Jessica Hergert

A study presented during the 2021 International Workshop on Chronic Lymphocytic Leukemia (CLL) showed the potential for effective detection of many genomic abnormalities in patients with CLL via optical genome mapping (OGM).

OGM detected 88% (n = 184) of previously known abnormalities and provided additional structural information in 45% (n = 19) of patients, most of which were associated with microarray copy number alternations (CNAs) or unknown cytogenetic elements reported by chromosome banding analysis (CBA).

Discordances in OGM were mainly found in patients with complex karyotypes (CKs) and occurred because of a CNA sensitivity of around 20% (n = 13; 45%), CNA masked regions (n = 2; 7%), CNA complex chromosomal microarray (CMA) profile (n = 3; 10%), a rearrangements sensitivity of around 5% (n = 2; 7%), rearrangements centromeric breakpoints (n = 7; 24%), and other (n = 2; 7%).

Curated results from OGM still detected a higher complexity compared with CBA and CMA; however, OGM demonstrated a good correlation with the other technologies (rp = .69; rp = .81, respectively). Patients with CK demonstrated significantly higher genomic complexity (

Notably, OGM detected new balanced rearrangements, particularly among patients with CK, that should be further validated.

“Further studies are required to define genomic complexity criteria by OGM and implement this technique in the routine management of patients with CLL,” lead study author Anna Puiggros, a medical associate for the pathology service at Hospital del Mar and a member of the Translational Research Group in Hematological Neoplasms at the Institut Hospital del Mar d’Investigacions Mèdiques, in Barcelona, Spain, and coauthors wrote in the poster.

CK is defined as the presence of at least 3 chromosomal aberrations in the same clone by CBA. In CLL, the presence of CK predicts for poor prognosis.

CBA, CMA, and fluorescence in situ hybridization (FISH) are current standard methods for risk stratification and identifying CK in patients with CLL; however, each method is associated with intrinsic limitations.

OGM is a novel method of risk stratification that relies on the imaging of long DNA molecules of greater than 250 kbp that has the potential to overcome some of the limitations associated with the aforementioned technologies. With OGM, long DNA molecules are labeled at specific sequences across the genome and imaged by a high-throughput, high-resolution machine. The resulting information features a map of the genomic location of every molecule that detects chromosomal abnormalities based on label patterns vs a reference genome and the number of molecules mapped in each region.

The goals of this study were “to compare the results obtained by OGM with previous CBA and CMA information [and] to analyze the usefulness of OGM in the assessment of genomic complexity in patients with CLL,” Puiggros and coauthors wrote. 

In the study, investigators analyzed 42 patients with CLL, 18 of whom carried CK by CBA. Patients were a median age of 66 years, and the majority (67%) were male. Sixteen percent of patients had Binet stage B or C disease.

Overall, 27 patients had low-complexity by OGM (LC-OGM) defined as less than 10 abnormalities, and 15 patients had high-complexity by OGM (HC-OGM) defined as 10 or more abnormalities.

The median time from diagnosis to OGM was 4 months in the LC-OGM cohort (range, 0-51) vs 18 months in the HC-OGM cohort (range, 0-54; P = .623). The median number of abnormalities identified by OGM was 6 (range, 2-9) vs 28 (range, 10-77), respectively (

 < .001). Patients had a median of 2 (range, 0-7) vs 10 (range, 1-29) CNAs identified by CBA (P = .001), respectively, and a median of 3 (range, 0-5) vs 17 (range, 5-48) translocations, respectively (P < .0 01).

Genomic complexity by conventional methods in the LC-OGM cohort vs the HC-OGM cohort revealed that 25.9% (n = 7) vs 73.3% (n = 11), respectively (

= .004), had CK by CBA, defined as at least 3 abnormalities; 3.7% (n = 1) vs 60% (n = 9), respectively (

< .001), had high CK by CBA defined as at least 5 abnormalities; 7.4% (n = 2) vs 53.3% (n = 8), respectively (

 = .001), had high genomic complexity by CMA, defined as at least 5 abnormalities including all classical CLL CNA abnormalities (n = 40); 7.4% (n = 2) vs 80% (n = 12), respectively (

 < .001), had high complexity by CBA and or CMA defined as at least 5 alterations; and 0% vs 53.3% (n = 8), respectively (

In the LC-OGM cohort vs the HC-OGM cohort, FISH testing identified 13q deletions in 74.1% (n = 20) vs 66.7% (n = 10) of patients, respectively (

= .434); trisomy 12 in 22.2% (n = 6) vs 13.3% (n = 2) of patients, respectively (

= . 39 5) ; 11q deletions/ATM mutations in 29.6% (n = 8) vs 26.7% (n = 4) of patients, respectively (

= . 5 6 6) ; 17p deletions/TP53 mutations in 3.7% (n = 1) vs 40% (n = 6) of patients, respectively (

= .002); and TP53 abnormalities in 3.7% (n = 1) vs 46.7% (n = 7) of patients, respectively (

