Jessica Hergert

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Final analysis results from the phase 3 IMpower110 trial showed that treatment with atezolizumab (Tecentriq) continued to demonstrate clinically meaningful benefits in overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and duration of response (DOR) when compared with chemotherapy in patients with wild-type (WT) nonsquamous or squamous non–small cell lung cancer (NSCLC) with high PD-L1 expression.

A presentation of the results given during the 2020 World Conference on Lung Cancer Singapore showed that at a median follow up of 31.3 months, the median OS was 20.2 months with atezolizumab (n = 107) versus 14.7 months with chemotherapy (n = 98) in the high PD-L1 expression WT group. The 6-month OS rate was 76.5% versus 70.4%, respectively. The 12-month OS rate was 66.1% versus 52.3%, respectively (HR, 0.76; 95% CI, 0.54-1.09).

The median PFS was 8.2 months with atezolizumab compared with 5.0 months with chemotherapy in the high PD-L1 expression WT population. The 6-month PFS rate was 60.3% versus 38.3%, respectively. The 12-month PFS rate was 39.2% versus 19.2%, respectively (HR, 0.59; 95% CI, 0.43-0.81; 

 = .0010). Moreover, the confirmed ORR was 40.2% with atezolizumab versus 28.6% with chemotherapy, and the median DOR was 38.9 months versus 8.3 months, respectively.

“Updated data from the IMpower110 [study] continue to support the use of atezolizumab for the first-line treatment of patients with non–small cell lung cancer whose tumors have high PD-L1 expression,” said Roy S. Herbst, MD, PhD, Ensign Professor of Medicine and professor of pharmacology, and chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital, as well as the associate cancer center director for Translational Research at Yale Cancer Center, in a virtual presentation of the data.

On May 18, 2020, the FDA approved atezolizumab as frontline treatment for patients with metastatic NSCLC whose tumors have high PD-L1 expression, as determined by an FDA-approved test, and do not harbor 

 aberrations based on the interim results of the IMpower110 trial.

Findings from the primary analysis, which were reported with a median follow up of 15.7 months, demonstrated that the median OS was 20.2 months with atezolizumab versus 13.1 months with chemotherapy in the high PD-L1 expression WT group. The 6-month OS rate was 76.3% months versus 70.1%, respectively. The 12-months OS rate was 64.9% versus 50.6%, respectively (HR, 0.59; 95% CI, 0.40-0.89; 

The primary end point of the IMpower110 trial was OS in the WT population, with key secondary end points including investigator-assessed PFS, ORR, and DOR per RECIST v1.1 criteria. Notably, OS was tested in a hierarchical design, first in the high PD-L1 expression WT population (n = 205), followed by the high or intermediate PD-L1 expression WT population (n = 328), followed by the any PD-L1 expression WT population (n = 554).

Patients were randomized 1:1 to receive 1200 mg of atezolizumab every 3 weeks followed by atezolizumab maintenance therapy until progressive disease or loss of clinical benefit, or chemotherapy followed by maintenance therapy until progressive disease. In the chemotherapy arm, patients with nonsquamous NSCLC received cisplatin/carboplatin plus pemetrexed (Alimta) followed by pemetrexed maintenance therapy, and patients with squamous NSCLC received cisplatin/carboplatin plus gemcitabine followed by best supportive care.

No crossover was permitted for maintenance therapy.

Eligible patients had to have chemotherapy-naïve, stage IV nonsquamous or squamous NSCLC. Patients were PD-L1–selected with the VENTANA SP142 Immunohistochemistry (IHC) assay and stratified by sex, ECOG performance status, PD-L1 IHC expression, and histology.

Despite the numerical improvements in PFS and OS with atezolizumab in the high PD-L1 expression WT group, the updated data failed to show a statistically significant OS improvement with atezolizumab versus chemotherapy in patients with high or intermediate PD-L1 WT NSCLC. As such, OS in the any PD-L1 expression WT population was not formally tested.

