FDA Approves LIBTAYO® in Combination with Chemotherapy for Non-Small Cell Lung Cancer

SUMMARY: The FDA on November 8, 2022, approved LIBTAYO® (Cemiplimab-rwlc) in combination with platinum-based chemotherapy for adult patients with advanced Non-Small Cell Lung Cancer (NSCLC) with no EGFR, ALK, or ROS1 aberrations. 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.

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 T cells of the immune system. Immuno-Oncology (IO) therapies unleash the T cells by blocking the Immune checkpoint proteins, thereby resulting in T cell proliferation, activation, and a therapeutic response. Immunotherapy with PD-1 (Programmed cell Death 1) and PD-L1 (Programmed cell Death Ligand 1) inhibitors have demonstrated a clear survival benefit both as a single agent or in combination, compared with standard chemotherapy, in both treatment-naive and previously treated patients for advanced NSCLC. It is now standard therapy for patients with lung cancer.

KEYTRUDA® (Pembrolizumab; anti PD-1) and TECENTRIQ® (Atezolizumab; anti PD-L1) are both approved in combination with platinum-based chemotherapy for the first-line treatment of patients with metastatic NSCLC. The FDA approval of TECENTRIQ® with platinum-doublet chemotherapy is however limited to non-squamous histology.

LIBTAYO® is a fully human monoclonal antibody targeting the immune checkpoint receptor PD-1. LIBTAYO® monotherapy was approved by the FDA in 2021 after it demonstrated significantly improved Overall Survival and Progression Free Survival compared with chemotherapy, in patients with advanced Non-Small Cell Lung Cancer with PD-L1 of at least 50%. The researchers in EMPOWER-Lung 3 evaluated the efficacy of first line LIBTAYO® in combination with investigator’s choice of platinum-doublet chemotherapy, among patients with advanced NSCLC, with either squamous or non-squamous histology, and any level of PD-L1 expression.

EMPOWER-Lung 3 is a randomized, multicenter, multinational, double-blind, active-controlled Phase III trial in which 466 patients with advanced NSCLC who had not received prior systemic treatment were randomized (2:1) to receive either Cemiplimab 350 mg IV once every 3 weeks (N=312) or placebo (N=154) every 3 weeks, in combination with four cycles of chemotherapy. Investigators’ choice of histology-specific chemotherapy options included Paclitaxel plus Carboplatin, Paclitaxel plus Cisplatin, Pemetrexed plus Carboplatin and Pemetrexed plus Cisplatin. Patients were treated for a maximum of 108 weeks, or until disease progression or unacceptable toxicity. For patients with non-squamous histology assigned to a Pemetrexed-containing regimen, maintenance Pemetrexed was mandatory. Patients were enrolled irrespective of PD-L1 expression or tumor histology and had advanced or metastatic NSCLC, with no ALK, EGFR or ROS1 aberrations. Among those enrolled, 43% had tumors with squamous histology, 67% had tumors with less than 50% PD-L1 expression, 15% had inoperable locally advanced disease not eligible for definitive chemoradiation, and 7% had pretreated and clinically stable brain metastases. The Primary endpoint was Overall Survival (OS). Secondary endpoints included Progression Free Survival (PFS) and Overall Response Rate (ORR) as assessed by Blinded Independent Central Review (BICR).

The trial was stopped early upon recommendation by the Independent Data Monitoring Committee (IDMC) after the LIBTAYO® combination demonstrated a statistically significant and clinically meaningful improvement in Overall Survival, compared to placebo plus chemotherapy. The median OS was 21.9 months in the LIBTAYO® plus chemotherapy group and 13.0 months in the placebo plus chemotherapy group (HR=0.71; P=0.0140). This represented a 21% relative reduction in the risk of death in the LIBTAYO® plus chemotherapy group. The 12-month probability of survival was 66% for the LIBTAYO® combination versus 56% for chemotherapy.

The median PFS per BICR was 8.2 months in the LIBTAYO® plus chemotherapy group and 5.0 months in the placebo plus chemotherapy group (HR=0.56; p<0.0001). This represented a 44% reduction in the risk of disease progression in the LIBTAYO® plus chemotherapy group. The 12-month probability of PFS for the LIBTAYO® combination was 38%, versus 16% for chemotherapy. The confirmed ORR per BICR was 43% and 23% in the respective treatment groups and the median Duration of Response was 16 months versus 7 months respectively. The most common (15% or more) adverse reactions were alopecia, musculoskeletal pain, nausea, fatigue, peripheral neuropathy, and decreased appetite.

It was concluded that LIBTAYO® is only the second anti-PD-1/PD-L1 agent to show efficacy in advanced Non-Small Cell Lung Cancer either as monotherapy in those with PD-L1 expression 50% or more, or in combination with chemotherapy, irrespective of PD-L1 expression or tumor histology.

Cemiplimab plus chemotherapy versus chemotherapy alone in non-small cell lung cancer: a randomized, controlled, double-blind phase 3 trial. Gogishvili M, Melkadze T, Makharadze T, et al. Nature Medicine 2022;(28):2374-2380.

Lung Cancer Screening with Low Dose CT Associated with Favorable Stage Shift and Improved Survival

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. The 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.

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. Surgical resection is the primary treatment for approximately 30% of patients with NSCLC who present with early Stage (I–IIIA) disease. In spite of the favorable stage shift as a result of lung cancer screening, low Health Care Provider knowledge of the lung cancer screening guidelines represents a potential barrier to implementation, and no clinical trials have shown these favorable benefits in a real world setting.

