Frontline treatment with apatinib in combination with gefitinib (Iressa) demonstrated superior progression-free survival (PFS) in patients with advanced 

mutant non–small cell lung cancer (NSCLC), according to results from the phase 3 ACTIVE trial (NCT02824458).1

A total of 313 patients enrolled on ACTIVE trial were randomized 1:1 to receive apatinib plus gefitinib (n = 157) or placebo plus gefitinib (n = 156). At median follow-up of 15.8 months, the median PFS in the apatinib arm was 13.7 months compared with 10.2 months with the EGFR inhibitor alone (HR, 0.71; 95% CI, 0.54-0.95; P = .0189).1

“Apatinib combined with gefitinib is expected to become a new first-line treatment option for EGFR-mutant NSCLC patients,” said Li Zhang, MD, who presented the data as part of the 2020 ESMO Virtual Congress. “Furthermore, this dual oral regimen will definitely provide a more convenient treatment for patients who require long-term administration.” Zhang is a professor of medical oncology, director of Phase I Unit of Sun Yat-Sen University Cancer Centre (SYSUCC), and deputy director of the Lung Cancer Research at SYSUCC.

Patients with detectable EGFR exon 19 deletions (Ex19del) and exon 21 (L858R) mutations were well balanced between the study arms: 51.6% and 47.1% in the apatinib arm versus 53.2% and 46.8% in the placebo arm. Stratified PFS data showed a similar PFS benefit for patients with Ex19del (HR, 0.67; 95% CI, 0.45-0.99) and those with L858R mutations (HR, 0.72; 95% CI, 0.48-1.09).

Secondary end points of the trial included investigator-assessed PFS, objective response, and duration of response. Median PFS via investigator assessment was 13.8 months with apatinib versus 12.0 months with placebo (HR, 0.71; 95% CI, 0.53-0.95; P = .0186). The objective response rates were 77.1% and 73.7%, respectively (P = .5572). Specifically, 1 patient in the apatinib arm achieved a complete response (CR), 120 (76.4%) had a partial response (PR), and 12 (7.6%) had stable disease (SD). No patients achieved a CR in the placebo arm, however, 115 (73.7%) patients had a PR and 22 (14.1%) had SD. The disease control rates were 84.7% and 87.8%, respectively (P = .3466).1

The depth of response was also evaluated and defined as the best percentage change from baseline in sum of diameters of the target lesions. A reported depth of response of at 30% in change in lesion size was reported for 89.2% of patients treated with apatinib plus gefitinib and 79.5% of patients treated with gefitinib alone (P = .0209). The percentage of patients who had a depth of response of at least 50% were 64.3% and 52.6%, respectively (P = .0238).1

Duration of response (DOR) was evaluable in 121 patients in the apatinib arm and 115 patients in the placebo arm. The median DOR was 12.9 months (95% CI, 11.2-14.7) and 9.3 months (95% CI, 9.2-11.1), respectively (HR, 0.64; 95% CI, 0.47-0.88; log-rank P = .005).1

Overall survival data were immature at the time of cutoff, with only 29.4% of the predetermined events reached.

In terms of safety, “no unexpected safety signals were identified beyond the established safety profile of each single agent,” Zhang explained. “As expected, apatinib plus gefitinib increased the risk of treatment-emergent adverse events [TEAEs] compared with placebo plus gefitinib. Roughly 50% of patients in the combination group experienced dose interruption or reduction.”

Grade 3 or higher TEAEs were reported in 84.1% of patients treated in the combination arm versus 37.7% of patients in the placebo arm. In regard to dose interruption and reduction, the rates were 59.9% and 48.4% versus 22.7% and 4.5%, respectively. Further, discontinuation of treatment due to TEAEs was 5.1% with the combination and 3.2% with placebo.

The most common grade 3 or higher TEAEs in the apatinib arm were hypertension (46.5%), proteinuria (17.8%), alanine aminotransferase increase (11.5%), and weight decrease (11.5%). Grade 3 or higher TEAEs were less common in the placebo arm. The most commonly reported were alanine aminotransferase increase (10.4%), aspartate aminotransferase increase (3.2%), hypertension (2.6%), and diarrhea (1.3%).1

Next-generation sequencing (NGS) performed at baseline and post-progression provided further efficacy indicators in patient subgroups. Biomarker analysis at baseline demonstrated an improved PFS in patients with TP53-mutant disease treated with the apatinib and gefitinib combination (HR, 0.56; 95% CI, 0.31-1.01) compared with those who do not harbor the mutation (HR, 0.92; 95%, 0.50-1.67). More specifically, a PFS benefit was observed in patients with TP53 exon 8 mutations, with a hazard ratio of 0.24 (95% CI, 0.06-0.91) favoring the apatinib group. The hazard ratio was 0.79 (95% CI, 0.41-1.52) in patients without the exon 8 mutation.1

“Subgroup analysis by baseline p53 mutation status showed that the PFS hazard ratio favored the combination treatment for patients with p53 exon 8 mutation…However, due to the small sample size [N = 18] this benefit will need to be further confirmed by a large-scale clinical study,” said Zhang. Seven patients in the apatinib combination arm harbored the TP53 exon 8 mutation compared with 11 in the placebo arm.

