number of doses was 9.0 for OPDIVO® and 4.0 for YERVOY®. In the control arm, 75% of patients received four cycles of chemotherapy and 67% patients who had non-squamous tumor histology receiving Pemetrexed maintenance. About 29% patients in the control arm had completed the full four cycles of chemotherapy without optional Pemetrexed maintenance therapy. The median duration of therapy was 6.1 months in the experimental arm and 2.5 months in the control arm.

With a median follow up of 30.7 months, OPDIVO® plus YERVOY® with a limited course of chemotherapy continued to prolong Overall Survival (OS), when compared to chemotherapy (Median OS 15.8 versus 11.0 months; HR=0.72). The 2-year OS rate was 38% versus 26%. This OS benefit was observed across most key subgroups including those with PD-L1 expression of less than 1%, more than 1%, as well as by histology. More importantly, patients with pretreated CNS metastases at baseline had a median OS of 19.9 months in the experimental group versus 7.9 months in the control group, respectively (HR=0.47).

PFS continued to be prolonged in the experimental group compared to the control group, with an Hazard Ratio of 0.67 and 2-year PFS rates of 20% versus 8%, respectively. The ORR was 38% in the experimental group and 25% in the control group (P=0.0003). 34% versus 12% of all responses respectively, were ongoing at 2 years. The median PFS2 in all randomized patients was 13.9 months in the experimental group and 8.7 months in the control group (HR=0.66). Again, PFS2 also favored the experimental arm over the control arm in subgroups by PD-L1 expression, and by histology.

No new safety signals were observed and majority of Grade 3/4 toxicities were mostly observed during the first two treatment cycles in the experimental group. In patients who discontinued all components of the experimental treatment (OPDIVO® plus YERVOY® with chemotherapy) due to toxicities (N=61), the median OS was 27.5 months and 56% of responders had an ongoing response, more than 1 year after discontinuation of therapy. After discontinuing the experimental regimen, patients remained treatment-free for a median of 11.9 months and had a 48% chance of being treatment-free at 1 year.

The researchers concluded that with a 2-year minimum follow-up, OPDIVO® plus YERVOY® with two cycles of chemotherapy provided durable efficacy benefits over conventional chemotherapy, with a manageable safety profile. They added that this treatment regimen remains an efficacious first line treatment of advanced Non Small Cell Lung Cancer.

First-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone (four cycles) in advanced non-small-cell lung cancer: CheckMate 9LA 2-year update. Reck M, Ciuleanu T-E, Cobo M, et al. https://doi.org/10.1016/j.esmoop.2021.100273

FDA Approves EXKIVITY® for Metastatic Non Small Cell Lung Cancer with EGFR exon 20 Insertion Mutations

RR

SUMMARY: The FDA on September 15, 2021, granted accelerated approval to EXKIVITY® (Mobocertinib), for adult patients with locally advanced or metastatic Non Small Cell Lung Cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after Platinum-based chemotherapy. The FDA also approved the Oncomine Dx Target Test as a companion diagnostic device to select patients with the above mutations for EXKIVITY® treatment.

The American Cancer Society estimates that for 2021, about 235,760 new cases of lung cancer will be diagnosed and 131,880 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

Approximately 10-15% of Caucasian patients and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR mutations and 90% of these mutations are either exon 19 deletions or L858R substitution mutation in exon 21. EGFR exon 20 insertion mutations are the third most common after L858R and exon 19 deletions, and occur in about 2-3% patients with NSCLC, and are insensitive to EGFR Tyrosine Kinase Inhibitors (TKIs) due to an altered conformation of the kinase active site. Next-Generation sequencing provides an alternative to Polymerase Chain Reaction (PCR)-based tests, which fail to identify 50% or more of exon 20 insertion mutations. Patients with EGFR exon 20 insertion mutations have a 5 year Overall Survival (OS) of 8% in the frontline setting, compared to an OS of 19% for patients with EGFR exon 19 deletions or L858R mutations. There is therefore a clinically unmet need for this patient group, as there are no approved targeted therapies available and platinum-doublet chemotherapy remains the standard of care for these patients.

EXKIVITY® is a novel oral EGFR TKI, that was designed to address the unmet need in patients with EGFR exon 20 insertion mutant positive NSCLC. EXKIVITY® was designed to potently inhibit oncogenic variants containing activating mutations in exon 20, with selectivity over Wild Type EGFR.