The authors in this study evaluated whether the introduction of Low Dose CT screening in 2013 resulted in an increase in the percentage of Stage I NSCLC diagnosed among patients potentially eligible for screening, along with an increase in median all cause survival among these patients, and whether any effects on stage extend to the entire study population or only select population groups. The researchers analyzed data from two large comprehensive US cancer registries-the National Cancer Database and the Surveillance Epidemiology End Results (SEER) program database using a quasi-experimental observational design. A total of 763 474 patients were identified for analysis in this study. They included those who were diagnosed as having NSCLC between 2010 and 2018 and who would have been eligible for screening by age criteria (age 55-79 years) and a comparator NSCLC patient cohort who would have been ineligible for screening (age 45-55). The authors then compared the rate of change in the percentage of patients with Stage I cancer at diagnosis between 2010 and 2018.

It was noted that among the screen eligible cohort of NSCLC patients, the percentage of patients with Stage I disease at diagnosis increased by 3.9% each year from 2014, following a minor change from 2010 to 2013. The rate of increase in Stage I diagnoses was more rapid in high lung cancer screening states. These findings however were not seen in the younger, screening ineligible patients. These results consistently noted across multiple analyses.

The median all cause survival of screening eligible patients aged 55-80 years increased at 11.9% per year from 2014 to 2018 (from 19.7 to 28.2 months). In multivariable adjusted analysis, the hazard of death decreased significantly faster after 2014 compared with before 2014 (P<0.001).

Disparities were however noted, and the benefits from this significant shift in the stage of the disease was not realized in racial or ethnic minority groups and those living in lower income or less educated regions. By 2018, Stage I NSCLC was the predominant diagnosis among non-Hispanic white people, whereas the economically deprived group of patients, were more likely to have Stage IV disease at diagnosis. Increases in the detection of early stage lung cancer in the US from 2014 to 2018 led to an estimated 10,100 averted deaths.

It was concluded from this study that although the adoption of lung cancer screening has been slow nationwide, this study indicated the beneficial effect of lung cancer screening and a recent stage shift toward Stage I NSCLC, with improved survival, following the introduction of lung cancer screening. This study also highlighted the disparities in the stage of lung cancer diagnosed between patient populations, reinforcing the need for equitable access to screening in the US.

Association of computed tomography screening with lung cancer stage shift and survival in the United States: quasi-experimental study. Potter AL, Rosenstein AL, Kiang MV, et al. BMJ 2022; 376 doi: https://doi.org/10.1136/bmj-2021-069008 (Published 30 March 2022)

FDA Grants Tumor-Agnostic Accelerated Approval to RETEVMO®

SUMMARY: The FDA on September 21, 2022, granted accelerated approval to Selpercatinib (RETEVMO®) for adult patients with locally advanced or metastatic solid tumors with a Rearranged during Transfection (RET) gene fusion that have progressed on or following prior systemic treatment, or who have no satisfactory alternative treatment options. The FDA on the same day also granted Regular approval to Selpercatinib for adult patients with locally advanced or metastatic Non Small Cell Lung Cancer (NSCLC) with a Rearranged during Transfection (RET) gene fusion, as detected by an FDA-approved test. FDA also approved the Oncomine Dx Target (ODxT) Test as a companion diagnostic for Selpercatinib.

In addition to the well characterized gene fusions involving ALK and ROS1 in NSCLC, genetic alterations involving other kinases including EGFR, BRAF, RET, NTRK, are all additional established targetable drivers. These genetic alterations are generally mutually exclusive, with no more than one predominant driver in any given cancer. The hallmark of all these genetic alterations is oncogene addiction, in which cancers are driven primarily, or even exclusively, by aberrant oncogene signaling, and are highly susceptible to small molecule inhibitors.

RET kinase is a transmembrane Receptor Tyrosine Kinase and plays an important role during the development and maintenance of a variety of tissues, including neural and genitourinary tissues. RET signaling activates downstream pathways such as JAK/STAT3 and RAS/RAF/MEK/ERK and leads to cellular proliferation, survival, invasion, and metastasis. Oncogenic alterations to the RET proto-oncogene result in uncontrolled cell growth and enhanced tumor invasiveness. RET alterations include RET rearrangements, leading to RET fusions, and activating point mutations occurring across multiple tumor types. RET fusions have been identified in approximately 2% of NSCLCs, 10-20% of non-medullary thyroid cancers. Activating RET point mutations account for approximately 60% of sporadic Medullary Thyroid Cancers (MTC) and more than 90% of inherited MTCs. Other cancers with documented RET alterations include colorectal, pancreas, breast, and several hematologic malignancies.

Selpercatinib is a highly selective and potent, oral anti-RET Tyrosine Kinase Inhibitor (TKI) designed to inhibit native RET signaling, as well as anticipated acquired resistance mechanisms. Selpercatinib selectively targets wild-type RET as well as various RET mutants and RET-containing fusion products. Additionally, Selpercatinib inhibits Vascular Endothelial Growth Factor Receptor 1 (VEGFR1), VEGFR3, Fibroblast Growth Factor Receptor 1 (FGFR1), FGFR2, and FGFR3. This results in inhibition of cell growth of tumors that exhibit increased RET activity.

The LIBRETTO-001 is the largest open-label, multicenter, Phase I/II trial in patients with advanced solid tumors, including RET fusion-positive solid tumors, RET-mutant Medullary Thyroid Cancers, and other tumors with RET activation, treated with a RET inhibitor. To investigate the efficacy of Selpercatinib, the trial was conducted in 2 parts: Phase 1 (dose escalation) and Phase II (dose expansion). Patients with advanced cancer were eligible, if they have progressed on or were intolerant to available standard therapies, or no standard or available curative therapy existed, or in the opinion of the Investigator, they would be unlikely to tolerate or derive significant clinical benefit from appropriate standard of care therapy, or they declined standard therapy. A dose of 160 mg BID was the recommended Phase II dose. Up to about 850 patients with advanced solid tumors harboring a RET gene alteration in tumor and/or blood were enrolled in 6 different Phase II cohorts, based on tumor type, RET alteration and prior therapy. Identification of RET gene alterations were prospectively determined in local laboratories using either Next Generation Sequencing, Polymerase Chain Reaction, or Fluorescence In Situ Hybridization. The Phase II portion of the trial had a Primary endpoint of Objective Response Rate (ORR) by Blinded Independent Review Committee (BIRC) and Secondary endpoints of Duration of Response, CNS Objective Response Rate, Progression Free Survival (PFS) and safety.

