Caroline Seymour

Adjuvant treatment with atezolizumab (Tecentriq) led to a significant improvement in disease-free survival (DFS) vs supportive care in patients with PD-L1–positive non–small cell lung cancer (NSCLC). Findings from the phase 3 IMpower010 trial (NCT02486718) were presented at the 2021 American Society of Clinical Oncology Annual Meeting.

In patients with stage II to IIIA NSCLC with at least 1% PD-L1 expression on tumor cells, the median DFS was not evaluable ([NE]; 95% CI, 36.1-NE) with atezolizumab (n = 248) vs 35.3 months with best supportive care (n = 228; 95% CI, 29.0-NE; HR, 0.66; 95% CI, 0.50-0.88; 

= .004). The 2-year DFS rate was 74.6% with atezolizumab vs 61.0% with best supportive care, and 3-year rates were 60.0% and 48.2%, respectively (TABLE 1).

In patients with stage II to IIIA NSCLC, the median DFS was 42.3 months with atezolizumab (n = 442; 95% CI, 36.0-NE) vs 35.3 months with best supportive care (n = 440; 95% CI, 30.4-46.4; HR, 0.79; 95% CI, 0.64-0.96; 

 = .02). The 2-year DFS rate was 70.2% with atezolizumab vs 61.6% with best supportive care, and 3-year rates were 55.7% and 49.4%, respectively (TABLE 2).

“Though surgery can cure some patients with early- stage lung cancer, disease recurrence is still very common,” said lead study author Heather A. Wakelee, MD, a thoracic specialist, professor of medicine, and chief of the Division of Oncology at Stanford University Medical Center, and deputy director of the Stanford Cancer Institute. “Until this trial, the only treatment that was known to help reduce that risk for most patients was chemotherapy, or osimertinib [Tagrisso] for the small group of patients with tumors with an EGFR mutation. These data show that personalized medicine with atezolizumab can reduce the chance of NSCLC returning after surgery for patients who have a tumor that expresses the biomarker PD-L1.”

Despite the progress that has been made for patients with early-stage disease who harbor EGFR sensitizing mutations, the standard of care remains platinum-based chemotherapy for most patients with resected NSCLC.

To be eligible for enrollment in the IMpower010 trial, patients had to have completely resected stage IB to IIIA NSCLC. Stage IB tumors had to be at least 4 cm. Additionally, patients had to have an ECOG performance status of 0 or 1, a lobectomy or pneumonectomy, and tumor tissue for PD-L1 analysis.

Following 1 to 4 cycles of cisplatin plus pemetrexed, gemcitabine, docetaxel, or vinorelbine (n = 1280), patients were randomized 1:1 to 1200 mg of atezolizumab every 21 days for 16 cycles (n = 1005) or best supportive care (n = 1005). No crossover was allowed.

Investigator-assessed DFS in patients with stage II to IIIA disease and PD-L1 expression of at least 1% on tumor cells per the SP263 assay, all randomized patients with stage II to IIIA disease, and the intention-to-treat (ITT) population with stage IB to IIIA disease served as the primary end point.

Key secondary end points included overall survival (OS) in the ITT population and DFS in the PD-L1high population.

Hierarchical statistical testing was organized such that positive DFS in the PD-L1–positive population would allow for DFS analysis in the stage II to IIIA population. This was followed by DFS analysis in the ITT population, which in turn was followed by OS analysis in the ITT population.

In patients with stage IB to IIIA NSCLC, the statistical significance boundary for DFS was not crossed with atezolizumab vs best supportive care. The median DFS was NE with atezolizumab (n = 507; 95% CI, 36.1-NE) vs 37.2 months with best supportive care (n = 498; 95% CI, 31.6-NE; HR, 0.81; 95% CI, 0.67-0.99; 

 = .04). The 2-year DFS rate was 71.4% with atezolizumab vs 63.6% with best supportive care. The 3-year DFS rates were 57.9% and 52.6%, respectively.

Regarding safety, all-grade adverse effects (AEs) occurred in 92.7% of patients in the atezolizumab arm (n = 495) vs 70.7% of patients in the best supportive care arm (n = 495). Of these AEs, 21.8% in the atezolizumab arm and 11.5% in the best supportive care arm were grade 3 or 4.