Further, in analysis of patients who experienced progressive disease, 43.7% patients (n = 103) in the apatinib arm and 41.4% patients (n = 111) in the placebo arm provided blood samples for NGS.

A similar resistance pattern was found in both groups in regard to the development of T790M mutation. In total, 37.8% of patients treated with apatinib who experienced progressive disease were T790M-positive compared with 37.0% of patients in the placebo arm.1

Delaying EGFR-TKI resistance has been an ongoing challenge in the NSCLC treatment landscape. Despite an observed PFS benefit with the EGFR TKI gefitinib in patients following failure of chemotherapy, a majority of patients experience disease progression or relapse within 1 year.2

Apatinib, is a novel small-molecule, multi-targeted TKI, that selectively inhibits VEGFR2. Investigators of the ACTIVE trial hypothesized that simultaneously targeting EGFR and VEGFR pathways may be a feasible therapeutic strategy for patients with EGFR-mutant NSCLC based on early preclinical studies that demonstrated the dual blockade’s efficacy delaying the emergence of resistant tumors.2

Apatinib is currently approved in China for the treatment of patients with advanced gastric cancer following failure of frontline standard chemotherapy following superior observed PFS and OS data over placebo and a manageable safety profile.2

1. Zhang L. ACTIVE: apatinib plus gefitinib versus placebo plus gefitinib as first-line treatment for advanced epidermal growth factor receptor-mutant (EGFRm) non-small-cell lung cancer (NSCLC): a multicentered, randomized, double-blind, placebo-controlled phase III trial (CTONG1706). Presented at: 2020 ESMO Congress; September 19-21, 2020; virtual. Abstract LBA50.

2. Zhang Z, Luo F, Zhang Y, et al. The ACTIVE study protocol: apatinib or placebo plus gefitinib as first-line treatment for patients with EGFR-mutant advanced non-small cell lung cancer (CTONG1706). Cancer Commun (Lond).2019;39(1):69. doi:10.1186/s40880-019-0414-4

Articles

Apatinib in combination with gefitinib in the first-line setting demonstrated superior progression-free survival (PFS) in patients with advanced EGFR-mutant non–small cell lung cancer.

Frontline Apatinib/Gefitinib Combo Improves PFS in EGFR-Mutant NSCLC

Patients with stage 2 or 3 triple-negative breast cancer (TNBC) experienced improved pathologic complete responses (pCR) with the addition of neoadjuvant atezolizumab (Tecentriq) to nab-paclitaxel (Abraxane) plus doxorubicin and cyclophosphamide, according to data from the phase 3 IMpassion031 trial that were presented during the 

Findings from the randomized, multi-center trial, which were simultaneously published in 

, demonstrated that patients with early-stage disease who received the neoadjuvant atezolizumab and chemotherapy regimen achieved a pCR rate of 57.6% compared to 41.1% in the group who received the placebo plus chemotherapy regimen (

“The combination of atezolizumab with neoadjuvant chemotherapy for stage 2-3 TNBC provides clinically meaningful pCR benefit with an acceptable safety profile independent of PD-L1 status,” said senior study author Nadia Harbeck, MD, PhD, head of the Breast Center at the University of Munich, during a virtual presentation of the data. “Thus, this new combination therapy may offer an improved curative treatment option for this patient population with high unmet medical need.”

Previously, results from the IMpassion130 trial demonstrated that adding atezolizumab to nab-paclitaxel improved progression-free survival (PFS) and overall survival (OS) in patients with PD-L1 positive metastatic TNBC with an acceptable safety profile compared with nab-paclitaxel alone. However, as Harbeck noted during her presentation, adding atezolizumab to the treatment regimen was associated with a benefit in the patient population, regardless of PD-L1 status.

Traditionally, treatments for early-stage TNBC in the neoadjuvant setting have comprised anthracycline-cyclophosphamide and taxane-based chemotherapy regimens. To compare the efficacy and safety of adding atezolizumab to nab-paclitaxel followed by doxorubicin plus cyclophosphamide compared with placebo and the subsequent chemotherapy regimen, Harbeck and colleagues recruited 455 patients from July 7, 2017 to September 24, 2019.

A total of 333 patients met eligibility criteria. Of the eligible patient population, 165 patients were randomly assigned to receive intravenous atezolizumab at 840 mg every 2 weeks plus nab-paclitaxel at 125 mg/m² every week for 12 weeks followed by doxorubicin at 60 mg/m² and cyclophosphamide at 600 mg/m² every 2 weeks for 8 weeks, which was then followed by surgery. The remaining patients randomly were assigned to receive placebo plus the chemotherapy regimen, which was also followed by surgery.

After a median follow-up of 20.6 months, 11 patients in the atezolizumab arm were either not treated (n = 1) or had discontinued neoadjuvant treatment (n = 10) prior to receiving surgery. Fifteen patients in the placebo arm were also not evaluable as 1 patient was not treated, and 14 patients discontinued treatment prior to surgery.

A pathologic complete response was observed in 68.8% of patients with PD-L1-positive disease (n = 77) who received atezolizumab compared with a pCR of 49.3% in a total of 75 patients who were treated with the placebo-chemotherapy regimen (

 =.021). However, as Harbeck noted, this did not reach statistical significance.