RET Fusion-Positive Solid Tumors

This group included 41 patients and the most common cancers were pancreatic adenocarcinoma (27%), colorectal (24%), salivary (10%), and unknown primary (7%). Majority of the patients (90%) received 2 prior systemic therapies and 32% had received 3 or more. The median age of patients was 50 years, 54% were female, 68% were White, 24% were Asian, and 95% had metastatic disease. RET fusion-positive status was detected in 98% of patients using NGS and 2% using FISH.

The Objective Response Rate was 44%, with 5% Complete Response and 39% Partial Response. The median Duration of response was 24.5 months and 67% of patients had a Duration of Response of 6 months or more.

The NSCLC Cohort

Selpercatinib was previously granted accelerated approval in May 2020 for patients with metastatic RET fusion-positive NSCLC based on initial Overall Response Rate (ORR) and Duration of Response (DOR) among 144 patients enrolled in the LIBRETTO-001 trial. The conversion to regular and traditional FDA approval was based on data from an additional 172 patients and 18 months of additional follow up, to assess durability of response. Patients received Selpercatinib until disease progression or unacceptable toxicity and efficacy was evaluated in a total of 316 patients with locally advanced or metastatic RET fusion-positive NSCLC. The median age of patients was 61 years, 58% were female, 49% were White, 41% were Asian and 97% had metastatic disease. Previously treated patients received a median of two prior systemic therapies and 58% had received prior anti PD 1/PD-L1 therapy.

Among the 69 treatment-naïve patients, the ORR was 84%, with 6% Complete Response and 78% Partial Response. The median Duration of Response was 20.2 months and 50% of patients had a Duration of Response of 12 months or more. Among the 247 previously treated patients, the ORR was 61%, with 7% Complete Response and 54% Partial Response. The median Duration of Response was 28.6 months and 63% of patients had a Duration of Response of 12 months or more.

It is estimated that up to 50% of RET fusion-positive NSCLC patients can have brain metastases, and in the subset of patients with brain metastases (N=21), treatment with Selpercatinib demonstrated a CNS Objective Response Rate of 85%, and 38% of responders had an intracranial Duration of Response of 12 months or greater. The most common toxicities in patients were edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, constipation, rash, nausea, and headache.

LIBRETTO-001 is the largest trial ever reported in RET-altered cancer patients and represents an important milestone in the Precision Medicine arena. Selpercatinib is the first and only RET inhibitor to receive both tumor-agnostic accelerated approval and traditional approval in NSCLC, reinforcing its benefits across diverse tumor types.

Selpercatinib in patients with RET fusion–positive non–small-cell lung cancer: updated safety and efficacy from the registrational libretto-001 phase I/II trial.Published September 19, 2022. Drilon A, Subbiah V, Gautschi O, et al. J Clin Oncol. doi:10.1200/JCO.22.00393

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-selpercatinib-locally-advanced-or-metastatic-ret-fusion-positive-solid-tumors

FDA Grants Regular Approval to TABRECTA® for Metastatic Non-Small Cell Lung Cancer

SUMMARY: The FDA on August 10, 2022, granted regular approval to TABRECTA® (Capmatinib), for adult patients with metastatic Non-Small Cell Lung Cancer (NSCLC) whose tumors have a mutation leading to Mesenchymal-Epithelial Transition (MET) exon 14 skipping, as detected by an FDA-approved test. 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.

MET is a widely expressed Receptor Tyrosine Kinase and plays a pivotal role in cell growth, proliferation, and survival. The MET gene encodes for a protein known as the Hepatocyte Growth Factor (HGF) Receptor. Upon binding by Hepatocyte Growth Factor (HGF), the HGF Receptor is activated, with resulting activation of the downstream RAS/RAF/MEK/ERK and PI3K/AKT/mTOR signaling pathways, thereby serving different important biological functions. Alterations in the MET gene leading to abnormal MET signaling, has been identified in different types of cancers including thyroid, lung, breast, liver, colon, kidney, ovary, and gastric carcinoma.

Two key MET alterations include MET exon 14 skipping mutations and MET amplification. MET exon 14 skipping mutations occur in approximately 5% of NSCLC patients with enrichment in sarcomatoid lung cancers (22%). MET exon 14 skipping mutation is a recognized oncogenic driver and is a molecular genetic abnormality indicating the presence of a splice site mutation that results in a loss of transcription of exon 14 of the MET gene. Most exon 14 mutations occur in never-smokers and is seen in both squamous and adenocarcinoma histology. Patients whose cancers have MET exon 14 skipping generally have very high response rates to MET inhibitors and molecular testing for MET exon 14 skipping should therefore be performed on all lung cancers, because this is a targetable alteration. MET amplification has been more commonly seen in smokers, and responses in patients with MET-amplified tumors might be more variable and dependent on level of amplification, with higher responses noted in tumors with more than 5-6- fold amplification. Tumors with MET exon 14 skipping mutations usually do not harbor activating mutations in EGFR, KRAS, or BRAF or concurrent ALK, ROS1 or RET translocations. However, it appears that cMET exon 14 skipping is not mutually exclusive with cMET amplification.