Patients with high or intermediate PD-L1 expression derived a median OS of 19.9 months with atezolizumab versus 16.1 months with chemotherapy (HR, 0.87; 95% CI, 0.66-1.14; 

 = .3091). The median PFS was 7.3 months versus 5.5 months, respectively (HR, 0.64; 95% CI, 0.50-0.82; 

The confirmed updated ORR with atezolizumab was 33.7% versus 32.1% with chemotherapy in patients with high or intermediate PD-L1 expression. The median DOR was 38.9 months with atezolizumab versus 5.8 months with chemotherapy.

“With 17 months of additional follow up, atezolizumab continued to show numerical overall survival benefit in the PD-L1–high or –intermediate population; however, this was not statistically significant,” explained Herbst. “Therefore, overall survival was not formally tested in the any PD-L1 population, and the presented analysis in this population is descriptive only.”

Findings from the primary analysis demonstrated that the median OS was 18.9 months with atezolizumab versus 14.7 months with chemotherapy in the any PD-L1 expression population (HR, 0.85; 95% CI, 0.69-1.04; 

 = .1070). The updated median PFS was 5.8 months versus 5.6 months, respectively (HR, 0.72; 95% CI, 0.60-0.86; 

In the any PD-L1 expression group, the confirmed ORR was 31.4% with atezolizumab versus 32.1% with chemotherapy. The median DOR was 26.3 months with atezolizumab versus 5.7 with chemotherapy.

Notably, a similar proportion of patients across the 3 subpopulations received subsequent non-protocol cancer therapy; however, more patients with high PD-L1 expression received subsequent therapy and subsequent immunotherapy in the chemotherapy arm versus the atezolizumab arm at the interim and updated OS analyses.

At the interim analysis, 24.3% (n = 26) of patients in the atezolizumab arm received 1 or more therapies, including immunotherapy, chemotherapy, targeted therapy, and unknown therapy compared with 46.9% (n = 46) of patients in the chemotherapy arm. At the updated OS analysis, 35.5% (n = 38) and 54.1% (n = 53) of patients with high PD-L1 expression in the atezolizumab and chemotherapy arms, respectively, received subsequent cancer therapies.

After adjusting the for subsequent immunotherapy use, the median OS was 20.2 months with atezolizumab versus 13.0 months with chemotherapy in high PD-L1 expression WT patients (HR, 0.69; 95% CI, 0.48-0.99).

Regarding safety, the median treatment duration was 5.3 months with atezolizumab, 3.5 months with pemetrexed, 2.6 months with gemcitabine, 2.3 months with carboplatin, and 2.1 months with cisplatin.

No new or unexpected toxicities were observed with atezolizumab. All-grade, any-cause adverse effects (AEs) were observed in 92% of patients with atezolizumab compared with 95.1% of patients with chemotherapy. Of these, 62.9% and 85.2% were treatment related, respectively.

All-cause AEs with a greater than 5% difference between study arms that were more frequent with chemotherapy included anemia, nausea, neutropenia, constipation, thrombocytopenia, vomiting, blood creatinine, decreased platelet count, leucopenia, decreased neutrophil count, and alopecia. AEs that were more frequent with atezolizumab included pyrexia, increased aspartate aminotransferase, rash, nasopharyngitis, arthralgia, pruritus, and hypothyroidism.

Grade 3 or 4 AEs were observed in 33.9% of patients in the atezolizumab arm versus 53.2% in the chemotherapy arm. Grade 3 or 4 treatment-related AEs (TRAEs) were observed in 14.3% and 44.9% of patients, respectively. Serious AEs occurred in 31.8% and 29.3% of patients, respectively. Of these, 9.4% and 15.6% were treatment related.

Additionally, 4.2% of patients in each arm experienced grade 5 AEs, with 1 grade 5 TRAE observed in the chemotherapy arm.

AEs that led to treatment withdrawal occurred in 7.3% of patients who received atezolizumab compared with 17.1% of patients who received chemotherapy.

Finally, immune-mediated AEs were observed in 46.2% of patients with atezolizumab versus 18.3% of patients with chemotherapy. Of these, 8.7% and 1.5% were grade 3 or 4, respectively. Additionally, 13.3% and 1.5% of immune-mediate AEs required corticosteroids, respectively.