The present FDA approval of EXKIVITY® was based on an international, non-randomized, open-label, multicohort clinical trial (NCT02716116) which included patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. This trial was conducted in three parts- Dose escalation or Part 1, to determine the safety profile of EXKIVITY®, Expansion phase or Part 2, to evaluate the antitumor activity of EXKIVITY® in seven histologically and molecularly defined cohorts, and Extension phase or Part 3, to evaluate efficacy of EXKIVITY® in patients with locally advanced or metastatic NSCLC whose tumors harbor EGFR exon 20 insertion mutations, and who have been previously treated.

So, this 3-part, multicenter study has dose-escalation/expansion and extension (EXCLAIM) cohorts. Patients with EGFR exon 20 insertion positive metastatic NSCLC, with ECOG status 0-1, and one or more prior lines of therapy for locally advanced/metastatic disease, received EXKIVITY® 160 mg orally daily, until disease progression or intolerable toxicity. Efficacy was evaluated in 114 patients whose disease had progressed on or after Platinum-based chemotherapy. Among these platinum pretreated patients, the median age was 60 years, 66% were female, 60% were Asian, and 59% had 2 or more prior systemic therapies. The main efficacy outcome measures were confirmed Objective Response Rate (ORR) assessed by blinded Independent Review Committee (IRC) and Duration of Response.

At a median follow up of 14.2 months, the ORR was 28%, with a median Duration of Response of 17.5 months. The median Progression Free Survival was 7.3 months and the median Overall Survival was 24 months. Clinically meaningful improvements were observed for dyspnea, coughing, chest pain, and these benefits were evident by cycle 2, and maintained throughout treatment. The most common adverse reactions were rash, nausea, stomatitis, vomiting, diarrhea, decreased appetite, paronychia, fatigue, dry skin, and musculoskeletal pain.

It was concluded that EXKIVITY® is the first and only oral therapy specifically designed to target EGFR exon 20 insertions, and the present FDA approval is an important addition, designed for this patient population.

Mobocertinib (TAK-788) in EGFR exon 20 insertion (ex20ins)+ metastatic NSCLC (mNSCLC): additional results from platinum-pretreated patients (pts) and EXCLAIM cohort of phase 1/2 study. Ramalingam SS, Zhou C, Kim TM, et al. J Clin Oncol. 2021;39(suppl 15):9014. DOI:10.1200/JCO.2021.39.15_suppl.9014.

Real-world evidence: What can it inform us about the second-line treatment of metastatic squamous NSCLC?

RR

Written by Dr. Solly S. Chedid
Sponsored and developed by Boehringer Ingelheim Pharmaceuticals.

Immunotherapies have changed the way we initiate treatment for many patients with advanced squamous non-small cell lung cancer (NSCLC).1 As immunotherapy has become a standard first-line treatment, non-immunotherapy options are important to consider for second-line treatment. Currently, there is no clear standard of care for second-line therapy in patients with advanced squamous NSCLC who progress after immuno-chemotherapy. Therefore, an unmet need remains for studies designed to understand the effectiveness and safety of second-line treatments in these patients. Here we will review newly published real-world evidence on second-line treatments of patients with squamous NSCLC with afatinib (GILOTRIF®) following immuno-chemotherapy.

GILOTRIF is the only oral, chemotherapy-free option for treating patients with squamous NSCLC that has progressed after platinum-based chemotherapy.2 The efficacy and safety of GILOTRIF were demonstrated in the pivotal LUX-Lung 8 trial. In LUX-Lung 8, treatment with GILOTRIF led to statistically significant improvements in progression-free survival (median 2.4 vs 1.9 months) and overall survival (median 7.9 vs 6.8 months) compared with erlotinib. In LUX-Lung 8, the most common adverse reactions reported in the GILOTRIF treated patients (≥20% all grades) were diarrhea (75%), rash/acneiform dermatitis (70%), stomatitis (30%), decreased appetite (25%), and nausea (21%).

The Real-world Effectiveness of 2L Treatment of Squamous mNSCLC Study is the first to evaluate the real-world use of GILOTRIF following first-line immuno-chemotherapy in patients with squamous NSCLC.1 It is a retrospective, non-interventional, multisite cohort study using electronic medical records of patients with advanced or metastatic squamous NSCLC treated with pembrolizumab and platinum-doublet chemotherapy in the first line. Patients were treated with either GILOTRIF or physician’s choice chemotherapy in the second line. Study endpoints included patient demographics and clinical characteristics, time on second-line treatment, and incidence of severe (Grade ≥3) immune-related adverse events (irAEs). This study analysis was not powered to compare characteristics or outcomes between the cohorts. In addition, the results of this study are not intended for direct comparison with clinical trials. The main limitations of this study are its retrospective nature, potential for selection bias, and lack of a comparator arm.