TABRECTA® is a highly potent and selective, reversible inhibitor of MET tyrosine kinase. The FDA in May 2020 granted accelerated approval for the same indication based on the primary findings from the GEOMETRY mono-1 trial, which is a non-randomized, open-label, multi-cohort, Phase II study, conducted to evaluate the efficacy and safety of single-agent TABRECTA® in adult patients with EGFR wild-type, ALK-negative, metastatic NSCLC, whose tumors have a mutation that leads to MET exon 14 skipping (METex14), as detected by an RNA-based RT-PCR. The conversion to regular approval was based on data from an additional 63 patients (Total N=160), as well as an additional 22 months of follow- up time, to assess durability of response and verify clinical benefit.

In this updated analysis, a total of 160 patients (N=160) with metastatic NSCLC and confirmed MET exon 14 skipping mutations were included, of whom 60 patients were treatment naïve and 100 patients were previously treated. The patients received TABRECTA® at 400 mg orally twice daily until disease progression or unacceptable toxicity. The median patient age was 71 years and all NSCLC histologies including sarcomatoid/carcinosarcoma were included. Majority of the patients (77%) were white and 23% were Asian, 61% never smoked, 83% had adenocarcinoma, and 16% had CNS metastases. Among previously treated patients, 81% received one, 16% received two, and 3% received three prior lines of systemic therapy. Amongst previously treated patients, 86% received prior platinum-based chemotherapy. The Primary efficacy outcome was Overall Response Rate (ORR), and additional efficacy outcomes included Duration of Response, Time to Response, Disease Control Rate, Progression Free Survival (PFS) and Safety, as determined by a Blinded Independent Review Committee (BIRC).

Among the treatment-naïve patients (N=60), the ORR was 68% with a median Duration of Response of 12.6 months. Among the previously treated patients (N=100), the ORR was 44%, with a median Duration of Response of 9.7 months. The most common adverse events (occurring in at least 20% of patients) were peripheral edema, nausea, fatigue, vomiting, dyspnea, and decreased appetite. TABRECTA® can also cause Interstitial Lung Disease, hepatotoxicity and photosensitivity.

It was concluded that TABRECTA® is a new treatment option for patients with MET exon 14 skipping- mutated advanced NSCLC, regardless of the line of therapy, with deep and durable responses, and with manageable toxicity profile.

Capmatinib in MET exon 14-mutated, advanced NSCLC: Updated results from the GEOMETRY mono-1 study. Wolf J, Garon EB, Groen HJM, et al. DOI: 10.1200/JCO.2021.39.15_suppl.9020 Journal of Clinical Oncology – published online before print May 28, 2021.

FDA Grants Accelerated Approval to ENHERTU® for HER2-Mutant Non Small Cell Lung Cancer

SUMMARY: The FDA on August 11, 2022, granted accelerated approval to ENHERTU® (fam-trastuzumab deruxtecan-nxki), for adult patients with unresectable or metastatic Non-Small Cell Lung Cancer (NSCLC) whose tumors have activating human Epidermal Growth Factor Receptor 2 or HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy. This is the first drug approved for HER2-mutant NSCLC. FDA also approved Oncomine™ Dx Target Test (tissue) and Guardant360® CDx (plasma) as companion diagnostics for ENHERTU®. If no mutation is detected in a plasma specimen, the tumor tissue should be tested.

The American Cancer Society estimates that for 2022, about 236,740 new cases of lung cancer will be diagnosed and 135,360 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

The 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 are detected in 2 to 4% of NSCLCs. They are more often detected in younger, female and never-smokers, and almost exclusively in Adenocarcinomas. Next-generation sequencing is used to identify HER2 mutations. Majority 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, aggressive form of disease and poor prognosis, and with an increased incidence of brain metastases. 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 or HER2-Low breast cancer 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.

In the DESTINY-Lung01 Phase II, open-label, two-cohort trial of heavily pretreated population of patients with HER2-mutated advanced NSCLC, treatment with ENHERTU® 6.4 mg/kg given by IV infusion every 3 weeks resulted in an Objective Response Rate (ORR) of 55%, with a 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 (NEJM 2022;386:241-251).

The present FDA approval was based on DESTINY-Lung02, which is a global, multicenter, multi-cohort, randomized, blinded, dose-optimization, Phase II trial, in which the safety and efficacy of two doses ENHERTU® (5.4mg/kg or 6.4mg/kg) was evaluated, in patients with HER2 mutated metastatic NSCLC, with disease recurrence or progression during or after at least one regimen of prior anticancer therapy that must have contained a platinum-based chemotherapy. This study enrolled 152 patients (N=152) and patients were selected for treatment with ENHERTU® based on the presence of activating HER2 (ERBB2) mutations in a tumor specimen. Patients were randomized to receive ENHERTU® 6.4 mg/kg or 5.4 mg/kg by IV infusion every 3 weeks, until unacceptable toxicity or disease progression. The Primary endpoint of the trial was Objective Response Rate (ORR) as assessed by Blinded Independent Central Review (BICR). Secondary endpoints included Disease Control Rate (DCR), Duration of Response (DoR), Progression Free Survival (PFS), Overall Survival (OS) and Safety. The primary/interim efficacy analysis included a pre-specified cohort of 52 patients (N=52). The median age in this cohort was 58 years, 69% were female; 79% were Asian, 12% were White, and 10% were of other races.

ENHERTU® 5.4mg/kg IV demonstrated a confirmed Objective Response Rate of 57.7%, with a Complete Response Rate of 1.9%, Partial Response Rate of 55.8%, and median Duration of Response of 8.7 months. The most common adverse effects included nausea, alopecia, increased AST and ALT, cytopenias, and was consistent with previous clinical trials, with no new safety concerns identified.