Grade 5 treatment-related AEs occurred in 0.8% and 0% of patients in the atezolizumab and best supportive care arms, respectively. AEs leading to treatment withdrawal occurred in 18.2% and 0% of patients, respectively.

Planned analyses of DFS and OS in the ITT population will continue with longer follow-up.

“For the first time, we are seeing that an immunotherapy is effective when used to treat early-stage lung cancer. The IMpower010 trial demonstrates that, for certain patients, atezolizumab can delay progression to advanced disease and perhaps even the need for more aggressive therapy. This could be an important advance in our understanding of immunotherapy and a step forward for many patients with lung cancer,” concluded Julie R. Gralow, MD, FACP, FASCO, chief medical officer and executive vice president at ASCO.

Wakelee HA, Altorki NK, Zhou C, et al. IMpower010: primary results of a phase III global study of atezolizumab versus best supportive care af-ter adjuvant chemotherapy in resected stage IB-IIIA non-small cell lung cancer (NSCLC). 

. 2021;39(suppl 15):8500. doi:10.1200/JCO.2021.39.15_suppl.8500

Articles

Adjuvant treatment with atezolizumab led to a significant improvement in disease-free survival versus supportive care in patients with PD-L1–positive non–small cell lung cancer.

Atezolizumab Is Linked to Improvement in DFS  in Early-Stage NSCLC

The most exciting development in cholangiocarcinoma is molecular profiling, according to Flavio G. Rocha, MD, FACS, FSSO, during a presentation during the 6th Annual School of Gastrointestinal Oncology® hosted by the Physicians Education Resource®, LLC (PER®). Although the genetic makeup of biliary tract cancer is rich, only recently has the field been able to show the benefit of treating patients with effective targeted agents, such as pemigatinib (Pemazyre) and ivosidenib (Tibsovo) in the advanced setting, Rocha said, adding that the momentum is expected to continue in the preoperative setting. Rocha serves as Hedinger Chair, division head and professor of surgery in the Division of Surgical Oncology at Oregon Health & Science University in Portland.

One of the first demonstrations of the potential application of molecular profiling came from the phase 2 FIGHT-202 trial (NCT02924376) which stratified patients with pretreated locally advanced or metastatic cholangiocarcinoma with known FGFR status into 1 of 3 cohorts.¹ Cohort A (planned, n = 100) consisted of patients with FGFR2 fusions or rearrangements, cohort B (planned, n = 20) consisted of patients with other FGF/FGFR alterations, and cohort C (planned, n = 20) consisted of patients with no FGF/FGFR alterations. All patients received 13.5 mg of pemigatinib, a selective oral inhibitor of FGFR1/2/3, once daily for a schedule of 2 weeks on and 1 week off.

The primary end point, which was confirmed objective response rate (ORR) in cohort A by independent central review, was 35.5%, and the median duration of response was 7.5 months. The 35.5% ORR consisted of 3 (2.8%) complete responses, 35 (32.7%) partial responses, and 50 (46.7%) patients with stable disease, for a disease control rate of 82%.

At a median follow-up of 15.4 months and a median duration of treatment of 7.2 months, the median overall survival (OS) was 21.1 months in patients with 

 fusions/ rearrangements (95% CI, 14.8-not evaluable; cohort A). The median OS was only 6.7 months in patients with other 

 alterations (95% CI, 2.1-10.6; cohort B) after a median follow-up of 19.9 months, and it was only 4.0 months in patients without an 

alteration after a median follow-up of 24.2 months (95% CI, 2.3-6.5; cohort C).