1. Herbst RS, de Marinis F, Giaccone G, et al. IMpower110: updated OS analysis of atezolizumab vs platinum-based hemotherapy as first-line treatment in PD-L1–selected NSCLC. Presented at: 2020 World Conference on Lung Cancer Singapore. January 28-31, 2021. Abstract FP13.03.

2. FDA approves Genentech’s Tecentriq as a first-line monotherapy for certain people with metastatic non-small cell lung cancer. Published May 18, 2020. Accessed January 28, 2021. https://bit.ly/3fYAw29.

Articles

Final analysis results from the phase 3 IMpower110 trial show the benefit of atezolizumab over chemotherapy in a non–small cell lung cancer subgroup.

Atezolizumab Bests Chemotherapy in PD-L1–High Non–Small Cell Lung Cancer

Datopotamab deruxtecan (Dato-DXd; DS-1062) showed antitumor activity in the treatment of patients with advanced or metastatic non–small cell lung cancer (NSCLC), according to updated results of the phase 1 TROPION-PanTumor01 trial.

The preliminary efficacy results presented during the International Association for the Study of Lung Cancer's 2020 World Conference on Lung Cancer (WCLC) showed that the antibody-drug conjugate (ADC) elicited an overall response rate of 23% (n = 9) at a dose of 4 mg/kg (n = 40), 21% (n = 8) at 6 mg/kg (n = 39), and 25% (n = 20) at 8 mg/kg (n = 80) per blinded independent central review. Confirmed complete or partial responses were observed in 7, 6, and 19 patients, respectively.

Additionally, 2 patients who received the 4 mg/kg dose, 2 patients who received the 6 mg/kg dose, and 1 patient who received the 8 mg/kg dose had suspected complete or partial responses, but longer follow up is needed to confirm.

The preliminary median progression-free survival was 4.3 months with the 4 mg/kg dose, 8.2 months with the 6 mg/kg dose, and 5.4 months with the 8 mg/kg dose.

Based on these findings, the 6 mg/kg dose of datopotamab deruxtecan was identified as the recommended dose for the registrational, randomized phase 3 TROPION-Lung01 trial (NCT04656652), which is evaluating datopotamab deruxtecan versus docetaxel in patients with previously treated advanced or metastatic NSCLC who do not harbor actionable genomic alterations.2

“Datopotamab deruxtecan showed impressive response rates in a heavily pretreated population,” said Alexander Spira, MD, PhD, FACP, lead study author and director of the Virginia Cancer Specialists Research Institute and phase I trial program, in a statement to 

. “Toxicity at the recommended phase 2 dose of 6 mg/kg appears to be very reasonable and is being used in the randomized phase 3 study versus docetaxel. The hope is not only to look at this [drug] in later lines, but also look to combine it with other agents, such as immunotherapy and potentially chemotherapy, in the future.”

The open-label TROPION-PanTumor01 trial marks the first-in-human study of datopotamab deruxtecan, a Trop-2–directed ADC, in patients with advanced solid tumors. Trop-2 is a transmembrane glycoprotein that is expressed in many cancers, including lung cancer. Moreover, Trop-2 overexpression is associated with poor outcome.

The ADC is comprised of a topoisomerase 1 inhibitor payload (exatecan derivative), a tetrapeptide-based linker, and a humanized Trop-2–directed monoclonal antibody.

Eligible patients had to have relapsed/refractory advanced or metastatic NSCLC that was unselected for Trop-2 expression. Japanese patients had to be 20 years or older, and patients from the United States had to be 18 years or older to be eligible for enrollment. Additionally, patients had to have an ECOG performance status of 0 or 1, and measurable disease per RECIST v1.1 criteria.

Patients with stable, treated brain metastases were eligible for enrollment.

The majority of patients evaluated in all 3 cohorts had received 3 or more prior lines of therapy, including platinum-based chemotherapy (median 94%), immunotherapy (median 83%), and TKIs (median 17%).A median of 37% of patients across the 3 dosing arms had a history of brain metastases and a median of 14% harbored 

The median duration of follow up was 7.4 months; a median of 42% of patients remained on datopotamab deruxtecan at the time of the data cutoff. Additionally, 46% of patients in the 4 mg/kg cohort, 51% of patients in the 6 mg/kg cohort, and 76% of patients in the 8 mg/kg cohort discontinued from study treatment because of progression or adverse effects (AEs).