It was concluded that ENHERTU® is the first HER2-directed treatment option for patients with HER2 mutated NSCLC, and fulfills an unmet medical need in this patient population.

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-her2-mutant-non-small-cell-lung

Late Breaking Abstract – ASCO 2022: Landmark Five Year Overall Survival Rates for OPDIVO® and YERVOY® Combination in NSCLC

SUMMARY: The American Cancer Society estimates that for 2022, about 236,740 new cases of lung cancer will be diagnosed and 135,360 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions by switching off the immune system T cells. Immune checkpoint proteins/receptors include CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152) and PD-1(Programmed cell Death 1). Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response. OPDIVO® (Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells. YERVOY® is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4.

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

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

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

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

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

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

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

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

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

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

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

Five-year survival outcomes with nivolumab (NIVO) plus ipilimumab (IPI) versus chemotherapy (chemo) as first-line (1L) treatment for metastatic non–small cell lung cancer (NSCLC): Results from CheckMate 227. Brahmer JR, Lee J-S, Ciuleanu T-E, et al. J Clin Oncol. 2022;40(suppl 17):LBA9025. doi:10.1200/JCO.2022.40.17_suppl.LBA9025

Late Breaking Abstract – ASCO 2022: Adagrasib in KRAS G12C Mutated Non Small Cell Lung Cancer

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

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

Adagrasib is a potent, orally available, small molecule covalent inhibitor of KRAS G12C. This drug irreversibly and selectively binds KRAS G12C in its inactive, GDP-bound state. Unlike LUMAKRAS® (Sotorasib), which is also a selective covalent inhibitor of KRAS G12C, Adagrasib has a longer drug half-life of 23 hours, as compared to 5 hours for LUMAKRAS®, has dose-dependent extended exposure, and can penetrate the CNS. Approximately, 27-42% of patients with NSCLC harboring KRAS G12C mutations have CNS metastases, with poor outcomes.

KRYSTAL-1 is a Phase I/II multiple expansion cohort trial involving patients with advanced solid tumors harboring a KRAS G12C mutation. Adagrasib demonstrated clinical activity in patients with KRAS G12C-mutated solid tumors, including colorectal, pancreatic, and biliary tract cancers. Further, preliminary data from two patients with untreated CNS metastases from a Phase 1b cohort showed antitumor activity against CNS metastases, with satisfactory concentrations of Adagrasib in the CSF.

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

The median follow up was 12.9 months and the median duration of treatment was 5.7 months. The confirmed Objective Response Rate was 42.9% and the median Duration of Response was 8.5 months. The median Progression Free Survival was 6.5 months and the median Overall Survival was 12.6 months, at a median follow up of 15.6 months. Among 33 patients with previously treated, stable CNS metastases, the intracranial confirmed Objective Response Rate was 33.3%. Treatment-related adverse events occurred in 97.4% of the patients and 53% were Grade 1 or 2 toxicities. Adagrasib was discontinued in 6.9% of patients due to adverse events.

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

Adagrasib in Non–Small-Cell Lung Cancer Harboring a KRASG12C Mutation. Jänne PA, Riely GJ, Gadgeel SM, et al. DOI: 10.1056/NEJMoa2204619

Consider Guideline-Recommended Biomarker Testing as an Integral Component of NSCLC Care

The NSCLC Landscape Has Evolved Significantly Due Largely to the Growing Number of Actionable Mutations1

Despite advancements in standard-of-care, advanced non-small cell lung cancer (NSCLC) continues to burden patients, with poor survival outcomes.2,3 NSCLC has been identified as the leading cause of cancer death worldwide with an estimated 1.8 million deaths in 2020.2 As the number of targeted therapies and approved companion diagnostics continues to grow, mortality and survival rates have begun to improve.3 With the addition of KRAS G12C, there are 9 actionable molecular biomarkers (as of February 2022) and more than 20 targeted therapies approved for use in advanced NSCLC.1,4 Guidelines recommend biomarker testing for all eligible patients at diagnosis of advanced NSCLC regardless of characteristics such as smoking history, race, or histology.5,6 Unfortunately, real-world evidence shows that far too many patients fail to receive the comprehensive biomarker testing.7

Adherence to Guidelines Can Improve Patient Outcomes8

As targeted therapies are approved, guidelines continue to update their recommendations on biomarker testing.5 As of March 2022, NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for NSCLC recommend broad molecular testing of actionable and emerging biomarkers for eligible patients with advanced or metastatic NSCLC (Figure 1).5 Similarly, the American Society of Clinical Oncology (ASCO) endorsed the 2018 College of American Pathologists (CAP)/International Association for the Study of Lung Cancer (IASLC)/Association for Molecular Pathology (AMP) guidelines, recommending comprehensive cancer panel testing for genetic biomarkers.9,10

Figure 1: NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for NSCLC5,*,†Advanced-Non-Squamous-NSCLC*The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for NSCLC provide recommendations for certain individual biomarkers that should be tested and recommend testing techniques but do not endorse any specific commercially available biomarker assays or commercial laboratories.5The NCCN Guidelines® for NSCLC recommend broad molecular testing to identify rare driver variants for which targeted therapies may be available to ensure patients receive the most appropriate treatment.5KRAS G12C and EGFR exon 20 mutations are used to determine subsequent (ie, second-line and beyond) therapy using targeted agents or other novel agents.5 §The definition of high-level MET amplification is evolving and may differ according to the assay used for testing. For NGS-based results, a copy number greater than 10 is consistent with high-level MET amplification.5 **For oncogenic or likely oncogenic HER2 mutations, refer to definitions at oncokb.org.5

