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

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

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?

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

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.

Adjuvant TECENTRIQ® Improves Disease Free Survival in Early Stage Non Small Cell Lung Cancer

SUMMARY: 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® (Atezolizumab) 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) 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.

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

FDA Approves LUMAKRAS® for KRAS G12C-Mutated Non Small Cell Lung Cancer

SUMMARY: The FDA on May 28, 2021, granted accelerated approval to LUMAKRAS® (Sotorasib), a RAS GTPase family inhibitor, for adult patients with KRAS G12C mutated locally advanced or metastatic Non Small Cell Lung Cancer (NSCLC), as determined by an FDA approved test, who have received at least one prior systemic therapy. The FDA also approved the QIAGEN therascreen® KRAS RGQ PCR kit (tissue) and the Guardant360® CDx (plasma) as companion diagnostics for LUMAKRAS®. If no mutation is detected in a plasma specimen, the tumor tissue should be tested.

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.

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 12-15% 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.Inhibiting-KRAS-G12C

LUMAKRAS® is a first-in-class small molecule that specifically and irreversibly inhibits KRAS-G12C and traps KRAS-G12C in the inactive GDP-bound state. Preclinical studies in animal models showed that LUMAKRAS® inhibited nearly all detectable phosphorylation of Extracellular signal-Regulated Kinase (ERK), a key downstream effector of KRAS, leading to durable complete regression of KRAS-G12C tumors.

The CodeBreaK clinical development program for LUMAKRAS® was designed to treat patients with an advanced solid tumor with the KRAS G12C mutation and address the longstanding unmet medical need for these cancers. This program has enrolled more than 800 patients across 13 tumor types since its inception.

CodeBreaK 100 is a Phase I and II, first-in-human, open-label, single arm, multicenter study, which enrolled patients with KRAS G12C-mutant solid tumors. Eligible patients must have received a prior line of systemic anticancer therapy, for their tumor type and stage of disease. The present FDA approval was based on a Phase II trial which enrolled 126 patients with NSCLC, 124 of whom had centrally evaluable lesions by RECIST criteria at baseline. Enrolled patients had locally advanced or metastatic NSCLC with a KRAS G12C mutation, who had progressed on an immune checkpoint inhibitor and/or platinum-based chemotherapy, and those with active brain metastases were excluded. Patient received LUMAKRAS® 960mg orally once daily, until disease progression or unacceptable toxicity. Imaging studies were done every 6 weeks up to week 48 and then once every 12 weeks thereafter. The Primary end point of the trial was Overall Response Rate (ORR) as assessed by blinded Independent Central Review. Secondary end points included Duration of Response (DOR), Disease Control Rate (DCR), time to recovery, Progression Free Survival (PFS), Overall Survival, and Safety. The examination of biomarkers served as an exploratory end point. Patients were followed for a median of 12.2 months.

The ORR was 37.1% and the median Duration of Response was 10 months. Three patients had a Complete Response and the Disease Control Rate was 80.6%. The median Time to response was 1.4 months and 72% of patients had an early rapid response on first CT scan at 6 weeks. Approximately 81% of patients had tumor shrinkage of any magnitude, and the median percentage of best tumor shrinkage among all responders was 60%, and these responses were durable. The median PFS was 6.8 months. In the exploratory biomarker analysis, tumor response to LUMAKRAS® was seen across subgroups, including patients with negative or low expression of PD-L1 and those with STK11 and TP53 mutations. The most common adverse reactions were diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity, and cough. The most common laboratory abnormalities were increase in liver function tests, anemia, hyponatremia and proteinuria.

It was concluded that patients with NSCLC have poor outcomes and limited treatment options following progression on first line treatment. LUMAKRAS® offers a new treatment option for this patient group, and it is the first KRAS-targeted therapy to be approved after nearly four decades of research. A global Phase III study (CodeBreaK 200) is underway, comparing LUMAKRAS® to Docetaxel in patients with KRAS G12C-mutated NSCLC.

CodeBreaK 100: Registrational Phase 2 Trial of Sotorasib in KRAS p.G12C Mutated Non-small Cell Lung Cancer. Li BT, Skoulidis F, Falchook G, et al. Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; virtual. Abstract PS01.07.