“By far, the cohort that had the [FGFR2] fusions and translocations really had the most benefit,” Rocha said. “In the second-line setting, we saw a median OS of 21 months [in that population], which far exceeds the current standard from the ABC-06 trial, which is [folinic acid, fluorouracil, and oxaliplatin] FOLFOX.” In April 2020, the FDA approved pemigatinib for the treatment of patients with previously treated, locally advanced, or metastatic cholangiocarcinoma with 

 fusions or rearrangements, as detected by an FDA-approved test, based on primary findings from the FIGHT-202 trial.²

Additional FGFR inhibitors under investigation in cholangiocarcinoma include infigratinib, (Truseltiq) which currently has priority review status with the FDA in this setting, as well as futibatinib, derazantinib, and erdafitinib (Balversa), all of which have shown ORRs ranging from approximately 20.7% to 57% in patients with 

“Because we don’t want to wait for the results [in the advanced setting], [we’re] teaming up with the cholangiocarcinoma foundation [and] working on the concept [of neoadjuvant therapy] in the OPT-IC trial,” Rocha said.

In the OPT-IC trial (NCT03579771), patients with resectable intrahepatic cholangiocarcinoma will undergo molecular profiling with circulating tumor DNA, followed by 1 cycle of gemcitabine, nab-paclitaxel (Abraxane), and cisplatin (GAP) chemotherapy. Patients with an FGFR2 fusion (planned, n = 10) will go on to receive an FGFR2 inhibitor for 2 cycles, followed by surgery and adjuvant therapy; patients without an FGFR2 fusion (planned, n = 30) will receive another 2 cycles of GAP chemotherapy, followed by surgery and adjuvant therapy. Feasibility will serve as the primary outcome of the study, followed by response and recurrence-free survival.

 mutations are another common alteration seen across the spectrum of extrahepatic and intrahepatic cholangiocarcinoma and gallbladder carcinoma, Rocha said.

Findings from the phase 3 ClarIDHy trial put ivosidenib on the map for patients with IDH1 mutations. In the trial, patients with pretreated 

-mutant cholangiocarcinoma were randomized 2:1 to 500 mg of oral ivosidenib once daily in 28-day cycles (± 2 days; n = 124) or placebo (n = 61).

Progression-free survival (PFS) served as the primary end point of the study. The median PFS was 2.7 months vs 1.4 months for ivosidenib and placebo, respectively (HR, 0.37; 95% CI, 0.25-0.54; 

 <.001). The 6-month PFS rate was 32% with ivosidenib vs not evaluable with placebo. The 12-month PFS rates were 22% and not evaluable, respectively. The disease control rates were 53% and 28%, respectively.

The IDH1 inhibitor also showed a nonstatistically significant improvement in OS. Although most patients crossed over to ivosidenib (57%), there was a 31% trend toward reduction in the risk of death with ivosidenib (HR, 0.69; 95% CI, 0.44-1.10; 

The median OS was 10.8 months with ivosidenib vs 9.7 months with placebo. At 6 months, 67% of patients in the ivosidenib arm remained alive compared with 59% in the placebo arm. Investigators performed an analysis looking at rank-preserving structural failure time (RPSFT) for placebo. With the RPSFT data, there was a 54% reduction in the risk of death with ivosidenib (HR, 0.46; 95% CI, 0.28-0.75; 

“When you actually looked at the adjusted data [accounting for the] patients [in the ivosidenib arm] who had [initially] received placebo, we saw an impressive difference of 10.8 months vs 6 months,” Rocha said.

On March 1, a supplemental new drug application was submitted to the FDA for ivosidenib tablets as a potential therapeutic option for patients with previously treated, IDH1-mutated cholangiocarcinoma, based on findings from the phase 3 ClarIDHy trial.

1. Vogel A, Sahai V, Hollebecque A, et al. FIGHT-202: a phase 2 study of pemigatinib in patients (pts) with previously treated locally advanced or metastatic cholangiocarcinoma (CCA). 

. 2019;30(suppl 5):V876. doi:10.1093/annonc/mdz394.031 

2. FDA approves first targeted treatment for patients with cholangiocarcinoma, a cancer of bile ducts. News release. FDA. April 17, 2020. Accessed March 22, 2021. https://prn.to/2xGXrO6. 

3. Rocha F. Emerging therapies and targets for cholangiocarcinoma. Presented at: 6th Annual School of Gastrointestinal Oncology®; March 20, 2021; virtual. 