Although adherence to guideline-recommended biomarker testing is associated with improved patient outcomes, real-world EMR data reveals suboptimal biomarker testing rates.8,11 In a retrospective study,†† 81% of patients with metastatic NSCLC did not receive testing for ALK, EGFR, ROS1, and BRAF before initiation of first-line treatment, despite availability of targeted therapies.11 Moreover, only 28% of patients received testing for all four genetic biomarkers and PD-L1 during the study period.11 In another retrospective study, less than 50% of patients with metastatic NSCLC received testing for all five biomarkers (EGFR, ALK, ROS1, BRAF, PD-L1) (Figure 2).7

Beyond the underutilization of biomarker testing, there remains an even greater need to increase broad molecular testing among racial and ethnic minority groups in the US.12,13 In one retrospective study, Black/African American patients with advanced NSCLC had significantly lower rates of testing with NGS assays (39.8%) compared with White patients (50.1%) (Figure 3).12

††A retrospective study assessing real-world biomarker testing patterns in patients with de novo mNSCLC (N=2,257) in the community oncology setting using the US Oncology Network electronic health records between January 1st, 2017 and September 31st, 2019 with follow-up through December 31st, 2019.11

Figure 2: MYLUNG Consortium™ EMR Analysis of Patients With Metastatic NSCLC7,‡‡MYLUNG-Consortium‡‡A retrospective, observational study assessing real-world biomarker testing patterns in patients with metastatic NSCLC(N=3,474) from community oncology practices within the US Oncology Network community practices between 2018 and 2020.7
Figure 3: EMR Analysis of Biomarker Testing in Patients With Advanced/Metastatic NSCLC12,§§
EMR-Analysis-of-Biomarker-Testing
§§From a retrospective cohort study of patients with advanced/metastatic: NSCLC (N=14,768) from ~800 sites of care identified via the Flatiron Electronic Health Record Database between 2017 and 2020. Of this study cohort, patients included White (n=9,793), Black/African American (n=1,288), and non-squamous NSCLC (n=10,333).

Collectively, these findings highlight the disparity in proactive disease management across different patient populations.7,11,12

Considerations Across the Biomarker Testing Journey

There are several different methods in which eligible patients can be tested for actionable genetic alterations, each with unique considerations as indicated below (Figure 4).

Figure 4: Comparing Biomarker Testing Methods and Sample Types
Comparing-Biomarker-Testing-Methods***Data from a review of common molecular assays for biomarker testing that analyzed common detected variants, sensitivities, and turnaround time.6 †††cfDNA refers to all circulating DNA (largely non-malignant), while ctDNA refers to the tumor-related component of cfDNA.15 ‡‡‡Data from a prospective study that enrolled patients with previously untreated metastatic NSCLC undergoing SOC tissue genotyping and comprehensive cfDNA analysis, with turnaround time defined as the number of days between test order date and the retrieval of test results.16

While tissue biopsy remains the “gold standard” in NSCLC, it may not be feasible (insufficient tissue) or pragmatic (urgent need to begin treatment) in all patients.17 Plasma ctDNA demonstrates complementary results to tissue-based assays and can be considered a valid tool for genotyping of newly diagnosed patients with advanced NSCLC.15 In a prospective study of patients with previously untreated, non-squamous metastatic NSCLC from 2016 to 2018, guideline-recommended biomarkers with FDA-approved therapies (EGFR Exon 19 deletion and L858R, ALK fusion, ROS1 fusion, BRAF V600E) showed ≥ 98.2% concordance between tissue and liquid-based testing.16 While concordance is high for any single test, high concordance for full panels will be required for liquid biopsies to become standard; additionally, negative results on liquid biopsy still require validation with tissue testing.16,17

Liquid biopsy may offer improvements in sample acquisition and small tissue samples and provides less invasive procedures and shortened turnaround times.17 Other considerations for maximizing the tissue journey include the use of comprehensive testing, rapid on-site evaluation (ROSE), and implementing reflex testing protocols with the help of a multidisciplinary team (MDT).17

Delays in Biomarker Testing Results May Impact Treatment Plan Decisions18

Longer turnaround times for molecular testing compared with turnaround times for PD-L1 testing by IHC may result in the initiation of immunotherapy before molecular testing results are received.18 Waiting for complete biomarker test results prior to initiating therapy can allow doctors to make the most informed decisions surrounding a patient’s treatment journey.18

Consider Comprehensive Biomarker Testing as an Important Part of Your Treatment Plan8

As the NSCLC landscape continues to progress with the increasing number of actionable biomarkers, there is a growing need for proactive and comprehensive molecular testing.7,17 Although real-world data has shown significant underuse of biomarker testing, rates can be improved with diligent observation of expanding guidelines and recommendations by expert panels and associations.7,8 In the coming years, clinicians may consider evolving institutional protocols, including enabling reflex testing, and work as an MDT to ensure biomarker testing is performed on all eligible patients with advanced NSCLC.17

[Abbreviations]
AA, African American; ALK, anaplastic lymphoma kinase; BRAF, proto-oncogene B-Raf; cfDNA, cell-free DNA; ctDNA, circulating tumor DNA; EGFR, epidermal growth factor receptor; EMR, electronic medical record; ERBB2, erb-b2 receptor tyrosine kinase 2; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; KRAS, Kirsten rat sarcoma viral oncogene homolog; MET, mesenchymal-to-epithelial transition; mNSCLC, metastatic non-small cell lung cancer; NSCLC, non-small cell lung cancer; NCCN, National Comprehensive Cancer Network; NGS, next-generation sequencing; NTRK, neurotrophic tyrosine receptor kinase; PD-L1, programmed cell death ligand 1; RET, rearranged during transfection; ROS1, c-ros oncogene 1; SOC, standard-of-care.