A pCR benefit was also observed with atezolizumab in the PD-L1-negative population. Patients who received the atezolizumab-chemotherapy regimen (n = 88) achieved a pCR rate of 47.7% compared with a pCR rate of 34.4% in patients (n = 93) who received the placebo-chemotherapy regimen.

There appears to be a positive trend for atezolizumab plus the chemotherapy regimen in improving EFS, DFS and OS, however, Harbeck noted that the data are immature and further research is ongoing.

Almost all patients (99.4%) in the atezolizumab arm experienced at least one adverse event. Moreover, 100% of the placebo arm experienced at least one adverse event. Treatment related grade 3-4 adverse events were reported in 56.7% of patients who received the atezolizumab-chemotherapy regimen and 53.3% of patients who received the placebo regimen.

The most common adverse events in the neoadjuvant phase in both the atezolizumab and placebo arm included, but were not limited to, alopecia (75% vs. 77.2%, respectively), nausea (64.6% vs. 67.1%, respectively) and diarrhea (41.5% vs. 44.3%, respectively).

The most common adverse event of special interest of any grade was rash in both the atezolizumab arm (48.8%) and placebo arm (49.1%).

“The results of IMpassion031 showed that the combination of atezolizumab with a platinum-free neoadjuvant regimen improved pathological complete response rate,” the authors conclude in the study published in 

. “This combination can also provide benefit to patients who are unfit for platinum-containing anthracycline-taxane-based neoadjuvant chemotherapy.”

Harbeck N, et al. IMpassion031: results from a phase 3 study of neoadjuvant (neoadj) atezolizumab plus chemotherapy in early triple-negative breast cancer (TNBC). Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract LBA11

Mittendorf EA, Zhang H, Barrios CH, et al. Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomized, double-blind, phase 3 trial. 

. 2020. doi:10.1016/S0140-6736(20)31953-X.

Patients with triple-negative breast cancer experienced improved pathologic complete responses with the addition of neoadjuvant atezolizumab to chemotherapy.

Addition of Atezolizumab Improves pCR in Early TNBC, Irrespective of PD-L1 Status

Olaparib (Lynparza) significantly prolonged overall survival (OS), compared with enzalutamide (Xtandi) or abiraterone (Zytiga) plus prednisone, in men with metastatic castration-resistant prostate cancer who had tumors with at least 1 alteration in 

 and whose disease had progressed during previous treatment with a next-generation hormonal agent.

In particular, the risk of death was 31% lower with olaparib than with control therapy, despite substantial crossover from control therapy to olaparib.

Updated fndings from the randomized, open-label phase 3 PROfound trial (NCT02987543) were presented at the 2020 ESMO Virtual Congress and were simultaneously published in the New England Journal of Medicine.1,2

“Exploratory analysis suggests that patients with BRCA mutations achieve the most benefit and additional studies may be required to further delineate genomic indicators of PARP response, particularly for those with less common gene alterations,” Joaquin Mateo, MD, Vall d'Hebron Institute of Oncology and Vall d'Hebron University Hospital, Barcelona, Spain, said during a presentation of the updated OS findings at the Congress.

“PROfound is the first randomized trial to prospectively demonstrate overall survival improvement in a molecularly-defined subset of prostate cancer, supporting implementation of genomic testing in daily clinical practice,” he added.

Median OS was superior with olaparib, compared with control therapy in cohort A (19.1 months vs 14.7 months; HR, 0.69; 95% CI, 0.50-0.97; 

 = .02) and cohort B (14.1 months vs 11.5 months; HR, 0.96; 95% CI, 0.63-1.49).

The crossover-adjusted analysis included 86 of 131 patients (66%) in the control group who had crossed over to receive olaparib, including 56 (67%) in cohort A. Patients were eligible for crossover if they had radiographic disease progression, no other subsequent anticancer therapy, any toxicities from prior therapy grade £ 1, and agreed to continue with the study visit schedule.

A sensitivity analysis that adjusted for crossover to olaparib showed a hazard ratio for death of 0.42 (95% CI, 0.19-0.91) in cohort A, and 0.83 (95% CI, 0.11-5.98) in cohort B. Moreover, the analysis showed a hazard ratio of 0.55 (95% CI, 0.29-1.06) in the overall population in the study.

Median duration of treatment with olaparib in patients who crossed over was 4.8 months, and median duration of treatment with control therapy was 3.9 months. The researchers noted that this was an investigator-assessed end point, which could mean the results are potentially subject to reporting bias. “Patients who crossed over from control therapy to receive olaparib had a shorter median duration of olaparib exposure (4.8 months) than those who were randomly assigned to receive olaparib (7.6 months). Thus, earlier treatment with olaparib may have an advantage over its use later in the disease course,” they wrote.2

The safety profile of olaparib appeared consistent with that found in the primary analysis. No cumulative toxic effects were observed during the extended exposure period.

The most common adverse events among the patients in the olaparib group and those who crossed over to receive olaparib were anemia (39%), nausea (36%), and fatigue or asthenia (32%). Treatment with olaparib was discontinued because of anemia in 7% of patients and because of neutropenia, thrombocytopenia, nausea, vomiting, or fatigue or asthenia in 1% of the patients for each.

