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ESMO Immuno-Oncology Congress

Pembrolizumab (Keytruda) induced treatment-related adverse effects (TRAEs) that were generally mild or moderate in severity, according to finding from a pooled analysis of more than 4000 patients with melanoma, non–small cell lung cancer (NSCLC), or renal cell carcinoma (RCC).

In data from a poster presented at the 2022 ESMO Immuno-Oncology Annual Congress, investigators found that 78.6% of patients assigned to pembrolizumab (n = 2060) experienced any-grade TRAEs compared with 58.7% of those assigned to placebo (n = 2065). In the pembrolizumab arm, 16.3% of patients experienced grade 3 to 5 TRAEs and 11.6% experienced serious TRAEs compared with 3.5% and 1.5%, respectively, in the placebo arm. Among patients assigned to pembrolizumab, 15.8% experienced TRAEs leading to discontinuation and 0.2% had TRAEs leading to death, compared with 2.1% and 0%, respectively, with placebo.

“The safety profile of adjuvant pembrolizumab in this analysis was consistent in severity and management with the established profile of pembrolizumab in advanced disease,” Jason Luke, MD, FACP, an associate professor of Medicine in the Division of Hematology/Oncology and the director of the Cancer Immunotherapeutics Center at the UPMC Hillman Cancer, and colleagues, wrote. “These data show that pembrolizumab has a manageable safety profile when used in the adjuvant setting and thus support the use of adjuvant pembrolizumab in patients with resected solid tumors.”

Investigators cautioned that although serious AEs are rare, physicians should be aware of the risk to inform and monitor their patients. They also noted that it is not possible to assess long-term irreversible toxic effects or late-onset AEs because the study reporting criteria did not fully support evaluation of all AE resolution or onset beyond 90 days after stopping treatment.

Investigators pooled patients from 4 phase 3 clinical trials:

KEYNOTE-716 (NCT03553836): Patients with completely resected stage IIB or IIC melanoma (N = 969)

Median time from randomization to data cutoff: 27.4 months (range, 14.0-39.4)

Median duration of pembrolizumab treatment: 11.1 months (range, 0-16.4)

KEYNOTE-054 (NCT02362594): Patients with completely resected stage IIIA, IIIB, or IIIC melanoma (N = 1013)

Median time from randomization to data cutoff: 59.1 months (interquartile range, 57.3-61.6)

Median duration of pembrolizumab treatment: 11.8 months (range, 0-15.7)

PEARLS/KEYNOTE-091 (NCT02504372): Patients with completely resected stage IB, II, or IIIA NSCLC (N = 1161)

Median time from randomization to data cutoff: 35.6 months (range, 16.5-68.0)

Median duration of pembrolizumab treatment: 11.7 months (range 0-18.9)

KEYNOTE-564 (NCT03142334): Patients with post-nephrectomy/metastasectomy RCC with a clear-cell component at high risk of recurrence (N = 984)

Median time from randomization to data cutoff: 30.1 months (range, 20.8-47.5)

Median duration of pembrolizumab treatment: 11.1 months (range, 0-14.3)

Patients in KEYNOTE-564 and KEYNOTE-716 received adjuvant pembrolizumab 200 mg (2 mg/kg up to 200 mg for pediatric patients) or placebo every 3 weeks for up to 17 cycles. In KEYNOTE-054 and PEARLS/KEYNOTE-091, patients received the same dose for up to 18 cycles.

The analysis population included all randomly assigned patients who received at least 1 dose of study treatment. Investigators monitored for AEs for up to 30 days after treatment completion and up to 90 days for serious AEs. Investigators determined whether AEs were treatment related. Immune-mediated AEs and infusion reactions were based on a list of terms prepared by the sponsor and included AEs regardless of attribution to study treatment by the investigator.

In the pembrolizumab arm, 48.2% of patients had melanoma, 28.2% had NSCLC, and 23.7% had RCC. In the placebo arm, the distribution was 47.8%, 28.1%, and 24.0%, respectively.

The median patient age was 61.0 years (range, 16-88) in the placebo group including 36.8% aged 65 years or older. In the placebo group, the median patient age was 61.0 years (range, 17-87) including 38.4% who were 65 years or older. Men made up about 65% of patients in both groups.

In the pembrolizumab arm, 36.9% of patients experienced any immune-mediated AE or infusion reaction, 8.8% of which were grade 3 to 5. The most common such events were hypothyroidism (18.5%), hyperthyroidism (11.0%), and pneumonitis (4.0%).