4. Abou-Alfa GK, Macarulla T, Javle MM, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. 

l. 2020;21(6):796-807. doi:10.1016/S1470-2045(20)30157-1 

5. Agios submits supplemental new drug application to FDA for Tibsovo (ivosidenib tablets) for patients with previously treated IDH1-mutant cholangiocarcinoma. News release. Agios Pharmaceuticals Inc; March 1, 2021. Accessed March 22, 2021. http://bit.ly/301kg9R

Although the genetic makeup of biliary tract cancer is rich, only recently has the field been able to show the benefit of treating patients with effective targeted agents, in the advanced setting.

Molecular Profiling Is the Future of Biliary Tract Treatment 

Regardless of age the combination of ribociclib (Kisqali) and endocrine therapy led to improved overall survival (OS) in pre- or postmenopausal patients with hormone receptor (HR)-positive, HER2-negative advanced breast cancer. The results of an exploratory analysis from the phase 3 MONALEESA-7 trial (NCT02278120) were presented during the 2021 European Society for Medical Oncology (ESMO) Breast Cancer Virtual Congress.

In patients under 40 years, the median OS was 51.3 months with ribociclib/endocrine therapy vs 40.5 months with placebo/endocrine therapy, translating to a 35% reduction in the risk of death with the CDK4/6 inhibitor (HR, 0.651; 95% CI, 0.431-0.983). The 4-year OS rates were 56.2% vs 34.4%, respectively.

In patients aged 40 or older, the median OS was 58.8 months with ribociclib/endocrine therapy vs 51.7 months with placebo/endocrine therapy. This translated to a 19% reduction in the risk of death with the CDK4/6 inhibitor (HR, 0.810; 95% CI, 0.617-1.065). The 4-year OS rates were 61.1% vs 47.8%, respectively.

“Ribociclib plus endocrine therapy prolonged OS and improved postprogression outcomes in pre- or perimenopausal patients with HR-positive, HER2-negative advanced breast cancer regardless of age. This effect was especially pronounced in women less than 40 [years old], who typically experience more aggressive disease,” said Yen-Shen Lu, MD, PhD, a clinical associate professor in the Department of Internal Medicine at National Taiwan University College of Medicine, and division chief of medical oncology in the Department of Oncology at National Taiwan University Hospital in Taipei, Taiwan, in a virtual presentation of the data.

Patients under 40 years of age with HR-positive, HER2-negative advanced breast cancer typically have more aggressive disease and a worse prognosis compared with older patients.

Specifically, patients under 40 years have a higher breast cancer mortality rate vs those aged 40 or older. Therefore, investigators conducted an exploratory analysis to evaluate the effect of age on the efficacy and safety of ribociclib/endocrine therapy vs placebo/endocrine therapy in the MONALEESA-7 trial.

 Prior results from the trial showed a significant improvement in progression-free survival (PFS), OS, and quality of life with the combination of ribociclib and endocrine therapy vs placebo plus endocrine therapy in patients with pre- or perimenopausal HR-positive, HER2-negative advanced breast cancer.

Moreover, an exploratory analysis performed with a median follow-up of 53.5 months demonstrated sustained OS with ribociclib/endocrine therapy vs placebo/endocrine therapy in the overall population. The median OS was 58.7 months vs 48.0 months, respectively (HR, 0.76; 95% CI, 0.61-0.96). In the exploratory analysis, baseline characteristics were generally well balanced between patients under 40 years and those aged at least 40 with no notable differences between the cohorts, said Shen Lu.

Additional findings indicated that PFS2, defined as the time from randomization to tumor progression on next-line treatment or death from any cause, favored ribociclib/endocrine therapy vs placebo/endocrine therapy in patients under 40 years and those aged 40 or older. In the former group, the median PFS2 was 46.0 months with ribociclib/endocrine therapy vs 25.5 months with placebo/endocrine therapy (HR, 0.588; 95% CI, 0.401-0.862). In the latter group, the median PFS2 was 43.6 months with ribociclib/endocrine therapy vs 32.7 months with placebo/endocrine therapy (HR, 0.705; 95% CI, 0.555-0.894).