[References]
1. Majeed U, et al. J Hematol Oncol. 2021;14:108.
2. Sung H, et al. CA Cancer J Clin. 2021;71:209-249.
3. Siegel RL, et al. CA Cancer J Clin. 2021;71:7-33.
4. Food and Drug Administration. www.fda.gov. Accessed October 6, 2021.
5. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer. V.3.2022. ©National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed March 16, 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 any way.
6. Pennell NA, et al. Am Soc Clin Oncol Educ Book. 2019;39:531-542.
7. Robert NJ, et al. Presented at: The American Society of Clinical Oncology Annual Meeting; June 4–8, 2021; Virtual Meeting. Abstract 102.
8. John A, et al. Adv Ther. 2021;38:1552-1566.
9. Hanna N, et al. J Clin Oncol. 2017;35:3484-3515.
10. Lindeman NI, et al. Arch Pathol Lab Med. 2018;142:321-346.
11. Nadler ES, et al. Presented at: The American Society of Clinical Oncology Annual Meeting; June 4–8, 2021; Virtual Meeting. Abstract 9079.
12. Bruno DS, et al. Presented at: The American Society of Clinical Oncology Annual Meeting; June 4–8, 2021; Virtual Meeting. Abstract 9005.
13. Hann KEJ, et al. BMC Public Health. 2017;17:503.
14. Pennell NA, et al. JCO Precis Oncol. 2019;3:1-9.
15. Rolfo C, et al. J Thorac Oncol. 2021;16:1647-1662.
16. Leighl NB, et al. Clin Cancer Res. 2019;25:4691-4700.
17. Gregg JP, et al. Transl Lung Cancer Res. 2019;8:286-301.
18. Smeltzer MP, et al. J Thorac Oncol. 2020;15:1434-1448.

USA-510-80864 02/22

Mutations of STK11/KRAS Genes and Efficacy of Immunotherapy in NSCLC

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.

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 T cells of the immune system. 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.

TECENTRIQ® (Atezolizumab) is an anti-PDL1 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 and thus enabling the activation of T cells. AVASTIN® (Bevacizumab) is a biologic antiangiogenic antibody, directed against Vascular Endothelial Growth Factor (VEGF), and prevents the interaction of VEGF to its receptors (Flt-1 and KDR) on the surface of endothelial cells. The interaction of VEGF with its receptors has been shown to result in endothelial cell proliferation and new blood vessel formation. Combining TECENTRIQ® and AVASTIN® is supported by the following scientific rationale. AVASTIN® in addition to its established anti-angiogenic effects, may further enhance the ability of TECENTRIQ® to restore anti-cancer immunity, by inhibiting VEGF-related immunosuppression, promoting T-cell tumor infiltration and enabling priming and activation of T-cell responses against tumor antigens.

IMpower150 is a multicenter, open-label, randomized, Phase III study, conducted to evaluate the efficacy and safety of TECENTRIQ® in combination with Carboplatin and Paclitaxel with or without AVASTIN®, in patients with Stage IV, treatment naïve, non-squamous NSCLC. This study enrolled 1,202 patients, who were randomized (1:1:1) to receive either TECENTRIQ® along with Carboplatin and Paclitaxel (ACP-Group A), TECENTRIQ® and AVASTIN® along with Carboplatin and Paclitaxel (ABCP-Group B), or AVASTIN® plus Carboplatin and Paclitaxel (BCP-Group C – control arm). During the treatment-induction phase, patients in Group A received TECENTRIQ® 1200 mg IV along with Carboplatin AUC 6 and Paclitaxel 200mg/m2 IV on Day 1 of a 3-week treatment cycle for 4 or 6 cycles. Following the induction phase, patients received maintenance treatment with TECENTRIQ® on the same dose schedule until disease progression. Patients in Group B received AVASTIN® 15 mg/kg IV, along with TECENTRIQ®, Carboplatin and Paclitaxel IV, Day 1 of a 3-week treatment cycle for 4 or 6 cycles followed by maintenance treatment with the TECENTRIQ® and AVASTIN® until disease progression. Patients in the control Group C received AVASTIN® plus Carboplatin and Paclitaxel every 3 weeks for 4 or 6 cycles followed by AVASTIN® maintenance treatment until disease progression. Among randomized patients with tumors demonstrating no ALK and EGFR mutations, ABCP was associated with significant improvements in Progression Free Survival (PFS) and Overall Survival (OS), compared with BCP, in an updated OS analysis. ABCP also prolonged OS and PFS compared with BCP in an exploratory subgroup analysis of patients with EGFR-sensitizing mutations.

The Serine‐Threonine Kinase 11 (STK11) gene is located on the short arm of chromosome 19 and germline STK11 mutations are often detected in Peutz‐Jeghers syndrome, an Autosomal Dominant disorder resulting in mucocutaneous hyperpigmentation, hamartomas throughout the gastrointestinal tract, and a predisposition for breast, lung, pancreas, and gastrointestinal malignancies including cancers of the colon and small bowel. Both STK11 (also called LKB1) and KEAP1 mutation occur in about 17% of NSCLC (adenocarcinomas), respectively, and correlates with poor outcome with immune checkpoint inhibitors or immune checkpoint inhibitors plus chemotherapy. Although immune checkpoint inhibitors with or without chemotherapy have demonstrated survival benefit in patients with KRAS mutated tumors, it remains unclear how co-occurring STK11, KEAP1, and TP53 mutations affect outcomes following immune checkpoint blockade.

The authors in this publication conducted a retrospective exploratory analysis of the efficacy of ABCP (TECENTRIQ® and AVASTIN® along with Carboplatin and Paclitaxel), in patients with KRAS mutations and co-occuring STK11, KEAP1, or TP53 mutations, from the IMpower150 nonsquamous NSCLC patient population. Mutation status was determined by circulating tumor DNA Next-Generation Sequencing.