In the placebo arm, 9.3% of patients experienced any immune-mediated AE or infusion reaction, 1.1% of which were grade 3 to 5. The most common such events were hypothyroidism (3.7%), hyperthyroidism (1.3%), and pneumonitis (1.4%).

Median time to onset of first immune-mediated AE or infusion reaction was 2.6 months with pembrolizumab vs 4.1 months with placebo.

More than 90% of patients in both treatment groups experienced any-cause AEs. In the pembrolizumab arm, 31.7% of such AEs were grade 3 to 5 and 23.0% were serious, compared with 20.9% and 15.7%, respectively, with placebo. The rate of discontinuation due to any-cause AEs was 18.1% with pembrolizumab and 4.1% with placebo. Fifteen (0.7%) and 12 (0.6%) patients died due to any-cause AEs in the pembrolizumab and placebo arms, respectively.

Luke JJ, Robert C, Carlino MS, et al. Safety profile of adjuvant pembrolizumab (pembro) in melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC): Pooled analysis of phase III clinical trials. 

 2022;16(suppl_1): 100102-100102. doi:10.1016/iotech/iotech100102


Pembrolizumab induced treatment-related adverse effects that were generally mild or moderate in severity, according to finding from a pooled analysis of more than 4000 patients with melanoma, non–small cell lung cancer, or renal cell carcinoma.


Pembrolizumab Appears Safe Across Melanoma, NSCLC, RCC in Pooled Analysis

Concurrent adagrasib (MRTX849) and pembrolizumab (Keytruda) produced preliminary activity when administered as first-line treatment in patients with non–small cell lung cancer harboring a 

 G12C mutation, irrespective of PD-L1 status, according to data from the KRYSTAL-1 (NCT03785249) phase 1b and the KRYSTAL-7 (NCT04613596) phase 2 cohorts.

Data presented at the 2022 ESMO Immuno-Oncology Annual Congress showed that at a median follow-up of 3.5 months, the doublet elicited an objective response rate (ORR) of 49% (95% CI, 35%-63%) among the 53 clinically evaluable patients on KRYSTAL-7 who received at least 1 on-study scan. Of those who responded to treatment, 2% experienced a complete response and 47% experienced a partial response. Forty percent of patients achieved stable disease, and 11% experienced disease progression. The disease control rate (DCR) reported in this population was 89% (95% CI, 77%-96%).

Clinical activity with the regimen was observed across all PD-L1 subgroups. Specifically, responses were experienced by 59% of those with a PD-L1 tumor proportion score (TPS) of 50% or higher (n = 13/36), 48% of those with a score of 1% to 49% (n = 10/28), and 30% of those with a score of less than 1% (n = 3/11).

Moreover, at a median follow-up of 19.3 months, adagrasib plus pembrolizumab induced an ORR of 57% in evaluable patients enrolled to the phase 1b cohort of KRYSTAL-1, with a DCR of 100%. Responses occurred in both patients with a PD-L1 TPS of at least 50%, 1 of the 4 patients with a PD-L1 TPS of 1% to 49%, and in the 1 patient who had a PD-L1 TPS of less than 1%. All 4 responders experienced a durable response that persisted for longer than 9 months; 2 of these patients were still receiving the regimen for longer than 18 months.

“Initial results across all cohort suggest the concurrent combination of adagrasib and pembrolizumab may provide a chemotherapy-free option for treatment-naïve NSCLC with a manageable safety profile and encouraging clinical activity,” Pasi A. Jänne, MD, PhD, lead study author, senior physician, and director of the Lowe Center for Thoracic Oncology, the Belfer Center for Applied Cancer Science, and the Chen-Huang Center for EGFR Mutant Lung Cancers at the Dana-Farber Cancer Institute, Boston, MA, stated in a press release.

Approximately 14% of patients with NSCLC (adenocarcinoma) have tumors that harbor a 

 Adagrasib, a KRAS G12C inhibitor, was designed to have a half-life of 23 hours, a dose-dependent pharmacokinetic (PK) profile, and the ability to penetrate the central nervous system (CNS).

Prior data have demonstrated the activity of the agent in those with 

 G12C–mutated solid tumors, including those with NSCLC and CNS metastases.

 In preclinical models, investigators have observed a boost in immune response when adagrasib was paired with a PD-1 inhibitor.

Increased innate and adaptive immune responses have also been reported in patients who have received the KRAS G12C inhibitor.