Additional data showed that 15% (n = 6) of patients in the 4 mg/kg group, 21% (n = 8) of patients in the 6 mg/kg group, and 9% (n = 7) of patients in the 8 mg/kg group experienced progressive disease. Datopotamab deruxtecan induced a disease control rate of 73% (n = 29) with 4 mg/kg, 67% (n = 26) with 6 mg/kg, and 80% (n = 64) with 8 mg/kg.

The pharmacokinetic profile of datopotamab deruxtecan remained consistent throughout 3 cycles of treatment, irrespective of the dose. Moreover, the half-life of the agent was 4.6 days for the 6 mg/kg dose, supporting the every 3-week dosing schedule.

Regarding safety, the toxicity profile observed with datopotamab deruxtecan was consistent with previously reported findings. Notably, grade 3 or higher treatment-emergent AEs were observed in 10% of patients in the 4 mg/kg cohort, 16% of patients in the 6 mg/kg cohort, and 34% of patients in the 8 mg/kg cohort. Serious treatment-related TEAEs occurred in 8%, 9%, and 20% of patients, respectively.

Common grade 3 or greater TEAEs included nausea, stomatitis, fatigue, vomiting, decreased appetite, constipation, infusion-related reactions, mucosal inflammation, anemia, and cough. Overall, patients who received the 8 mg/kg dose had higher rates of these TEAEs compared with those who received the 4 mg/kg or 6 mg/kg doses.

Notably, 8% (n = 14) of patients experienced interstitial lung disease (ILD) as determined by an independent adjudication committee. One grade 3 ILD event was observed with the 4 mg/kg dose of datopotamab deruxtecan, and 1 grade 2 ILD event was observed with the 6 mg/kg dose. The remainder of ILD events occurred in the 8 mg/kg cohort, 3 of which were grade 5.

1. Spira A, Lisberg AE, Sands JM, et al. Datopotamab deruxtecan (Dato-DXd; DS-1062), a TROP2 ASC, in patients with advanced NSCLC: updated results of TROPION-PanTumor01 phase 1 study. Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; virtual. Abstract OA03.03.

2. Study of DS-1062A versus docetaxel in previously treated advanced or metastatic non-small cell lung cancer without actionable genomic alterations (TROPION-LUNG01). ClinicalTrials.gov. Posted December 7, 2020. 

Datopotamab deruxtecan showed antitumor activity in the treatment of patients with advanced or metastatic non–small cell lung cancer, according to updated results of the phase 1 TROPION-PanTumor01 trial.

ADC Datopomab Deruxtecan Shows Responses Across Doses in Advanced NSCLC

Positive response and disease control rates were observed in 2 separate studies when patients with head and neck squamous cell carcinoma (HNSCC) and melanoma received the combination of eganelisib (IPI-549), a selective PI3K-γ inhibitor, and nivolumab (Opdivo). In the first study, updated findings from an expansion cohort of the ongoing phase 1/1b MARIO-1 trial (NCT02637531), presented during the 35th Annual Meeting & Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2020) (

The overall response rate (ORR) in evaluable patients who had 2 or fewer prior lines of therapy (n=10) was 20.0% with the combination. In this population, 2 patients achieved a partial response (PR) and 2 achieved stable disease (SD). Further, the disease control rate (DCR) was 40.0% among these patients. The median progression-free survival (PFS) for patients who had 2 or fewer prior lines of therapy was 23 weeks (95% CI, 9-49).

“There is a significant unmet need for patients with head and neck cancer, especially those who are refractory to anti–PD-1 antibodies,” said lead study author Ezra Cohen, MD, FRCPSC, FASCO, chief of the Division of Hematology-Oncology and a medical oncologist at the University of California, San Diego Health, in a presentation during the meeting. “Checkpoint inhibitors are only active in about 16% of patients and there are limited treatment options for those who don’t respond.”