Of evaluable patients with unmutated IGHV (n = 38), 51.9% (n = 14) of patients in the LC-OGM cohort compared with 60% (n = 9) of patients in the HC-OGM cohort had unmutatedIGHV (

Finally, in the LC-OGM cohort, 51.9% (n = 14) of patients were treated, the median time to first treatment was 53 months (95% CI, 2.7-83.3), and the median follow-up time was 45 months (range, 0-95). In the HC-OGM cohort, 80% (n = 12) of patients were treated (

 = .069), the median time to first treatment was 2 months (95% CI, 0.5-11. 5; 

 = .018), and the median follow-up time was 31 months (range, 0-82; 

Tumor DNA from peripheral blood was also analyzed by OGM; abnormalities identified by OGM were compared with available CBA, FISH, and CMA results. Additionally, clinical-biological characteristics and time-to-first treatment (TFT) were evaluated based on the complexity identified by OGM.

Further results showed that, as a continuous variable, the number of alterations defined by OGM demonstrated a concordance index for TFT (c-index = 0.623) that was similar to that observed with CBA (c-index = 0.602) and CMA (c-index = 0.657).

Additionally, patients with 10 or more alternations identified by OGM demonstrated a worse clinical evolution.

1. Puiggros A, Ramos-Campoy S, de la Rosa M, et al. Optimal genome mapping: a new promising tool to assess genomic complexity in chronic lymphocytic leukemia (CLL). Presented at: 2021 International Workshop on Chronic Lym-phocytic Leukemia; September 17-20, 2021; virtual. Poster 1084272. https://bit.ly/3koE0Q0

Articles

Optical genome mapping may help to detect genetic abnormalities in patients with CLL. 

Genomic Complexity in CLL Is Detected With Optical Genome Mapping 

Umbralisib (Ukoniq) and ublituximab (U2) in combination with pembrolizumab (Keytruda) showed long-lasting responses in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and Richter transformation, according to findings from the 5-year updated analysis of a phase 1/2 study (NCT02535286) presented during the 2021 International Workshop on CLL (iwCLL).

In patients with CLL (n = 11), the overall response rate (ORR) was 91% (n = 10), which comprised 1 (9%) complete response (CR) and 9 (82%) partial responses (PRs). An additional patient (9%) achieved stable disease (SD) (TABLE). The ORR was 83% in patients with Bruton tyrosine kinase (BTK) inhibitor–refractory CLL (n = 6), and 80% of BTK inhibitor–refractory responders achieved a response following U2 induction prior to the addition of pembrolizumab.

In patients with Richter transformation (n = 9), the ORR was 25% (n = 2), which comprised 2 CRs. An additional 3 patients (38%) achieved SD. Further, patients with heavily refractory Richter transformation achieved durable responses.

“Although there are preclinical data to support a role for inhibiting the PD-1/PD-L1 axis in CLL, clinical experience with checkpoint inhibitor monotherapy has been disappointing, with a 0% ORR in CLL and limited durability in Richter transformation,” said lead study author Lindsey E. Roeker, MD, a hematologic oncologist at Memorial Sloan Kettering Cancer Center, in a presentation of the data.

“Given that there is a known interaction between the PI3K signaling pathway and immune checkpoint surveillance, it was thought that PI3K inhibition and checkpoint blockade may act synergistically,” Roeker added.

Umbralisib is an oral PI3Kδ and CK1ε inhibitor that has demonstrated encouraging activity in CLL in combination with ublituximab, a glycoengineered CD20-directed monoclonal antibody.

On May 25, 2021, the FDA accepted a biologics license application for the U2 regimen for the treatment of patients with CLL and small lymphocytic lymphoma.2 The acceptance was based on findings from the phase 3 UNITY- CLL trial (NCT02612311), in which the doublet improved progression-free survival (PFS) vs obinutuzumab (Gazyva) plus chlorambucil in patients with CLL.

To evaluate U2 in combination with pembrolizumab, the multicenter phase 1/2 study utilized a dose-escalation, 3 + 3 design to evaluate the safety of the triplet in patients with CLL and Richter transformation.

Cohort 1 (n = 5 patients with CLL; n = 4 patients with Richter transformation) received 100 mg of pembrolizumab and cohort 2 (n = 6 patients with CLL; n = 5 patients with Richter transformation) received 200 mg of pembrolizumab. The investigators collected peripheral blood and/or bone marrow samples at screening, as well as during cycles 2 and 6 for correlative study.

Safety served as the primary end point of the study, with efficacy (ORR and PFS) and the characterization of immunophenotypic profiles of B and T cells as key secondary end points.

Patients with CLL who progressed on at least 1 prior therapy were eligible for enrollment. A mid-study amendment required all patients with CLL to be refractory to a BTK inhibitor, defined as disease progression within 6 months of prior BTK inhibitor therapy.