The PROfound trial enrolled patients with metastatic castration-resistant prostate cancer who had alterations in at least 1 of 15 prespecified genes with a direct or indirect role in homologous recombination repair (HRR) and whose disease had progressed during previous treatment with a next- generation hormonal agents.

Cohort A (n = 245) consisted of patients with at least 1 alteration in 

, while cohort B (n = 142) comprised patients with at least one alteration in any of the other 12 prespecified genes.

Patients were randomly assigned 2:1 to receive either olaparib or the physician’s choice of enzalutamide or abiraterone. In cohort A, 162 patients received 300 mg olaparib twice daily and 83 patients were assigned to control therapy. In cohort B, 94 patients received the same olarparib regimen while 48 patients were in the control arm.

The primary end point was imaging-based progression-free survival (PFS) in cohort A, according to blinded independent central review.3

In cohort A, imaging-based PFS was significantly longer in the olaparib arm, compared with the control arm (median, 7.4 months vs. 3.6 months; HR, 0.34; 95% CI, 0.25-0.47; 

 < .001). In the initial analysis, a significant benefit was also observed with confirmed objective response rate and the time to pain progression.

“PROfound is the first positive phase 3 PARP inhibitor trial in metastatic castration-resistant prostate cancer, meeting its primary end point of prolonged radiographic progression-free survival for metastatic castration-resistant prostate cancer with alterations in 

progressing on prior next-generation hormonal agents and treated with olaparib versus with enzalutamide or abiraterone,” Mateo said, adding that these data supported the FDA’s approval of olaparib in this setting.

1. J.S. de Bono, J. Mateo, K. Fizazi, et al. Final overall survival (OS) analysis of PROfound: Olaparib vs physician’s choice of enzalutamide or abiraterone in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract 610O.

2. M. Hussain, J. Mateo, K. Fizazi, et al. Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer. 

3. de Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. 

The PARP inhibitor reduced the risk for death by 31% in men with metastatic castration-resistant prostate cancer, compared with enzalutamide or abiraterone plus prednisone.

Olaparib Significantly Improves OS in mCRPC Subgroup

Frontline lorlatinib (Lorbrena) significantly improved progression-free survival (PFS), compared with crizotinib (Xalkori) in patients with ALK-positive non–small cell lung cancer (NSCLC), according to data from a planned interim analysis of the phase 3 CROWN trial that were presented at the 2020 ESMO Virtual Congress.

The third-generation ALK TKI was also associated with higher overall and intracranial response rates.

“These results of the CROWN study support the use of lorlatinib as a highly effective first-line therapy for patients with advanced ALK-positive non–small cell lung cancer,” lead study author Ben Solomon, MD, a medical oncologist in the Lung Service and the Head and Neck service, and group leader of the Molecular Therapeutics and Biomarkers Laboratory in the Research Division, Peter MacCallum Cancer Centre in Australia, said in a presentation during the meeting.

The median PFS by blinded independent central review (BICR) was not estimable (NE; 95% CI, NE-NE) for lorlatinib compared with 9.3 months (95% CI, 7.6-11.1) for crizotinib, leading to a 72% reduction in the risk of disease progression or death (HR, 0.28; 95% CI, 0.19-0.41; 1-sided P <.001).

The intracranial objective response rate (IC-ORR) was 82% in patients with measurable brain metastases, with a complete response (CR) rate of 71% with lorlatinib, along with a significantly prolonged time to IC progression, versus crizotinib.

ALK rearrangements occur in approximately 3% to 5% of patients with NSCLC that result in sensitivity to small-molecule ALK TKIs. Furthermore, resistance to ALK TKIs is a common development and often includes central nervous system (CNS) progression.

Lorlatinib is a highly potent, brain-penetrant, third-generation ALK TKI that is currently approved by the FDA as a treatment for patients with ALK-positive metastatic NSCLC following progression on 1 or more prior ALK-targeted TKI.

The phase 3 CROWN trial randomized 296 patients 1:1 with lorlatinib at 100 mg daily (n = 149) compared with crizotinib (Xalkori) at 250 mg twice daily (n = 147) as a first-line treatment for patients with ALK-positive NSCLC. Patients were stratified by presence of brain metastases and ethnicity (Asian vs non-Asian). No crossover between the 2 arms was permitted, and 5 patients on the crizotinib arm did not receive treatment.

To be eligible for enrollment, patients had treatment-naïve stage IIIB/IV disease, an ECOG performance status of 0 to 2, and at least 1 extracranial measurable target lesion via RECIST v1.1 criteria with no prior radiation required. Asymptomatic treated or untreated CNS metastases were permitted.

All patients underwent restaging chest/abdominal CT scans and brain imaging every 8 weeks. At the interim data cutoff date of March 20, 2020, 103 patients on lorlatinib and 31 patients on crizotinib remained on study treatment.

The primary end point was PFS by BICR; secondary end points were investigator-assessed PFS, BICR- and investigator-assessed ORR, IC-ORR, duration of response (DOR), and IC-DOR via BICR, IC-time to progression by BICR, OS, safety, quality of life.

The baseline characteristics were well balanced between the 2 arms. More than half of patients were female (59%), 48.5% were White, and 54% of patients had an ECOG performance status of 1. Fifty-nine percent of patients were never smokers, 33% were prior smokers, and 7.5% were current smokers. Ninety-three percent of patients had stage IV disease, and 26.5% of patients had brain metastases at baseline; 6.5% of patients had prior brain radiotherapy.