Eganelisib relieves immune suppression by reprogramming protumor macrophages or myeloid-derived suppressor cells. Further, T-cell activation can be maintained with the addition of checkpoint inhibitors, despite IFN-α–mediated upregulation of PD-L1, suggesting that the combination of eganelisib and nivolumab could offer synergistic antitumor benefit.

Twenty-one patients enrolled in the trial and received a combination of continuous eganelisib at 40 mg once daily plus a 240-mg flat dose of intravenous nivolumab once every 2 weeks in 28-day cycles.

All patients had previously been refractory to or relapsed following treatment with anti–PD-1/PD-L1 therapies. After starting therapy, patients were strat-ified as having progressive disease, SD, or objective response to determine the overall benefit of eganelisib.

The median age was 62 years (range, 29-80), and the majority of patients were male (n = 16; 76.2%). Patients had an ECOG performance status (PS) of 0 (n = 9; 42.9%) or 1 (n = 12; 57.1%).

Patients with known human papillomavirus (HPV) status (n = 12; 57.1%) were positive (n = 8; 38.1%), but the HPV status of 9 patients was unknown.

Twenty-one patients had received prior therapies. Ten patients had received 4 or more prior therapies (47.6%), 6 patients had received 3 therapies (28.6%), 3 patients had received 2 therapies (14.3%), and 2 patients had received 1 prior therapy (9.5%). Prior therapies included anti–PD-1/PD-L1 inhibition (100%), chemotherapy (n=14; 66.7%), anti-EGFR inhibition (n=12; 57.1%), anti–CLTA-4 inhibition (n=3; 14.3%), anti-CD20 inhibition (n=2; 9.5%), and an immune stimulatory agent (n = 2; 9.5%). As the last line of prior therapy, 85.7% of patients (n=18) received anti–PD-1/PD-L1 inhibition, 9.5% (n=2) received anti-CD20 inhibition, 4.8% received anti-EGFR inhibition (n=1), and 4.8% received an immune stimulatory agent (n=1).

Most patients (42.9%) had progressive disease as the best response to prior anti–PD-1/PD-L1 therapy, followed by 23.8% who achieved a PR, 19.0% who achieved SD, and 14.3% whose best response was unknown.

Among evaluable patients (n=20), the ORR was 10.0%; no patients who received 3 or more prior lines of therapy obtained a PR. Five patients who had 3 or more prior lines of therapy achieved SD. The DCR was 45.0% in the overall population and 50.0% in patients who had 3 or more prior lines of therapy.

Among evaluable patients, 11 developed progressive disease (n=6,≤2 prior lines; n=5, ≥3 prior lines). The median PFS in patients who had 3 or more prior lines of therapy was 20 months (95% CI, 16-33), and 17 months (95% CI, 9-24) in the total patient population.

Regarding patient disposition and exposure, all patients discontinued treatment for reasons including disease progression (n=15; 71.4%), adverse effect (AE; n=2; 9.5%), other (n = 2; 9.5%), death (n=1; 4.8%), and investigator decision (n=1; 4.8%).

The median duration of treatment exposure was 11.3 weeks (range, 2.6-48.7), with a median of 3 cycles of therapy completed (range, 1-14). The median rate of eganelisib dose compliance was 91.5%.

Regarding safety, the most common treatment-emergent AEs (TEAEs) occurring in 15% or more of patients included fatigue (n = 13; 61.9%), pyrexia (n = 9; 42.9%), decreased appetite (n = 9; 42.9%), pruritus (n=6; 28.6%), weight decrease (n=6; 28.6%), nausea (n=6; 28.6%), diarrhea(n=6; 28.6%), dyspnea (n=5; 23.8%), abdominal pain (n=5; 23.8%), vomiting (n=4; 19.0%), myalgia (n=4; 19.0%), dizziness (n=4; 19.0%), and headache (n=4; 19.0%).