The KRYSTAL-1 phase 1b and KRYSTAL-7 phase 2 cohorts included patients with 

G12C–mutated advanced, unresectable, or metastatic NSCLC who had not previously received systemic treatment for locally advanced or metastatic disease. Those with stable brain metastases were permitted.

In both studies, participants were given adagrasib at a twice-daily dose of 400 mg plus pembrolizumab at 200 mg every 3 weeks.

The primary end point of KRYSTAL-1 was safety, and secondary end points included ORR by RECIST v1.1 criteria, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). The KRYSTAL-7 phase 2 population included cohort 1a, those who had a PD-L1 TPS of less than 1%, and cohort 2, those with a PD-L1 TPS of 1% or higher. ORR by RECIST v1.1 criteria serves as the primary end point for KRYSTAL-7. Secondary end points comprise DOR, PFS, OS, safety, and PK.

Among the 75 patients enrolled to KRYSTAL-7, the median age was 66 years (range, 40-84); 51% of patients were female, 89% were White. Regarding ECOG performance status, 35% had a status of 0 and the remaining 65% had a status of 1. The majority (99%) were current or former smokers. Most patients had bone metastases at baseline (40%); 20% had liver metastases, 13% had adrenal metastases, and 12% had CNS metastases.

Additional data from this cohort showed that the median time to response to adagrasib plus pembrolizumab was 1.4 months. Of the 26 responders, 6 experienced a response after more than 2 months of treatment. Sixty-six percent of the 53 evaluable patients are still receiving the regimen, including in 24 patients with response.

Moreover, the doublet induced an ORR of 56% in a subset of response-evaluable patients who enrolled at least 6 months before the data cutoff date of August 30, 2022 (n = 14/25). Six of the 26 clinical responses happened at the time of the second on-study scan or later.

Regarding safety, 83% of the 75 patients in the KRYSTAL-7 cohort experienced an any-grade treatment-related adverse effect (TRAE); 15% had grade 1 TRAEs, 24% had grade 2 TRAEs, 40% had grade 3 TRAEs, and 4% had grade 4 TRAEs. No grade 5 TRAEs occurred.

The most common TRAEs experienced with the combination were nausea, diarrhea, vomiting, increased alanine (ALT) and aspartate (AST) aminotransferase, fatigue, decreased appetite, and increased amylase. The median time to onset for ALT and AST increase was 26 days and 37 days, respectively; only 1 patient reported new onset treatment-associated ALT/AST increase following 3 months.

Thirty-one percent and 41% of patients, respectively, experienced TRAEs that resulted in a dose reduction or interruption of adagrasib. Three percent of patients experienced TRAEs that led to discontinuation of both agents; 3% of patients experienced TRAEs that resulted in discontinuation of pembrolizumab alone.

“Based on these findings, phase 3 trials are planned in first-line NSCLC, evaluating concurrent adagrasib at 400 mg twice daily plus pembrolizumab vs standard of care by PD-L1 status,” Jänne, who is also a professor of medicine at Harvard Medical School, Boston, MA, concluded.

Jänne PA, Smit EF, de Marinis F, et al. Preliminary safety and efficacy of adagrasib with pembrolizumab in patients with advanced non-small cell lung cancer (NSCLC) harboring a KRASG12C mutation. Presented at: 2022 ESMO Immuno-Oncology Annual Meeting; December 7-9, 2022; Geneva, Switzerland. Presentation LBA4

Mirati Therapeutics presents late-breaking results evaluating concurrent adagrasib and pembrolizumab in first-line advanced/metastatic non-small cell lung cancer (NSCLC). News release. Mirati Therapeutics, Inc. December 5, 2022. Accessed December 7, 2022. 

Nassar AH, Adib E, Kwiatkowski DJ. Distribution of 

G12C somatic mutations across race, sex, and cancer type. 

. 2021;384(2):185-187. doi:10.1056/NEJMc2030638

Hallin J, Engstrom LD, Hargis L, et al. The KRASG12C inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients. 

. 2020;10(1):54-71. doi:10.1158/2159-8290.CD-19-1167

Ou S-HI, Jänne PA, Leal TA, et al. First-in-phase I/IB dose-finding study of adagrasib (MRTX849) in patients with advanced 

. 2022;40(23):2530-2538. doi:10.1200/JCO.21.02752

Jänne PA, Riely GJ, Gadgeel SM, et al. Adagrasib in non-small-cell lung cancer harboring a 

. 2022;387(2):120-131. doi:10.1056/NEJMoa2204619

Sabari JK, Spira AI, Heist RS, et al. Activity of adagrasib (MRTX849) in patients with KRASG12C-mutated NSCLC and active, untreated CNS metastases in the KRYSTAL-1 trial. 