A total of 200 patients were included in this study; 99 received GILOTRIF, and 101 received chemotherapy in the second line.1 More patients in the GILOTRIF cohort had mixed histology, were epidermal growth factor receptor (EGFR) mutation−positive, and were never smokers than those in the chemotherapy cohort. There were geographic differences between the cohorts; more patients from the Northeast received GILOTRIF, and more patients from the South received chemotherapy. In the GILOTRIF cohort, 45% of patients had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ranging from 0 to 1, while 55% had an ECOG PS of 2 or higher. In the chemotherapy arm, 50% of patients had ECOG PS 0 to 1, and 50% had ECOG PS of 2 or higher. Other characteristics, such as median age and stage at diagnosis, were similar in both cohorts.

The median time on treatment for the GILOTRIF cohort was 7.3 months. In patients with mixed histology, the median time on treatment was 8.1 months, and for patients with squamous histology it was 5.8 months.1 EGFR mutation−positive and EGFR mutation−negative patients remained on GILOTRIF for a median of 7.4 and 5.9 months, respectively. The median time on treatment from initiation of second-line chemotherapy was 4.2 months.

   Time on Treatment in the Real-World Effectiveness Study1
Time-on-GILOTRIF-Chemotherapy
The most common adverse drug reactions with GILOTRIF were diarrhea (26%), rash (6%), stomatitis, fatigue, and nausea (5% each).1 Six out of 99 patients experienced a Grade 3/4 irAE during second-line GILOTRIF therapy; each of these patients also experienced a Grade 3 irAE during first-line treatment. The 6 patients in the GILOTRIF cohort who experienced Grade 3/4 irAEs were treated with steroids, and none were hospitalized. Given the real-world nature of the study, adverse event data may be underreported or underdocumented; in addition, censoring may also bias results.

Such real-world evidence (RWE) studies have limitations, including their retrospective nature and potential for selection bias.1 However, in addition to clinical data collected in registrational clinical trials, data from RWE studies such as this can add important information to help evaluate the clinical utility of a drug in the real-world setting.3 RWE studies can be derived from rich data sources, such as electronic health records, registries, and claims databases, which reflect real-world use, outcomes, and the patient diversity seen in clinical practice.

Despite several limitations highlighted in this paper, the study adds to the body of evidence supporting the effectiveness and safety of GILOTRIF when given as a second-line treatment following immuno-chemotherapy in routine clinical practice.1

INDICATION AND USAGE

GILOTRIF is indicated for the treatment of patients with metastatic squamous NSCLC progressing after platinum-based chemotherapy.