The median duration of follow-up for PFS was 18.3 months and 14.8 months, respectively. Additional results showed that the 12-month PFS rate, assessed by BICR, with lorlatinib was 78% and 39% with crizotinib.

The investigator-assessed median PFS was NE (95% CI, NE-NE) with lorlatinib compared with 9.1 months (95% CI, 7.4-10.9) with crizotinib, leading to a 79% reduction in the risk of disease progression or death (HR, 0.21; 95% CI, 0.14-0.31; 1-sided P <.001). The 12-month PFS rates were 80% and 35% with lorlatinib and crizotinib, respectively.

The PFS benefit by BICR was upheld across prespecified subgroups, including presence of brain metastases (HR, 0.20), ECOG performance status (HR, 0.28), gender (HR, 0.31 for male; HR, 0.26 for female), age (HR, 0.22 for younger than 65 years; HR, 0.35 for older than 65 years), smoking status (HR, 0.24 for never smokers; HR, 0.36 for current/former smokers), and histology (HR, 0.26).

Also by BICR, the ORR was 76% (95% CI, 68-83)with lorlatinib and 58% (95% CI, 49-66) with crizotinib (odds ratio [OR] 2.25; 95% CI, 1.35-3.89). In the lorlatinib arm, there was a 3% CR rate and a 73% partial response rate; 13% of patients had stable disease. In the crizotinib arm, these rates were 0%, 58%, and 28%, respectively. Seven percent and 5% of patients on lorlatinib and crizotinib, respectively, had progressive disease; 4 and 11 patients on each arm were not evaluable. The median DOR was not evaluable with lorlatinib and 11.0 months with crizotinib. The median time to response was 1.8 months in both arms.

IC-OR, via BICR, was 66% in patients on lorlatinib versus 20% with crizotinib with measurable or nonmeasurable brain metastases at baseline (OR, 8.41; 95% CI, 2.59-27.23); the IC-CR rates were 61% and 15%, respectively. The IC-OR was 82% in patients on lorlatinib versus 23% with crizotinib only with measurable brain metastases (OR, 16.83; 95% CI, 1.95-163.23); the IC-CR rates were 71% and 8%, respectively. The median DOR was not evaluable in either lorlatinib group and was 9.4 months in the both measurable/nonmeasurable group and 10.2 months in the only-measurable brain metastases group on crizotinib.

The median time to CNS progression was not estimable with lorlatinib and 16.6 months with crizotinib (HR, 0.07; 95% CI, 0.03-0.17; 1-sided P <.001).

OS data are still immature, Soloman said, but added that the median OS was not estimable in both arms and favored lorlatinib (HR, 0.72; 95% CI, 0.41-1.25).

The median treatment duration was not estimable with lorlatinib and 9.6 months with crizotinib. Regarding safety, grade 3/4 AEs occurred in 72% of lorlatinib-treated patients versus 56% of those on crizotinib; serious AEs were reported in 34% and 27% of patients, respectively. Solomon noted that the majority of grade 3/4 AEs on the lorlatinib arm were laboratory abnormalities regarding cholesterol and triglycerides, that were asymptomatic and readily managed.

AEs occurring in the lorlatinib arm at more than 10% than crizotinib hypocholesterolemia, hypertriglyceridemia, edema, weight gain, peripheral neuropathy, and cognitive effects. AEs more frequently associated with crizotinib included diarrhea, nausea, vision disorder, vomiting, increased aspartate aminotransferase/alanine aminotransferase, and constipation.

There were 7 fatal AEs in each arm; 7% and 49% of patients on lorlatinib had AEs that led to treatment discontinuation and temporary dose interruption, respectively, versus 9% and 47% of patients on crizotinib. Additionally, the change from baseline in global QoL scores was 4.65 (95% CI, 1.14-8.16), favoring lorlatinib.

Solomon B, Bauer T, de Marinis F, et al. Lorlatinib vs crizotinib in the first-line treatment of patients with advanced ALK-positive non–small cell lung cancer: results of the phase 3 CROWN study. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract LBA2.

First-line treatment with the third-generation ALK TKI was also associated with higher overall and intracranial response rates in patients with ALK-positive non–small cell lung cancer.

Frontline Lorlatinib Improves PFS in Patients with Advanced ALK-Positive NSCLC

Treatment with dostarlimab induced durable antitumor activity in patients with advanced or recurrent DNA mismatch repair deficient (dMMR) and proficient (MMRp) endometrial cancer, according to updated results from the phase 1 GARNET trial (NCT02715284) that were presented during the 2020 ESMO Virtual Congress.1

Moreover, the agent showed notable disease control rate (DCR) and a promising safety profile.

Results showed that the investigational PD-1 antibody elicited an objective response rate (ORR) of 44.7% in patients with dMMR disease and 13.4% in those with MMRp disease. In the dMMR cohort (n = 103), 11 complete responses (CRs) were observed, along with 35 partial responses (PRs). Thirteen patients achieved stable disease (SD), while 39 patients experienced disease progression. In the MMRp cohort (n = 142), 3 patients had CRs, 16 had PRs, 31 achieved stable disease, and 77 patients experienced progressive disease.