. 2022;40(suppl 17):LBA9009. doi:10.1200/JCO.2022.40.17_suppl.LBA9009

Klempner SJ, Weiss J, Pelster M, et al. LBA24 KRYSTAL-1: updated efficacy and safety of adagrasib (MRTX849) with or without cetuximab in patients with advanced colorectal cancer (CRC) harboring a KRASG12C mutation. 

. 2022;33(suppl 7):S1391. doi:10.1016/j.annonc.2022.08.020

Bekaii-Saab TS, Spira AI, Yaeger R, et al. KRYSTAL-1: updated activity and safety of adagrasib (MRTX849) in patients (pts) with unresectable or metastatic pancreatic cancer (PDAC) and other gastrointestinal (GI) tumors harboring a 

. 2022;40(suppl 4):519. doi:10.1200/JCO.2022.40.4_suppl.519

Briere DM, Li S, Calinisan A, et al. The KRASG12C inhibitor MRTX849 reconditions the tumor immune microenvironment and sensitizes tumors to checkpoint inhibitor therapy. 

. 2021;20(6):975-985. doi:10.1158/1535-7163.MCT-20-0462

Concurrent adagrasib and pembrolizumab produced preliminary activity when administered as first-line treatment in patients with non–small cell lung cancer harboring a KRAS G12C mutation, irrespective of PD-L1 status, according to data from the KRYSTAL-1 phase 1b and the KRYSTAL-7 phase 2 cohorts.

Frontline Adagrasib Plus Pembrolizumab Elicits Encouraging Clinical Activity in KRAS G12C+ Advanced NSCLC

Solange Peters, MD, 
presented on findings 
from the phase 2 PERLA 
trial during the 2022 ESMO 
Immuno-Oncology Conference. 

Treatment with dostarlimab (Jemperli) plus chemotherapy reduced the risk of disease progression or death by 30% compared with pembrolizumab (Keytruda) plus chemotherapy as a frontline treatment for patients with metastatic non-squamous non–small cell lung cancer (NSCLC), according to phase 2 findings from the PERLA study presented at the ESMO Immuno-Oncology Congress 2022.

In the randomized phase 2 study, the median progression-free survival (PFS), which was a secondary end point, with dostarlimab/chemo was 8.8 months (95% CI, 6.7-10.4) compared with 6.7 months (95% CI, 4.9-7.1) with pembrolizumab/chemo (HR, 0.70; 95% CI, 0.50-0.98). The objective response rate (ORR) by blinded independent review, which was the primary end point, was 46% with dostarlimab compared with 37% for pembrolizumab.

“PERLA is the first large global, randomized, double-blind, phase 2 study to directly compare PD-1 inhibitors,” Solange Peters, MD, head of the Medical Oncology Service and chair of Thoracic Oncology at Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland, said in a presentation during the meeting. “These results therefore support the further investigation of dostarlimab as a treatment backbone for use in combination with standard of care and/or future novel cancer therapies.”

In the study, 243 patients were randomized to chemotherapy combined with either dostarlimab (n = 121) at 500 mg every 3 weeks or pemetrexed (n = 122) at 200 mg every 3 weeks. Chemotherapy consisted of pemetrexed combined with carboplatin or cisplatin at standard doses. Patients were stratified by PD-L1 status, which was assessed using the 22C3 pharmDx assay using tumor proportion score. Median follow up was 5.8 months in the dostarlimab arm and 5.0 months for pembrolizumab.

Baseline characteristics between the arms were balanced, with nearly half of patients aged 65 or older (46% vs 53%, for dostarlimab and pembrolizumab arms, respectively). ECOG status was either 0 or 1, with most patients having a score of 1 (69% and 59%, respectively). Most patients were former smokers (86%) and half were enrolled in Europe (51% vs 53%), with few enrolled in the United States (N = 3). Brain metastases were diagnosed in 18% of patients in the dostarlimab arm and in 12% of those in the pembrolizumab group. Liver metastases were present at baseline in 16% and 11% of patients in each group, respectively.

ORR in the dostarlimab/chemo arm consisted primarily of partial responses (n = 54; 45%), with 2 patients having a complete response (2%). Additionally, 40% of patients (n = 48) experienced stable disease. In the pembrolizumab/chemo arm, 42 patients had a partial response (34%) and 3 experienced a complete response (2%). The stable disease rate in this group was 43%. The rates of progressive disease were 10% and 9%, respectively.