FDA Approves Bispecific Antibody RYBREVANT® for Metastatic Non Small Cell Lung Cancer

SUMMARY: The FDA on May 21, 2021, granted accelerated approval to RYBREVANT® (Amivantamab-vmjw), a bispecific antibody directed against Epidermal Growth Factor (EGF) and MET receptors, 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. FDA also approved the Guardant360® CDx (Guardant Health, Inc.) as a companion diagnostic for RYBREVANT®.

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.

Epidermal Growth Factor Receptor (EGFR) plays an important role in regulating cell proliferation, survival and differentiation, and is overexpressed in a variety of epithelial malignancies. EGFR targeted Tyrosine Kinase Inhibitors (TKIs) such as Gefitinib, Erlotinib, Afatinib, Dacomitinib and Osimertinib target the EGFR signaling cascade. However, patients eventually will develop drug resistance due to new EGFR mutations. Another important cause of drug resistance to TKIs is due to the activation of parallel RTK (Receptor Tyrosine Kinase) pathways such as Hepatocyte Growth Factor/Mesenchymal-Epithelial Transition factor (HGF/MET) pathway, thereby bypassing EGFR TKI inhibitors.

RYBREVANT® is a fully-human bispecific antibody directed against EGFR and MET receptors. RYBREVANT® binds extracellularly and simultaneously blocks ligand-induced phosphorylation of EGFR and c-MET, inhibiting tumor growth and promoting tumor cell death. Further, RYBREVANT® downregulates receptor expression on tumor cells thus preventing drug resistance mediated by new emerging mutations of EGFR or c-MET. By binding to the extracellular domain of the receptor protein, RYBREVANT® can bypass primary and secondary TKI resistance at the active site.

The present FDA approval was based on CHRYSALIS, an ongoing multicenter, non-randomized, open label, multicohort, Phase I clinical trial (NCT02609776) which included patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. The purpose of study is to evaluate the safety, pharmacokinetics, and preliminary efficacy of RYBREVANT® as a monotherapy and in combination with Lazertinib, and to determine the recommended Phase 2 dose (RP2D) (monotherapy), recommended Phase 2 combination dose (RP2CD) (combination therapy), and to determine recommended Phase 2 Dose (RP2q3W) with combination chemotherapy (RYBREVANT® in combination with standard of care Carboplatin and Pemetrexed) in 21 day treatment cycle for participants with advanced NSCLC.

In this analysis of the Phase 1 CHRYSALIS study, researchers assessed the efficacy and safety of RYBREVANT® in patients with NSCLC and EGFR exon 20 insertion mutations, who had progressed on prior Platinum-based chemotherapy, and were treated at the recommended Phase II dose of RYBREVANT® 1050 mg (1400 mg for patients weighting 80 kg or more). The median patient age was 61 years, 51% were female, and median prior lines of therapy was one. The Primary endpoint was Overall Response Rate (ORR). Secondary endpoints included Duration of Response (DOR), Clinical Benefit Rate, Progression Free Survival (PFS) and Overall Survival (OS).

It was noted that among this post-platinum cohort of patients (N=81), at a median follow up of 9.7 months, the ORR was 40%, with 4% Complete Reponses and 36% achieving Partial Responses (PR). Responses were durable with median Duration of Response of 11.1 months, with 63 % having responses of at least six months or greater duration. The median PFS was 8.3 months and median OS was 22.8 months. The Clinical Benefit Rate (PR or more, or Stable Disease of 11 weeks or more) was 74%. The most common adverse reactions (20% or more) were rash, infusion-related reactions, paronychia, fatigue, musculoskeletal pain, stomatitis, nausea, vomiting, constipation, edema, cough and dyspnea.

The authors concluded that RYBREVANT® demonstrated robust and durable antitumor activity in patients with EGFR exon 20 insertion mutations, with a manageable safety profile.

Amivantamab in Post-platinum EGFR Exon 20 Insertion Mutant Non-small Cell Lung Cancer. Sabari JK, Shu CA, Park K, et al. Presented at: IASLC 2020 World Conference on Lung Cancer Singapore. January 28-31, 2021. Abstract OA04.04

Five-Year Efficacy Outcomes with KEYTRUDA® versus Chemotherapy in Metastatic NSCLC

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.

Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options, by improving Overall Response Rate and prolongation of survival across multiple tumor types. Immune Checkpoint Inhibitors (ICIs) target Programmed cell Death protein-1 (PD-1) receptors on T cells, as well as Programmed cell Death Ligand-1 (PD-L1), PD-L2 and Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system, which are upregulated in some tumor types. T-cell proliferation and cytokine production is inhibited upon binding of the PD-1 ligands PD-L1 and PD-L2, to the PD-1 receptor found on T cells.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response. Unleashing the T cells results in T cell proliferation, activation and a therapeutic response. High level of PD-L1 expression is defined as membranous PD-L1 expression on at least 50% of the tumor cells, regardless of the staining intensity. It is estimated that based on observations from previous studies, approximately 25% of the patients with advanced NSCLC have a high level of PD-L1 expression, and high level of PD-L1 expression has been associated with significantly increased response rates to KEYTRUDA®.

KEYNOTE-024 is an open-label, randomized, Phase III trial in which KEYTRUDA® administered at a fixed dose was compared with investigator’s choice of cytotoxic chemotherapy, as first line therapy, for patients with advanced NSCLC, with tumor PD-L1 expression of 50% or greater. Three hundred and five (N=305) treatment naïve patients with advanced NSCLC and PD-L1 expression on at least 50% of tumor cells, were randomly assigned in a 1:1 ratio to receive either KEYTRUDA® (N=154) or chemotherapy (N=151). Enrolled patients had no sensitizing EGFR mutations or ALK translocations. Treatment consisted of KEYTRUDA® administered at a fixed dose of 200 mg IV every 3 weeks for up to 2 years or the investigator’s choice of Platinum-based chemotherapy for 4-6 cycles. Pemetrexed (ALIMTA®) based therapy was permitted only for patients who had non-squamous tumors and these patients could receive ALIMTA® maintenance therapy after the completion of combination chemotherapy. Patients in the chemotherapy group who experienced disease progression were allowed to cross over to the KEYTRUDA® group. The Primary end point was Progression Free Survival (PFS) and Secondary end points included Overall Survival (OS), Objective Response Rate (ORR) and Safety. In an updated analysis of the KEYNOTE-024 study, after a median follow up of 25.2 months, the median OS was 30 months in the KEYTRUDA® group and 14.2 months in the chemotherapy group (HR=0.63; P=0.002). This OS benefit was maintained even after adjusting for crossover.

The authors in this publication reported the 5-year efficacy and safety outcomes from this pivotal Phase III KEYNOTE-024 trial. The median time from randomization to data cutoff was 59.9 months. Among patients initially assigned to chemotherapy, 66% received subsequent anti PD-1 or PD-L1 therapy (66% cross over rate). In the KEYTRUDA® group, 52.9% received additional anticancer therapy.

The median OS was 26.3 months for KEYTRUDA® and 13.4 months for chemotherapy (HR=0.62). Kaplan-Meier estimates of the 5-year OS rate were 31.9% for the KEYTRUDA group and 16.3% for the chemotherapy group. The ORR was 46.1% among patients in the KEYTRUDA® group versus 31.1% in the chemotherapy group and the median Duration of Response was 29.1 months in the KEYTRUDA® group and 6.3 months in the chemotherapy group.

The authors concluded that first line KEYTRUDA® provides a durable and clinically meaningful long-term Overall Survival benefit, when compared to chemotherapy, in patients with metastatic NSCLC, with PD-L1 Tumor Proportion Score of at least 50%.They added that this is first 5-year follow up of any first line Phase III immunotherapy trial for Non Small Cell Lung Cancer.

Five-Year Efficacy Outcomes With Pembrolizumab vs Chemotherapy in Metastatic NSCLC With PD-L1 Tumor Proportion Score of at Least 50%: KEYNOTE-024 Trial. Reck M , Rodríguez–Abreu D, Robinson AG, et al. DOI: 10.1200/JCO.21.00174 Journal of Clinical Oncology. Published online April 19, 2021.