Furthermore, the time to first chemotherapy was delayed with ribociclib/endocrine therapy vs placebo/endocrine therapy across both age subgroups. In patients under 40 years, the median time to first chemotherapy was not evaluable with ribociclib/endocrine therapy vs 36.6 months with placebo/endocrine therapy (HR, 0.649; 95% CI, 0.416-1.011). In patients aged 40 or older, the median time to first chemotherapy was 50.2 months vs 36.8 months, respectively (HR, 0.693; 95% CI, 0.534-0.898).

The addition of ribociclib to endocrine therapy also prolonged chemotherapy-free survival in both age subgroups. In patients under the age of 40, the median chemotherapy-free survival was 46.5 months with ribociclib/endocrine therapy vs 22.7 months with placebo/endocrine therapy (HR, 0.582; 95% CI, 0.398-0.851). In patients aged 40 or older, the median chemotherapy-free survival was 41.5 months vs 27.6 months, respectively (HR, 0.679; 95% CI, 0.541-0.852).

In patients under 40 years, 76.5% discontinued treatment in the ribociclib/endocrine therapy arm vs 90.9% in the placebo/endocrine therapy arm. In those aged 40 or older, 79.7% vs 90.8% discontinued treatment in the ribociclib/endocrine therapy and placebo/endocrine therapy arms, respectively (TABLE).

Subsequent antineoplastic treatment in those under 40 years was received by 77.3% of patients in the ribociclib/endocrine therapy arm vs 75.0% of patients in the placebo/endocrine therapy arm. In patients aged 40 or older, 77.2% vs 79.2% received subsequent antineoplastic treatment in the ribociclib/endocrine therapy and placebo/endocrine therapy arms, respectively.

Among patients under the age of 40, sub-sequent CDK4/6 inhibition at any point after study discontinuation was received by 16.0% vs 27.5% in the ribociclib/endocrine therapy and placebo/endocrine therapy arms, respe-tively. Among those aged 40 or older, 11.6% vs 25.7% of patients in the ribociclib/endocrine therapy and placebo/endocrine therapy arms, respectively, received subsequent CDK4/6 inhibition.

“In patients who discontinued treatment, subsequent antineoplastic therapy use, including CDK4/6 inhibitors, was comparable in both age subgroups,” said Lu. “Despite a higher proportion of patients in the placebo arm receiving subsequent CDK4/6 inhibition, the OS benefit of ribociclib was evident in both age subgroups.”

Adverse events (AEs) were consistent with those reported in the overall population. Treatment discontinuation due to AEs with ribociclib/endocrine therapy and placebo/endocrine therapy, respectively, occurred in 5.1% vs 3.4% of patients under 40 years and in 4.6% vs 3.6% of those aged 40 or older.

“The safety findings were similar in both groups compared with those of the overall population, and there were no notable safety differences between the age subgroups,” concluded Lu.

1. Lu YS, El-Saghir N, Hurvitz S, et al. Overall survival results by age subgroup from the phase III MONALEESA-7 trial of premenopausal patients with HR+/HER2- advanced breast cancer treated with endocrine therapy ±ribociclib.

. 2021;32(suppl 2):S60-S78. doi:10.1016/annonc/annonc508

Regardless of age the combination of ribociclib and endocrine therapy led to improved overall survival in pre- or postmenopausal patients with hormone receptor-positive, HER2-negative advanced breast cancer.

OS Improves With Addition of Ribociclib/Endocrine Therapy in Advanced Breast Cancer

A frontline regimen nivolumab (Opdivo), ipilimumab (Yervoy), and 2 cycles of chemotherapy yielded an improvement in overall survival (OS) vs chemotherapy alone in patients with advanced non–small cell lung cancer (NSCLC). The benefit was observed regardless of tumor mutational burden (TMB) status in the tissue or blood, according to findings from an analysis of the phase 3 CheckMate 9LA trial (NCT03215706) that were presented during the European Lung Cancer Virtual Congress 2021.

In the randomized population, the median OS was 15.6 months with the triplet vs 10.9 months with chemotherapy monotherapy (HR, 0.66; 95% CI, 0.55-0.80). The 1-year survival rates were 63% and 47%, respectively.

In the tissue TMB–evaluable population, the median OS was 15.6 months with the triplet vs 11.9 months with chemotherapy alone (HR, 0.75; 95% CI, 0.59-0.95). The 1-year survival rates were 61% and 50%, respectively.