The median duration of response (DOR) was not reached in the dMMR cohort (range, 2.63-28.09+) nor the MMRp cohort (range, 1.54+ to 30.36+). Additionally, DCRs with dostarlimab in the dMMR cohort and the MMRp cohorts were 57.3% (95% CI, 47.2-67.0) and 35.2% (95% CI, 27.4-43.7), respectively.

“Dostarlimab demonstrated durable antitumor activity in both dMMR and MMRp advanced and recurrent endometrial cancer,” Ana Oaknin, MD, PhD, lead study author and head of the Gynecologic Cancer Program at Vall d’Hebron Institute of Oncology, in Barcelona, Spain, said in a presentation during the congress. “The dMMR status determined by immunohistochemistry (IHC) was associated with a higher response rate. Dostarlimab also demonstrated a notable DCR in patients with MMRp endometrial cancer, a cohort that was comprised of a higher percentage of patients with Type II disease, which is historically associated with a worse prognosis.”

In the single-arm, phase 1 study, investigators set out to evaluate dostarlimab monotherapy in patients with advanced solid tumors. Part 2B of the trial was comprised of 5 expansion cohorts: dMMR/microsatellite instability–high (MSI-H) endometrial cancer (cohort A1), MMRp (cohort A2), non–small cell lung cancer (cohort E), dMMR/MSI-H non-endometrial cancer (cohort F), and platinum-resistant ovarian cancer without 

At the 2020 ESMO Virtual Congress, Oaknin shared data from the 2 endometrial-cancer cohorts: dMMR and MMRp. Mismatch repair status was determined by IHC. In part 2B of the trial, the PD-1 inhibitor was given at the recommended dose determined from parts 1 and 2A of the trial: 500 mg intravenously (IV) every 3 weeks for 4 cycles followed by 1000 mg IV every 6 weeks until progressive disease.

To be eligible for participation, patients had to have progressed on or following treatment with a platinum-doublet therapy, they had to have received 2 or fewer prior lines of therapy for recurrent or advanced disease, and they had to have measurable disease at baseline. Additionally, patients could not have received previous PD-1/PD-L1 inhibitor therapy, and they had to undergo screening based on local MMR/MSI testing performed in a certified local laboratory and have confirmed MMR IHC results.

The primary end points of the trial were ORR and DOR.

 were presented during the 2020 Society of Gynecologic Oncology Virtual Congress. In a cohort of 71 patients with endometrial carcinoma, dostarlimab elicited an ORR of 42% (95% CI, 31-55); this comprised a CR rate of 13% and a PR rate of 30%.3 The DCR with the agent had been 58%, and at a median follow-up of 11.2 months, the median DOR had not yet been reached.

At the data cutoff date of March 1, 2020, a total of 126 patients in the dMMR cohort and 145 patients in the MMRp cohort were enrolled to the trial and received treatment with dostarlimab; these patients comprise the safety population of the trial. To be eligible for inclusion in the efficacy population, participants had to have at least 6 months of follow-up time on the study with at least 1 measurable lesion at baseline. A total of 103 patients in the dMMR cohort and 142 in the MMRp cohort satisfied those criteria, according to Oaknin.

The demographic and baseline characteristics between the 2 cohorts proved to be similar, with the most notable difference related to histology. In the dMMR cohort, the most common histology was endometroid carcinoma type I at 68.0% (n = 70) and 23.2% (n = 33) in the MMRp cohort. The majority of participants in the latter cohort, or 76.8% (n = 109), had type II endometrial carcinoma compared with 31.1% (n = 32) in the dMMR cohort. Of the 109 MMRp patients, 54 had serous histology.

Additionally, 63.1% (n = 65) received 1 prior line of therapy in the dMMR cohort and 45.8% (n = 6%) in the MMRp cohort; 26.2% (n = 27) and 43.7% (n = 62), respectively, received 2 prior lines; and 10.7% (n = 11) and 10.6% (n = 15), respectively, received 3 or more prior lines of treatment.

Additional results from the trial showed that the Kaplain Meier–estimated probability of patients remaining in response in the dMMR and MMRp cohorts at 6 months was 97.8% and 83.0%, respectively. At 12 months, these estimated rates were 90.6% and 61.3%, respectively, and at 18 months, they were 79.2% and 61.3%, respectively.

The median follow-up time in the dMMR cohort was 16.3 months, while the follow-up time in the MMRp cohort was 11.5 months. In the dMMR cohort, 89% of patients (n = 41/46) continued to respond to treatment at the time of data cutoff; this was also true for 63.2% (n = 12/19) of those in the MMRp cohort. “The duration of response among responders to dostarlimab was quite long and the majority of those who responded remained in response at the time of data cutoff,” noted Oaknin.

Regarding safety, any-grade treatment-emergent adverse effects (TEAEs) occurred in 95.2% (n = 120) of patients in the dMMR cohort (n = 126) and 100% of those in the MMRp cohort (n = 145). Grade 3 or higher TEAEs were observed in 48.4% (n = 61) and 55.9% (n = 81) of those in the dMMR and MMRp cohorts, respectively.