IMPORTANT SAFETY INFORMATION FOR GILOTRIF® (AFATINIB) TABLETS
WARNINGS AND PRECAUTIONS

Diarrhea
• GILOTRIF can cause diarrhea which may be severe and can result in dehydration with or without renal impairment. In clinical studies, some of these cases were fatal.
• For patients who develop Grade 2 diarrhea lasting more than 48 hours or Grade 3 or greater diarrhea, withhold GILOTRIF until diarrhea resolves to Grade 1 or less, and then resume at a reduced dose.
• Provide patients with an anti-diarrheal agent (e.g., loperamide) for self-administration at the onset of diarrhea and instruct patients to continue anti-diarrheal until loose stools cease for 12 hours.
Bullous and Exfoliative Skin Disorders
• GILOTRIF can result in cutaneous reactions consisting of rash, erythema, and acneiform rash. In addition, palmar-plantar erythrodysesthesia syndrome was observed in clinical trials in patients taking GILOTRIF.
• Discontinue GILOTRIF in patients who develop life-threatening bullous, blistering, or exfoliating skin lesions. For patients who develop Grade 2 cutaneous adverse reactions lasting more than 7 days, intolerable Grade 2, or Grade 3 cutaneous reactions, withhold GILOTRIF. When the adverse reaction resolves to Grade 1 or less, resume GILOTRIF with appropriate dose reduction.
• Postmarketing cases of toxic epidermal necrolysis (TEN) and Stevens Johnson syndrome (SJS) have been reported in patients receiving GILOTRIF. Discontinue GILOTRIF if TEN or SJS is suspected.
Interstitial Lung Disease
• Interstitial Lung Disease (ILD) or ILD-like adverse reactions (e.g., lung infiltration, pneumonitis, acute respiratory distress syndrome, or alveolitis allergic) occurred in patients receiving GILOTRIF in clinical trials. In some cases, ILD was fatal. The incidence of ILD appeared to be higher in Asian patients as compared to white patients.
• Withhold GILOTRIF during evaluation of patients with suspected ILD, and discontinue GILOTRIF in patients with confirmed ILD.
Hepatic Toxicity
• Hepatic toxicity as evidenced by liver function tests abnormalities has been observed in patients taking GILOTRIF. In 4257 patients who received GILOTRIF across clinical trials, 9.7% had liver test abnormalities, of which 0.2% were fatal.
• Obtain periodic liver testing in patients during treatment with GILOTRIF. Withhold GILOTRIF in patients who develop worsening of liver function. Discontinue treatment in patients who develop severe hepatic impairment while taking GILOTRIF.
Gastrointestinal Perforation
• Gastrointestinal (GI) perforation, including fatal cases, has occurred with GILOTRIF. GI perforation has been reported in 0.2% of patients treated with GILOTRIF among 3213 patients across 17 randomized controlled clinical trials.
• Patients receiving concomitant corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), or anti-angiogenic agents, or patients with increasing age or who have an underlying history of GI ulceration, underlying diverticular disease, or bowel metastases may be at an increased risk of perforation.
• Permanently discontinue GILOTRIF in patients who develop GI perforation.
Keratitis
• Keratitis has been reported in patients taking GILOTRIF.
• Withhold GILOTRIF during evaluation of patients with suspected keratitis. If diagnosis of ulcerative keratitis is confirmed, interrupt or discontinue GILOTRIF. If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered. GILOTRIF should be used with caution in patients with a history of keratitis, ulcerative keratitis, or severe dry eye. Contact lens use is also a risk factor for keratitis and ulceration.
Embryo-Fetal Toxicity
• GILOTRIF can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.
• Advise females of reproductive potential to use effective contraception during treatment, and for at least 2 weeks after the last dose of GILOTRIF. Advise female patients to contact their healthcare provider with a known or suspected pregnancy.
ADVERSE REACTIONS
Adverse Reactions observed in clinical trials were as follows:
Previously Treated, Metastatic Squamous NSCLC
• In GILOTRIF-treated patients (n=392) the most common adverse reactions (≥20% all grades & vs erlotinib-treated patients (n=395)) were diarrhea (75% vs 41%), rash/acneiform dermatitis (70% vs 70%), stomatitis (30% vs 11%), decreased appetite (25% vs 26%), and nausea (21% vs 16%).
• Serious adverse reactions were reported in 44% of patients treated with GILOTRIF. The most frequent serious adverse reactions reported in patients treated with GILOTRIF were pneumonia (6.6%), diarrhea (4.6%), and dehydration and dyspnea (3.1% each). Fatal adverse reactions in GILOTRIF-treated patients included ILD (0.5%), pneumonia (0.3%), respiratory failure (0.3%), acute renal failure (0.3%), and general physical health deterioration (0.3%).
DRUG INTERACTIONS
Effect of P-glycoprotein (P-gp) Inhibitors and Inducers
• Concomitant use of P-gp inhibitors (including but not limited to ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, and amiodarone) with GILOTRIF can increase exposure to afatinib.
• Concomitant use of P-gp inducers (including but not limited to rifampicin, carbamazepine, phenytoin, phenobarbital, and St. John’s wort) with GILOTRIF can decrease exposure to afatinib.
USE IN SPECIFIC POPULATIONS
Lactation
• Because of the potential for serious adverse reactions in breastfed infants from GILOTRIF, advise women not to breastfeed during treatment with GILOTRIF and for 2 weeks after the final dose.
Females and Males of Reproductive Potential
• GILOTRIF may reduce fertility in females and males of reproductive potential. It is not known if the effects on fertility are reversible.
Renal Impairment
• Patients with severe renal impairment (estimated glomerular filtration rate [eGFR] 15 to 29 mL/min/1.73 m2) have a higher exposure to afatinib than patients with normal renal function. Administer GILOTRIF at a starting dose of 30 mg once daily in patients with severe renal impairment. GILOTRIF has not been studied in patients with eGFR <15 mL/min/1.73 m2 or who are on dialysis.
Hepatic Impairment
• GILOTRIF has not been studied in patients with severe (Child Pugh C) hepatic impairment. Closely monitor patients with severe hepatic impairment and adjust GILOTRIF dose if not tolerated.