Treatment-related adverse effects (TRAEs) included fatigue (n=8; 38.1%), pyrexia (n=3;14.3%), decreased appetite (n=3; 14.3%), pruritus(n=3; 14.3%), nausea (n=4; 19.0%), dyspnea(n=1; 4.8%), abdominal pain (n=2; 9.5%), vomiting (n=2; 9.5%), myalgia (n=2; 9.5%), and dizziness (n=1; 4.8%). Three patients experienced immune-related, treatment-related pruritus.

Grade 3 or greater TEAEs occurring in at least 5% of patients included anemia (n=3; 14.3%),disease progression (n=3; 14.3%), sepsis (n=2;9.5%), nausea (n=2; 9.5%), and abdominal pain(n=2; 9.5%). One patient each experienced treatment-related anemia, nausea, and abdominal pain. Investigators observed no immune-related, TRAEs of grade 3 or greater. 

“Eganelisib has the potential to benefit HPV-positive patients who have a T-cell inflamed phenotype, and further exploration in this combination is warranted,” said Cohen.To that end, a phase 2 window-of-opportunity study (NCT03795610) of eganelisib is ongoing in patients with locally advanced HPV-positive and HPV-negative HNSCC.

Similar Efficacy Seen With Melanoma Cohort

Additional findings from another expansion cohort of the study, which were also presented at the SITC meeting, showed that the combination of eganelisib and nivolumab induced an ORR of 10.3% (n = 4) among patients with melanoma (n =39).

 All 4 patients derived a PR. Ten patients had SD and 24 developed progressive disease.

Notably, all 4 patients had 2 or fewer prior lines of therapy, including those who progressed on immediate prior checkpoint inhibitors (n=19). This translated to an ORR of 21.1% in this subgroup; an additional 6 patients achieved SD and 9 had progressive disease.

“The significance of this efficacy within this [subgroup] is important as patients with melanoma, particularly BRAF wild-type melanoma, only usually have 2 or fewer lines of prior therapy with PD-1 and CLTA-4 [inhibitors] before needing to seek alternative treatment,” said lead study author Michael A. Postow, MD, a medical oncologist and chief of the Melanoma Service at Memorial Sloan Kettering Cancer Center in New York, New York, in a poster presentation of the data.

No patients who had 3 or more prior lines of therapy (n=21) derived a response. Four patients in this subgroup had SD, and 15 patients had progressive disease. Additionally, 1 patient’s best overall response was unknown.

The DCRs were 35.9% (n=14) in all patients, 52.6% (n=10) in patients with 2 or fewer prior treatments, and 20.0% (n = 4) in patients with 3 or more prior treatments. The median PFS was 9 weeks (range, 8-16), 17 weeks (range, 8-55), and 16 weeks (range, 8-19), respectively.

Baseline patient characteristics indicated that 100% of patients in the melanoma cohort were refractory to or relapsed following anti–PD-1/PD-L1 therapy. Moreover, 87.5% of patients (n=35) had immediate prior anti–PD-1/PD-L1 therapy.

Other prior treatments included anti–CLTA-4 therapy (n=28; 70.0%), investigational immunotherapy (n=17; 42.5%), MEK/ERK inhibitor(n =9; 22.5%), BRAF inhibitor (n = 5; 12.5%), and chemotherapy (n=4; 10.0%).

Ten percent (n=4) of patients derived a complete response as the best response to prior anti–PD-1/PD-L1 therapy; 7.5% (n =3) had a PR, 45.0%(n = 18) had SD, 25% (n = 10) had progressive disease, and 12.5% (n = 5) had an unknown best response to prior anti–PD-1/PD-L1 therapy.

All-grade TEAEs occurring in more than 15% of patients in the melanoma cohort included increased aspartate aminotransferase (AST; n=15; 37.5%) levels, increased alanine transaminase (ALT; n=15; 37.5%) levels, fatigue (n=11; 27.5%), and nausea (n=11; 27.5%). A proportion of each toxicity was found to be treatment related. Immune-related TRAEs included increased AST (n=13; 32.5%), increased ALT levels (n=13; 32.5%), pruritus (n=7; 17.5%),increased alkaline phosphatase levels (n=6;15.0%), and rash (n=7; 17.5%).