Any-grade toxicities determined to be related to study treatment were reported in 63.5% (n = 80) of those in the dMMR cohort and 71.7% (n = 104) in the MMRp cohort. Grade 3 or higher treatment-related AEs (TRAEs) occurred in 13.5% (n = 17) and 19.3% (n = 28) of those in the dMMR and MMRp cohorts, respectively. Serious toxicities related to treatment were reported in 9.5% (n = 12) and 9.0% (n = 13) of patients, respectively.

The 3 most commonly experienced TRAEs of any grade included fatigue (13.5% in dMMR and 20.7% in MMRp), diarrhea (15.9% and 13.1%, respectively), and nausea (12.7% and 14.5%). Grade 3 or higher TRAEs included anemia (4.0% and 1.4%), alanine aminotransferase (ALT; 1.6% and 1.4%), and diarrhea (1.6% and 1.4%).

The top 3 any-grade immune-related TRAEs included hypothyroidism (5.6% and 7.6%), diarrhea (4.8% and 3.4%), and increased aspartate aminotransferase (AST; 1.6% and 2.8%). Grade 3 or higher immune-related TRAEs included increased ALT (1.6% and 1.4%), diarrhea (1.6% and 1.4%), and increased amylase (0.8% and 1.4%).

Four percent of patients (n = 5) in the dMMR cohort experienced TRAEs that resulted in discontinuation of treatment and 6.9% (n = 10) of patients in the MMRp cohort. These toxicities included increased ALT (0.8% in dMMR and 1.4% in MMRp), increased AST (0.8% and 0.7%, respectively), and increased transaminases (1.6% and 0%). Notably, no deaths related to study treatment were reported.

“No new safety signals were detected and only 5% of patients discontinued dostarlimab due to TRAEs,” concluded Oaknin. “Finally, I must highlight that these cohorts are the largest prospective evaluation of a PD-L1/PD-1 therapy in endometrial carcinoma to date and follow-up is ongoing.”

Oaknin A, Gilbert L, Tinker AV, et al. Safety and antitumor activity of dostarlimab in patients with advanced or recurrent DNA mismatch repair deficient (dMMR) or proficient (MMRp) endometrial cancer: results from GARNET. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract LBA36.

GSK presents new data from the GARNET study demonstrating potential of dostarlimab to treat a subset of women with recurrent or advanced endometrial cancer. News release. GlaxoSmithKline plc. April 23, 2020. Accessed September 19, 2020. 

“Dostarlimab demonstrated durable antitumor activity in both dMMR and MMRp advanced and recurrent endometrial cancer,” said Ana Oaknin, MD, PhD.

Dostarlimab Shows Promising Antitumor Activity in Mismatch Repair Deficient, Proficient Endometrial Cancer

Sacituzumab govitecan-hziy (Trodelvy) demonstrated significant activity with favorable tolerability in heavily pretreated patients with metastatic urothelial carcinoma who progressed on both platinum-based chemotherapy and checkpoint inhibition, according to final results from cohort 1 of the phase 2 TROPHY-U-01 trial (NCT03547973).1

Results, presented during the virtual 2020 ESMO Congress, showed that the antibody-drug conjugate (ADC) elicited an overall response rate (ORR) of 27% (n = 31; 95% CI, 19%-37%), thus meeting the primary end point of the trial; this included a complete response (CR) rate of 5% (n = 6) and a partial response (PR) rate of 22% (n = 25). Moreover, the median duration of response (DOR) was 5.9 months with sacituzumab govitecan (95% CI, 4.70-8.60).

"The final results from TROPHY-U-01 cohort 1 confirmed the interim findings and the results from the prior phase 1 study, and showed that sacituzumab govitecan is generally well tolerated and has significant anticancer activity in heavily pretreated [patients with] metastatic urothelial cancer who have progressed on both platinum-based chemotherapy and checkpoint inhibitors,” Yohann Loriot, MD, PhD, lead author of the study and a medical oncologist at the Institut de Cancèrologie Gustave Roussy, in Villejuif, France, said in a presentation during the congress.

Sacituzumab govitecan is a Trop-2–directed ADC that is unique from other agents in its class because of its high drug-to-antibody ratio, as well as its bystander effect because of its hydrolysable linker hydrolysis, explained Loriot. The agent has demonstrated significant activity across several tumors. Earlier results from the IMMU-132-01 trial (NCT01631552) showed that the ADC resulted in a 31% ORR with a median progression-free survival (PFS) of 7.3 months and a median overall survival (OS) of 16.3 months, with an acceptable safety profile.

In the open-label, global phase 2 TROPHY-U-01 trial, investigators evaluated sacituzumab govitecan in 3 cohorts: patients with metastatic urothelial carcinoma who progressed on platinum-based chemotherapy and checkpoint inhibition (n = 100; cohort 1); those who were ineligible for platinum-based chemotherapy and progressed following checkpoint inhibition (n = 40; cohort 2); and those who never received checkpoint inhibitors but had progressed on platinum-based therapy (n = up to 61; cohort 3).

The data presented at the 2020 ESMO Congress comprised those of cohort 1, in which patients received 10 mg/kg of the ADC on days 1 and 8, every 21 days and continued treatment until loss of clinical benefit or intolerable toxicity. The primary end point of this analysis was ORR per central review and secondary end points included safety/tolerability, DOR, PFS, and OS.