In the blood TMB–evaluable population, the median OS was 15.3 months with the triplet vs 10.9 months with chemotherapy alone (HR, 0.68; 95% CI, 0.54-0.84). The 1-year survival rates were 62% and 48%, respectively.

“These findings from CheckMate 9LA show similar magnitude of OS benefit with nivolumab plus ipilimumab plus 2 cycles of chemotherapy vs chemotherapy regardless of TMB status in first-line advanced NSCLC, which is consistent with data previously reported for nivolumab plus ipilimumab,” said Luis G. Paz-Ares, MD, PhD, lead study author and chief of Medical Oncology Service at the Hospital Universitario 12 de Octubre in Madrid, Spain, in a virtual presentation of the data.

CheckMate 9LA enrolled patients with stage IV or recurrent NSCLC who did not have sensitizing 

 alterations, had not received prior systemic therapy, and had an ECOG performance status of 0 or 1. Patients were randomized 1:1 to 360 mg of nivolumab every 3 weeks plus 1 mg/kg of ipilimumab every 6 weeks plus two 3-week cycles of platinum-based chemotherapy (n = 361) or four 3-week cycles of platinum-based chemotherapy with optional pemetrexed (Alimta) maintenance.

OS served as the primary end point; secondary end points included progression-free survival (PFS), objective response rate (ORR), efficacy by PD-L1 expression, and efficacy by tissue TMB and blood TMB.

The combination of nivolumab and ipilimumab plus chemotherapy also led to a significant improvement in PFS and ORR vs chemotherapy alone as frontline treatment for patients with advanced NSCLC, according to primary findings from CheckMate 9LA.

On May 26, 2020, the FDA approved nivolumab plus ipilimumab and 2 cycles of platinum-doublet chemotherapy for the frontline treatment of patients with metastatic or recurrent NSCLC with no 

 genomic tumor aberrations, based on data from CheckMate 9LA.

Because the combination had shown clinical benefit vs chemotherapy irrespective of PD-L1 expression in the primary analysis, investigators evaluated the utility of TMB as a potential biomarker of response to the regimen. Tissue TMB was evaluated from baseline tumor samples using the FoundationOne CDx assay with the protocol-defined cutoff of 10 mutations per megabase. For blood TMB, plasma samples collected at baseline were used for isolation of circulating cell-free tumor DNA and then analyzed using the GuardantOMNI platform. Sixteen mutations per megabase and 20 mutations per megabase were the 2 protocol-defined cutoffs for blood TMB.

Among all randomized patients, 64% (n = 456) and 73% (n = 519) had tissue TMB– and blood TMB–evaluable samples, respectively.

Reasons for sample attrition in the tissue TMB and blood TMB groups, respectively, included lack of specimen (n = 19, n = 65), pre-analytical quality control failure (n = 3, n = 2), sample quality control failure (n = 142, n = 23), and next-generation sequencing quality control failure (n = 90, n = 84).

The baseline characteristics were generally well balanced among the randomized population, TMB-evaluable and -nonevaluable subgroups, and high- and low-tissue and blood TMB subgroups. Moreover, similar baseline characteristics were also seen among treatment arms across TMB subgroups.

A moderate correlation was seen between tissue TMB and blood TMB (Spearman rho, 0.54; 0.42-0.63). However, 1 discordant case was reported in which the blood TMB value was significantly higher than the paired tissue TMB value, at 172.6 mutations per megabase and 5.04 mutations per megabase, respectively.

Additional results indicated that higher tissue TMB and blood TMB appeared to be associated with greater ORR and PFS benefit.

Regarding response rates, the ORR in the tis-sue TMB group with at least 10 mutations per megabase was 46% in the triplet arm vs 28% in the chemotherapy-alone arm. In the less than 10 mutations per megabase group, the ORRs were 33% and 27%, respectively (

In the blood TMB group with at least 16 muta-tions per megabase, the ORR was 49% in the triplet arm vs 27% in the chemotherapy-alone arm. In the less than 16 mutations per megabase group, the ORRs were 33% and 28%, respectively.