The MARIO-1 trial is ongoing, evaluating the combination of eganelisib and nivolumab in patients with non–small cell lung cancer (part E),triple-negative breast cancer (TNBC; part F), adrenocortical carcinoma (part G), mesothelioma (part G), and high-circulating myeloid derived suppressor cells (part H).

Investigators are also evaluating eganelisib in combination with nivolumab as second-line therapy for patients with advanced urothelial carcinoma in the phase 2 MARIO-275 trial (NCT03980041). In addition, they are examining the agent in combination with atezolizumab (Tecentriq), nab-paclitaxel (Abraxane), and bevacizumab (Avastin) as first-line therapy for patients with TNBC or renal cell carcinoma in the phase 2 MARIO-3 trial (NCT03961698).

1. Cohen EEW, Postow M, Sullivan RJ, et al. Updated clinical data from the squamous cell carcinoma of the head and neck (SCCHN) expansion cohort of an ongoing ph1/1b study of eganelisib (formerly IPI-549) in combination with nivolumab. Paper presented at: 2020 STIC Annual Meeting; November 9-14, 2020; virtual. Abstract 352.

2. Postow M, Sullivan RJ, Cohen EEW, et al. Updated clinical data from the melanoma expansion cohort of an ongoing ph1/1b study of eganelisib (formerly IPI-549) in combination with nivolumab. Poster presented at: 2020 SITC Annual Meeting; November 9-14, 2020; virtual. Abstract 434.

Positive response and disease control rates were observed in 2 separate studies when patients with head and neck squamous cell carcinoma and melanoma received the combination of eganelisib and nivolumab.

Eganelisib/Nivolumab Combo Shows Positive Responses in Head and Neck Carcinoma, Melanoma

In patients with previously treated advanced hepatocellular carcinoma (HCC), single-agent pembrolizumab (Keytruda) maintained numerical improvement in survival (OS), updated findings randomized phase 3 KEYNOTE-240 trial show.

According to a presentation given at the 2021 Gastrointestinal Cancers Symposium, at a median follow up of 39.6 months for pembrolizumab (n = 278) and 39.8 months for placebo (n = 135), the median OS was 13.9 months (95% CI, 11.6-16.0) with pembrolizumab versus 10.6 months (95% CI, 8.3-13.5) with placebo (HR, 0.77; 95% CI, 0.62-0.96; 

 = .0112). Moreover, the estimated OS rates at 24 months were 28.8% and 20.4% for pembrolizumab and placebo, respectively. At 36 months, the estimated OS rates were 17.7% and 11.7%, respectively.

The median PFS was 3.3 months (95% CI, 2.8-4.1) with pembrolizumab compared with 2.8 months (95% CI, 1.6-3.0) with placebo (HR, 0.70; 95% CI, 0.56-0.89; 

 = .0011). The estimated 24-month PFS rates were 11.8% and 4.8%, respectively. The estimated 36-month PFS rates were 9% and 0%, respectively.

“Sorafenib-treated patients saw improvement in OS and PFS that was maintained over time with pembrolizumab compared with placebo,” said Philippe Merle, MD, PhD, a professor of hepato-gastroenterology and digestive oncology at the Centre of Research in Cancerology at Lyon University and Croix-Rousse Hospital in Lyon, France, during a virtual presentation of the data. “The safety profile of pembrolizumab remained consistent over time with no new or unexpected adverse events. These data support the benefit/risk profile of pembrolizumab.”

The study enrolled adult patients with confirmed diagnoses of advanced HCC who experienced progression after or intolerance to sorafenib (Nexavar). Patients were randomized 2:1 to receive 200 mg of intravenous pembrolizumab every 3 weeks plus best supportive care versus placebo plus best supportive care for 35 cycles or until progression, unacceptable toxicity, patient withdrawal of consent, or investigator decision.

Patients were stratified by geographic region (Asia without Japan versus non-Asia with Japan), macrovascular invasion (yes versus no), and alpha-fetoprotein level (AFP; < 200 ng/mL versus ≥ 200 ng/mL).