Among the KRAS mutated population, there was numerical improvement in median OS with ABCP compared to BCP (19.8 vs 9.9 months; HR=0.50), as well as PFS (8.1 vs 5.8 months; HR=0.42) respectively. The median OS with ACP (TECENTRIQ® along with Carboplatin and Paclitaxel) was 11.7 vs 9.9 months (HR=0.63), and PFS was 4.8 vs 5.8 months (HR=0.80), when compared with BCP (AVASTIN® plus Carboplatin and Paclitaxel). When compared to BCP, the ABCP group showed numerically greater survival than the ACP group among KRAS mutated patients. These results were consistent with reported survival improvements with immune checkpoint inhibitors in KRAS-mutant NSCLC.

In KRAS mutant patients across PD-L1 subgroups, OS and PFS were longer with ABCP when compared with BCP, but in PD-L1-low and PD-L1-negative subgroups, OS with ACP was similar to BCP. Conversely, in KRAS wild type patients, OS was longer with ACP than with ABCP or BCP across PD-L1 subgroups.

KRAS was frequently comutated with STK11, KEAP1, and TP53 and these subgroups conferred different prognostic outcomes. Within the KRAS mutated population, STK11 and/or KEAP1 mutations were associated with inferior OS and PFS across treatments compared with STK11-wild type and/or KEAP1wild type. In KRAS mutated patients with co-occurring STK11 and/or KEAP1 mutations (44.9%) or TP53 mutations (49.3%), survival was longer with ABCP than with ACP or BCP.

It was concluded that this analysis supported previous findings of mutation of STK11 and/or KEAP1 as poor prognostic indicators. Even though the clinical efficacy of ABCP (TECENTRIQ® and AVASTIN® along with Carboplatin and Paclitaxel) and ACP (TECENTRIQ® along with Carboplatin and Paclitaxel) was favorable compared with BCP (AVASTIN® plus Carboplatin and Paclitaxel) in these mutational subgroups, survival benefits were greater in the KRAS mutated and KEAP1 and STK11 wild type population versus KRAS mutated and KEAP1 and STK11 mutated population, suggesting both prognostic and predictive value of mutational analysis. The researchers added that these results suggest that TECENTRIQ® in combination with AVASTIN® and chemotherapy is an efficacious first-line treatment in metastatic NSCLC subgroups with KRAS mutations co-occurring with STK11 and/or KEAP1 or TP53 mutations and/or high PD-L1 expression.

Clinical efficacy of atezolizumab plus bevacizumab and chemotherapy in KRAS- mutated non-small cell lung cancer with STK11, KEAP1, or TP53 comutations: subgroup results from the phase III IMpower150 trial. West JH, McCleland M, Cappuzzo, F, et al. J Immunother Cancer. 2022 Feb;10(2):e003027. doi: 10.1136/jitc-2021-003027.

Segmentectomy versus Lobectomy in Small-Sized Peripheral Non-Small Cell Lung Cancer

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.

Lobectomy is the standard of care for early-stage resectable Non-Small Cell Lung Cancer (NSCLC). Pneumonectomy is rarely performed due to unacceptably high mortality rate. Sublobar resection (Wedge resection or Segmentectomy) is 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, even in good-risk patients in many institutions. 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. Wedge resection is inferior to anatomic segmentectomy and is associated with an increased risk of local recurrence and decreased survival in patients with Stage I NSCLC.

The clinical benefits and survival outcomes of segmentectomy have not been investigated in a randomized trial setting. The aim of this study was to investigate if segmentectomy was non-inferior to lobectomy in patients with small-sized peripheral NSCLC. In this randomized, controlled, multicenter, non-inferiority trial, 1106 patients (intention-to-treat population) were enrolled in Japan between Aug, 2009 and Oct 2014, and were randomly assigned 1:1 to receive either lobectomy (N=554) or segmentectomy (N=552). Enrolled patients had clinical Stage IA NSCLC based on contrast-enhanced CT scan and had a single tumor 2 cm or less in diameter, not located in the middle lobe, the center of which was in the outer third of the lung field, with no evidence of lymph node metastasis. Patient baseline clinicopathological factors were well balanced between the two treatment groups. The Primary endpoint was Overall Survival and Secondary endpoints included postoperative respiratory function at 6 months and 12 months, Relapse-Free Survival, proportion of local relapse and adverse events.

At a median follow up of 7.3 years, the 5-year Overall Survival was 94.3% for segmentectomy and 91.1% for lobectomy. Both superiority and non-inferiority in Overall Survival were confirmed using a stratified Cox regression model (HR=0.663; one-sided P<0.0001 for non-inferiority and P=0.0082 for superiority). This improved Overall Survival benefit was observed consistently across all predefined subgroups in the segmentectomy group. At 1 year follow-up, the significant difference in the reduction of median FEV1 between the two treatment groups was 3.5% (P<0.0001), but this however did not reach the predefined threshold for clinical significance of 10%. The 5-year Relapse-Free Survival was 88% for segmentectomy and 87.9% for lobectomy and was not statistically significant. The probability of local recurrence was approximately doubled and was 10.5% for segmentectomy and 5.4% for lobectomy (P=0.0018). Postoperative complications of grade 2 or worse occurred at similar frequencies in both treatment groups.

The authors concluded that this study is the first Phase III trial to show Overall Survival benefit with segmentectomy, compared to lobectomy, in patients with small-peripheral NSCLC. They added that segmentectomy should be the standard surgical procedure for this population of patients.

Segmentectomy versus lobectomy in small-sized peripheral non-small-cell lung cancer (JCOG0802/WJOG4607L): a multicentre, open-label, phase 3, randomised, controlled, non-inferiority trial. Saji H, Okada M, Tsuboi M, et al. The Lancet 2022;399:1607-1617.