GF PROF ISI 10.21.19

References

1. Kim ES, Kish JK, Cseh A, et al. Second-line afatinib or chemotherapy following immunochemotherapy for the treatment of metastatic, squamous cell carcinoma of the lung: real-world effectiveness and safety from a multisite retrospective chart review in the USA. Clin Lung Cancer. 2021;S1525-7304(21)00029-2.
2. GILOTRIF. Prescribing information. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2019.
3. Sherman RE, Anderson SA, Dal Pan GJ, et al. Real-world evidence — what is it and what can it tell us? N Engl J Med. 2016:8;375(23):2293-2297.

Please review the Full Prescribing Information and Patient Information.

KRAS Variant Status and Outcomes with Immune Checkpoint Inhibitor-Based Therapy in Advanced Non Small Cell Lung Cancer

RR

SUMMARY: The American Cancer Society estimates that for 2021, about 235,760 new cases of lung cancer will be diagnosed and 131,880 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.

Patients with advanced NSCLC without a driver mutation and with Programmed cell Death Ligand 1 (PD-L1) expression of 50% or greater, are often treated first line with Immune Checkpoint Inhibition (ICI) monotherapy or ICI in combination with chemotherapy. The choice between these two treatment regimens is usually based on tumor burden and patient comorbidities, as there are presently no biomarkers available to predict the risk and benefit of these treatment interventions. The KEYNOTE-042 study demonstrated that single agent Pembrolizumab given as first line therapy demonstrated Overall Survival (OS) benefit over chemotherapy, in patients with previously untreated advanced NSCLC, with PD-L1 expression of 1% or greater. In an exploratory analysis, this benefit was seen regardless of KRAS status, but was more pronounced in patients with KRAS variants than those without KRAS variants.

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. When mutated, KRAS oncogene has 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 12-15% of 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.

The authors conducted this study to evaluate the association of KRAS status with outcomes following ICI monotherapy versus chemoimmunotherapy in patients with PD-L1 of 50% or greater. The researchers used the Flatiron Health database, comprising 280 cancer clinics across the US and analyzed 1127 patients with advanced non-squamous NSCLC with PD-L1 expression of 50% or greater, known KRAS variant status, and no alteration in EGFR, ALK, or ROS1, who were treated with first line ICI monotherapy or chemoimmunotherapy between January 2016 and May 2020. Of the patients analyzed, 50.8% had KRAS variant status and 49.2% had KRAS wild type status. Patients with KRAS variant status were more likely to be female (58.7% versus 47.1%; P =0.002) and had smoking history (96.4% versus 87.7%; P < .001). Other patient demographics and patient characteristics, including age, race, ethnicity, Performance Status, and stage at diagnosis, were well balanced among the groups analyzed. Patient groups were stratified by treatment type and KRAS status (variant or wild type), and Overall Survival (OS) was compared between the treatment groups. Adjusted Hazard ratios for death associated with KRAS status and treatment regimen was estimated, using Cox proportional hazards models.

It was noted that among patients treated with ICI monotherapy, KRAS variant status was associated with superior median survival compared with KRAS wild type (21.1 months versus 13.6 months; HR=0.77; P=0.03), and this was statistically significant. However, among patients treated with chemoimmunotherapy, there was no significant median survival difference between patients with KRAS variant and KRAS wild type status (20.0 months versus 19.3 months; HR=0.99; P=0.93).

Among patients with KRAS variant status, the median OS did not differ between those treated with ICI monotherapy and chemoimmunotherapy (21.1 months versus 20.0 months; P =0.78), whereas among patients with KRAS wild type status, those treated with ICI monotherapy had numerically worse median survival than those treated with chemoimmunotherapy, although this difference was not statistically significant (13.6 months versus 19.3 months; HR=1.19; P =0.06).

In conclusion, this data suggests that chemoimmunotherapy might be favored over ICI monotherapy for patients with KRAS wild type tumors associated with high PD-L1 expression. The authors caution that in this analysis KRAS variant subtype and co-mutation status including TP53 and STK11 was unknown, and further investigation is needed to selection appropriate therapies for patients with PD-L1 High NSCLC.

Association Between KRAS Variant Status and Outcomes With First-line Immune Checkpoint Inhibitor–Based Therapy in Patients With Advanced Non–Small-Cell Lung Cancer. Sun L, Hsu M, Cohen RB, et al. JAMA Oncol. 2021;7:937-939.