To be eligible for enrollment, patients had to have measurable disease by RECIST v1.1 criteria, Child-Pugh liver class A disease, Barcelona Clinic Liver Cancer (BCLC) stage C disease, or BCLC stage B disease not amenable to locoregional therapy or refractory to locoregional therapy, and not amenable to a curative treatment approach, and an ECOG performance status (PS) of 0 or 1.

Prior findings of the KEYNOTE-240 trial revealed the coprimary end points of OS and PFS were numerically improved but were not statistically significant with pembrolizumab plus best supportive care versus placebo plus best supportive care.2

KEYNOTE-240 was a confirmatory trial for pembrolizumab, which was granted an accelerated approval by the FDA in November 2018 for the treatment of patients with HCC who were previously treated with sorafenib. The regulatory decision was based on data from the phase 2 KEYNOTE-224 trial.

The numerical improvements in OS and PFS were consistent and maintained, favoring pembrolizumab, with longer follow up across predefined subgroups, including age, sex, geographic region, ECOG PS, macrovascular invasion, AFP, reason for sorafenib discontinuation, extrahepatic spread, and etiology.

Further findings from the updated analysis showed that the objective response rate was 18.3% (95% CI, 14.0%-23.4%) with pembrolizumab compared with 4.4% (95% CI, 1.6%-9.4%) with placebo. The median time to response was 2.7 months (95% CI, 1.2-16.9) and 2.9 months (95% CI, 1.1-6.9), respectively. The median duration of response (DOR) was 13.9 months (range, 1.5+ - 41.9+) versus 15.2 months (range, 2.8-21.9), respectively. Moreover, 53.7% of responders in the pembrolizumab arm had a DOR of at least 12 months versus 50% of responders in the placebo arm.

Additionally, the disease control rate (DCR) was 61.9% with pembrolizumab versus 53.3% with placebo.

Best overall responses among patients who received pembrolizumab included 10 complete responses (CRs), 41 partial responses (PRs), and 121 instances of stable disease (SD). No patients achieved a CR with placebo, 6 had PRs, and 66 had SD.

Additionally, 85 patients in the pembrolizumab arm and 54 patients in the placebo arm experienced progressive disease. The median time-to-progression was 4.0 months (95% CI, 2.8-5.3) and 2.8 months (95% CI, 1.6-3.0), respectively.

Regarding safety, 61.3% (n = 171) of patients who received pembrolizumab and 48.5% (n = 65) of patients who received placebo developed any-grade treatment-related adverse effects (TRAEs). Grade 3/4 TRAEs occurred in 19% (n = 53) and 7.5% (n = 10) of patients, respectively. In the pembrolizumab arm, 6.8% (n = 19) of patients experienced TRAEs that led to treatment discontinuation, and 1 TRAE led to death. The death was attributed to malignant neoplasm progression. In the placebo arm, 0.7% of patients experienced TRAEs that led to treatment discontinuation.

AEs of special interest were observed in 17.9% (n = 50) of patients with pembrolizumab and 8.2% (n = 11) of patients with placebo. Of these, 7.2% (n = 20) and 0.7% (n = 1), respectively were grade 3/4. In the pembrolizumab group, 3.6% (n = 10) of AEs of special interest led to treatment discontinuation.

Immune-mediated hepatitis occurred in 3.6% (n = 10) of patients who received pembrolizumab and no patients who received placebo. Of these 10 patients, 8 (2.9%) received systemic corticosteroids. Additionally, no patients in either arm experienced a flare event of viral hepatitis.

1. Merle P, Edeline J, Bouattour M, et al. Pembrolizumab versus placebo in patients with advanced hepatocellular carcinoma previously treated with sorafenib: updated data from the randomized, phase 3 KEYNOTE-240 study. 

2. Finn RS, Ryoo BY, Merle P, et al. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase III trial. 

 2020;38(3):193-202. doi:10.1200/JCO.19.01307

In patients with previously treated advanced hepatocellular carcinoma (HCC), single-agent pembrolizumab (Keytruda) maintained numerical improvement in survival (OS), updated findings randomized phase 3 KEYNOTE-240 trial show. 

Jessica Hergert | Authors

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