In patient with a PD-L1 TPS of <1%, the ORR was 28% with dostarlimab/chemo (N = 50) and 33% for pembrolizumab/chemo (N = 51) and the PFS was 7.0 months and 6.9 months, respectively (HR, 0.77; 95% CI, 0.46-1.28). In patients with a PD-L1 TPS of 1% or greater, the ORR was 59% with dostarlimab/chemo (N = 71) vs 39% with pembrolizumab/chemo (N = 71). The PFS in this population was 10.4 months compared with 6.1 months, respectively (HR, 0.66; 95% CI, 0.41-1.03).

In those with a PD-L1 TPS of 1% to 49%, the ORR was 50% with dostarlimab/chemo (N = 44) vs 34% with pembrolizumab/chemo (N = 44) and the PFS was 9.0 months vs 5.4 months (HR, 0.67; 95% CI, 0.38-1.19). In patients with a TPS of 50% or more, the ORR was 74% with dostarlimab/chemo (N = 27) and 48% with pembrolizumab/chemo (N = 27). The PFS in this group was 10.4 months with dostarlimab/chemo and 6.7 months with pembrolizumab/chemo (HR, 0.60; 95% CI, 0.27-1.29).

Adverse events (AE) of any grade occurred in 97% of patients in both arms, with treatment-related AEs (TRAEs) occurring in 82% of those in the dostarlimab/chemo arm and for 79% of those in the pembrolizumab/chemo arm. TRAEs of grade 3 or higher in severity occurred in 36% of those in the dostarlimab/chemo arm and for 42% of those in the pembrolizumab/chemo arm. The most common TRAEs were anemia, asthenia, nausea, and neutropenia.

AEs led to discontinuation for 25% of those in the dostarlimab/chemo arm compared with 32% of those in the pembrolizumab/chemo arm. Serious AEs (SAEs) were reported in 38% and 45% of patients, with 12% and 10% experiencing a fatal SAE, in the dostarlimab/chemo and pembrolizumab/chemo arms, respectively. The rate of fatal treatment-related SAEs was 2% with dostarlimab/chemo and 4% with pembrolizumab/chemo.

Immune-related AEs (irAEs) were seen in 26% of patients treated with dostarlimab plus chemotherapy and for 34% of those receiving pembrolizumab and chemotherapy. The rates of grade 3 or higher irSAEs were 5% and 8%, for the dostarlimab and pembrolizumab groups, respectively.

“The proportion of patients experiencing TRAEs was similar between groups. Safety profiles were similar and broadly consistent with published data, and no new safety signals were identified for either therapy,” Peters said. “A numerical trend in the number of grade 3 or higher TRAEs, AEs leading to treatment discontinuation, SAEs, and irEAs in favor of dostarlimab was noted between groups.”

Dostarlimab is currently being investigated across several clinical trials, including those for endometrial cancer and rectal cancer. In August 2021, the PD-1 inhibitor received an accelerated approval as a treatment for adult patients with mismatch repair deficient recurrent or advanced solid tumors, following progression on other treatments and when no other satisfactory alternative treatment options existed. In addition to PERLA, dostarlimab is being explored in combination with docetaxel and cobolimab, a TIM-3 antagonist, in the COSTAR Lung study (NCT04655976).

Peters S, Lim SM, Ortega Granados AL, et al. Randomized double-blind phase II trial (PERLA) of dostarlimab (dostar) + chemotherapy (CT) vs pembrolizumab (pembro) + CT in metastatic non-squamous NSCLC: primary results. Presented at ESMO Immuno-Oncology Congress 2022; December 7-9, 2022; Geneva, Switzerland.

Treatment with dostarlimab (Jemperli) plus chemotherapy reduced the risk of disease progression or death by 30% compared with pembrolizumab (Keytruda) plus chemotherapy as a frontline treatment for patients with metastatic non-squamous non–small cell lung cancer.

ESMO Immuno-Oncology Congress | Conference

Pembrolizumab Appears Safe Across Melanoma, NSCLC, RCC in Pooled Analysis

Frontline Adagrasib Plus Pembrolizumab Elicits Encouraging Clinical Activity in KRAS G12C+ Advanced NSCLC

Frontline Dostarlimab Shows Superior PFS vs Pembrolizumab in NSCLC