A Simon 2-stage design was used with an enrollment of 100 patients at a 90% power to reject the null hypothesis of an ORR of 12% or less, explained Loriot. The 100-patient sample size was designed to have sufficient statistical power to confirm that the lower bound of the 95% CI would exclude an ORR of 15% or less, assuming a 24% ORR.

Previous results from an interim analysis of the trial presented during the 

sacituzumab govitecan elicited an ORR of 29%

 in 35 response-evaluable patients; this was comprised of 2 CRs, 6 PRs, and 2 additional PRs that had been pending confirmation. These data led to the continued enrollment of cohort 1, said Loriot.

The final intent-to-treat analysis was based on blinded independent central assessment of data per RECIST v1.1 criteria and the data cutoff for the final analysis presented at this year’s meeting was May 18, 2020.

The median age of participants was 66 years, with 23% of patients 75 years of age or older and 78% male. Moreover, the majority of patients were white, at 74%. Twenty-eight percent of patients had an ECOG performance status of 0, while 72% had a status of 1. Overall, 62% of patients had visceral metastases; 40% had lung metastases, 28% had liver metastases, and 12% had other.

Notably, the median number of prior anticancer regimens received was 3. “Therefore, this is a heavily pretreated patient population, and sacituzumab govitecan was the fourth line of therapy,” noted Loriot.

At the time of the final analysis, 14% of patients (n = 16/113) continued to receive treatment with sacituzumab govitecan. The majority of patients who discontinued treatment did so because of disease progression (66%; n = 75). Only 7% (n = 8) of patients discontinued the ADC because of toxicity. Three percent of patients (n = 3) discontinued because of withdrawn consent and 3% (n = 3) died. The median time on treatment was 3.7 months, according to Loriot, and the maximum time on treatment is 16 months thus far. Fifty-percent of patients (n = 56) are in follow-up for survival.

The median time to onset of response was 1.6 months. The ORR, median DOR, and median time to response reported were consistent with investigator assessments.

“There was a reduction in target lesion size in three-quarters of patients,” noted Loriot. Moreover, 27 of 31 responders were alive with 8 of these patients still experiencing a response and receiving the treatment at the time of the data cutoff.

Tumor assessments were made every 6 weeks through cycle 12, added Loriot. “Looking at the depth of reduction in tumor size in all patients, you can see that most patients, including many who did not meet the criteria for a CR or PR, had a reduction in tumor size that was sustained for a long period of time.”

The estimated median PFS with sacituzumab govitecan was 5.4 months (95% CI, 3.5-6.9), while the estimated median OS was 10.5 months (95% CI, 8.2-12.3).

With regard to safety, diarrhea was the most commonly experienced treatment-related adverse effect (TRAE), occurring in two-thirds of patients (all grade, 65%); this is consistent with what has been reported in prior studies with the ADC. However, most of these effects were grade 1/2, noted Loriot. Nine percent of patients experienced grade 3 diarrhea and only 1% experienced it as grade 4.

Forty-six percent of patients experienced neutropenia, with 22% having a grade 3 effect and 12% reporting a grade 4 effect. “However, neutropenia was manageable with dose reductions and granulocyte colony-stimulating factor; it was reversible,” said Loriot. “Thirty-percent of patients received GCSF either as primary prophylaxis or in response to neutropenia.”

Six percent of participants (n = 7) discontinued treatment because of TRAEs; 3 patients discontinued because of neutropenia or complications associated with the toxicity. Moreover, 1 treatment-related death was reported, with a patient presenting with sepsis due to febrile neutropenia.

“Sacituzumab govitecan received fast track designation [from the FDA] for this indication and may have the potential to change practice in this setting,” Loriot concluded.

These data have led to the initiation of the phase 3 confirmatory trial TROPiCs-04 (NCT04527991), which will enroll 482 patients with locally advanced and resectable or metastatic urothelial carcinoma who have progressed following platinum-based chemotherapy and checkpoint inhibition.

Participants will be randomized to either sacituzumab govitecan at 10 mg/kg on days 1 and 8 of each 21-day cycle or physician’s choice of chemotherapy consisting of docetaxel at 75 mg/m2, paclitaxel at 175 mg/m2, or vinflunine at 320 mg/m2. The primary end point of the trial is OS, while key secondary end points include PFS, ORR, DOR, and quality of life.

Loriot Y, Balar AV, Petrylak DP, et al. Final results from TROPHY-U-01 cohort 1: a phase 2 open-label study of sacituzumab govitecan (SG) in patients with metastatic urothelial cancer (mUC) and disease progression after platinum (PLT)-based reigmens and checkpoint inhibitors. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract LBA24.

Tagawa STT, Balar A, Petrylak DP, et al. Initial results from TROPHY-U-01: a phase 2 open-label study of sacituzumab govitecan in patients with metastatic urothelial cancer (mUC) after failure of platinum-based regimens or immunotherapy. Presented at: 2019 ESMO Congress; September 27 to October 1, 2019; Barcelona, Spain. Abstract LBA55.

Sacituzumab govitecan-hziy induced significant activity with favorable tolerability in heavily pretreated patients with metastatic urothelial carcinoma.