Notably, in the blood TMB group with at least 20 mutations per megabase, the ORR was 55% in the triplet arm vs 31% in the chemotherapy-alone arm. In the less than 20 mutations per megabase group, the ORRs were 33% and 27%, respectively.

Additionally, patients in the tissue TMB group with at least 10 mutations per megabase had a median PFS of 8.9 months with the triplet vs 4.7 months with chemotherapy alone (HR, 0.49; 95% CI, 0.34-0.70). The 1-year PFS rates were 45% and 13%, respectively.

Among patients with less than 10 mutations per megabase, the median PFS was 5.6 months with the triplet vs 5.0 months with chemotherapy alone (HR, 0.83; 95% CI, 0.63-1.10). The 1-year PFS rates were 25% and 19%, respectively.

In the blood TMB group, patients with at least 16 mutations per megabase derived a greater PFS benefit with the triplet (HR, 0.55; 95% CI, 0.39-0.78) vs those with less than 16 mutations per megabase (HR, 0.78; 95% CI, 0.60-1.00).

Similarly, patients with at least 20 mutations per megabase derived a greater PFS benefit with the triplet (HR, 0.48; 95% CI, 0.32-0.73) vs those with less than 20 mutations per megabase (HR, 0.78; 95% CI, 0.62-0.99).

However, similar OS outcomes were seen using tissue TMB and blood TMB at different cutoffs.

Among patients with a tissue TMB of at least 10 mutations per megabase, the median OS was 15.0 months in the triplet arm vs 10.8 months in the chemotherapy-alone arm (HR, 0.74; 95% CI, 0.51-1.08). The 1-year OS rates were 63% and 46%, respectively.

Among patients with less than 10 mutations per megabase, the median OS was 16.8 months in the triplet arm vs 12.4 months in the chemotherapy alone arm (HR, 0.75; 95% CI, 0.55-1.02). The 1-year OS rates were 58% and 52%, respectively.

Patients with a blood TMB of at least 16 mutations per megabase derived a modest OS benefit with the triplet (HR, 0.60; 95% CI, 0.42-0.86) vs those with less than 16 mutations per megabase (HR, 0.73; 95% CI, 0.55-0.96).

Similarly, patients with at least 20 mutations per megabase derived a subtle OS benefit with the triplet (HR, 0.54; 95% CI, 0.35-0.84) vs those with less than 20 mutations per megabase (HR, 0.74; 95% CI, 0.57-0.95).

When tissue TMB and blood TMB were evaluated as continuous variables, ranging from at least 5 mutations per megabase to at least 20 mutations per megabase and at least 5 mutations per megabase to at least 30 mutations per megabase, respectively, OS favored the triplet regimen across all categories.

Moreover, comparable OS benefit was seen across PD-L1 expression subgroups, irrespective of tissue or blood TMB level.

“Along with previously reported data from CheckMate 9LA, these results support the use of nivolumab plus ipilimumab plus 2 cycles of chemotherapy as first-line treatment for patients with advanced NSCLC regardless of PD-L1 expression, TMB status, or their combination,” concluded Paz-Ares.

1. Paz-Ares L, Ciuleanu TE, Cobo M, et al. First-line nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles chemotherapy (chemo) versus 4 cycles che-motherapy in advanced non-small cell lung cancer (NSCLC): association of blood and tissue tumor mutational burden (TMB) with efficacy in Check-Mate 9LA. Presented at: European Lung Cancer Virtual Congress 2021; March 25, 2021, Accessed May 27 2021. https://bit.ly/3cvoblW

A frontline regimen nivolumab, ipilimumab, and 2 cycles of chemotherapy yielded an improvement in overall survival versus chemotherapy alone in patients with advanced non–small cell lung cancer. The benefit was observed regardless of tumor mutational burden status in the tissue or blood.

Caroline Seymour | Authors

Articles

Atezolizumab Is Linked to Improvement in DFS in Early-Stage NSCLC

Molecular Profiling Is the Future of Biliary Tract Treatment

OS Improves With Addition of Ribociclib/Endocrine Therapy in Advanced Breast Cancer

Nivolumab/Ipilimumab Triplet Improves OS in Advanced NSCLC Compared With Chemotherapy Alone