Patients with Richter transformation were refractory to chemoimmunotherapy or ineligible for high-dose chemotherapy. Notably, patients with prior PD-1 inhibitor or PI3K inhibitor exposure were not excluded from the study.

Patients with CLL were a median age of 70 years (range, 60-81) and most patients were male (n = 7). Five patients had an ECOG performance status (PS) of 0, and 6 patients had an ECOG PS of 1. The median number of prior therapy regimens was 1 (range, 1-4); 64% (n = 7) of patients had received prior BTK inhibitors (ibrutinib [Imbruvica] or acalabrutinib [Calquence]) and 86% (n = 6) were refractory to their prior BTK inhibitor. Additionally, 73% of patients (n = 8) were refractory to their immediate prior therapy.

Most patients (n = 8; 73%) had at least 1 high-risk feature and 55% (n = 6) had 2 or more high-risk features, which included 17p deletions/TP53 mutations (n = 3; 27%); complex karyotype (n = 5; 45%); NOTCH1, ATM, or SF3B1 mutations (n = 5; 45%); unmutated IGHV (n = 4; 57%); and bulky disease (n = 7; 64%).

In the Richter transformation cohort, the median age was 66 years (range, 53-73), and 6 patients were male. An ECOG PS of 0, 1, and 2 was observed in 3, 5, and 1 patients, respectively. The median number of prior therapies was 5 (range, 1-9); 89% (n = 8) of patients had received prior ibrutinib and 100% were refractory to the BTK inhibitor. Prior regimens included chemotherapy (n = 9; 100%), idelalisib (Zydelig) plus rituximab (Rituxan; n = 2; 22%), venetoclax (Venclexta; n = 3; 33%), and chimeric antigen receptor (CAR) T-cell therapy or allogeneic transplant (n = 3; 33%). Most patients (n = 8; 89%) were refractory to their immediate prior treatment and had bulky disease.

The median follow-up was 48 months for all patients and 54 months for patients with CLL. Additional results showed that circulating FoxP3+ CD4+ T-cell levels did not change significantly among patients with CLL.

“The maintenance of T regs [regulatory T cells] throughout therapy may explain the limited autoimmune sequelae that were seen in this study,” Roeker said.

Regarding safety in both cohorts, all-causality, all-grade adverse effects (AEs) included neutropenia (n = 12; 60%), pyrexia (n = 10; 50%), diarrhea (n = 10; 50%), nausea (n = 9; 45%), chills (n = 9; 45%), cough (n = 9; 45%), fatigue (n = 9; 45%), thrombocytopenia (n = 8; 40%), decreased appetite (n = 8; 40%), headache (n = 8; 40%), infusion-related reactions (n = 7; 35%), and peripheral edema (n = 6; 30%), increased alkaline phosphatase (n = 6; 30%), leukopenia (n = 6; 30%), dizziness (n = 6; 30%), nasal congestion (n = 6; 30%), contusion (n = 5; 25%), myalgia (n = 5; 25%), oral candidiasis (n = 5; 25%), anemia (n = 5; 25%), pruritus (n = 5; 25%), increased alanine aminotransferase (ALT; n = 5; 25%), insomnia (n = 5; 25%), and vomiting (n = 5; 25%)

Grade 3 or higher AEs included neutropenia (n = 9; 45%), nausea (n = 1; 5%), fatigue (n = 1; 5%), thrombocytopenia (n = 3; 15%), leukopenia (n = 2; 10%), anemia (n = 1; 5%), and increased ALT (n = 3; 15%).

The investigators observed 1 dose-limiting toxicity of transient elevated liver function test (LFT) with 200 mg of pembrolizumab, which was subsequently resolved. The maximum- tolerated dose was not reached.

Grade 3 or 4 elevated LFT was observed in 20% (n = 4) of patients, but no grade 3 or 4 diarrhea was reported. One patient developed grade 5 colitis secondary to Clostridium difficile.

No dose reductions were required with pembrolizumab, but 4 patients required dose reductions with umbralisib because of grade 3 asthenia/fatigue, grade 3 neutrophil count decrease, grade 2 ALT increase, and grade 2 headache.

“Notably, immune-mediated toxicities were not increased above what would be expected with umbralisib or pembrolizumab alone,” Roeker concluded

1. Roeker LE, Shadman M, Svoboda J, et al. Phase I/II study of umbralisib, ublituximab, and pembrolizumab in patients with relapsed or refractory chronic lymphocytic leukemia and Richter transformation: 5-year follow-up. Poster presented at: 2021 iwCLL; September 17-20, 2021; virtual. Poster 1083523. https://bit.ly/39mpYYA

2. TG Therapeutics announces FDA acceptance of biologics license application for ublituximab in combination with UKONIQ (umbralisib) as a treatment for patients with chronic lymphocytic leukemia and small lymphocytic leukemia. News release. TG Therapeutics, Inc. May 25, 2021. Accessed October 14, 2021. https://bit.ly/3yOj3mG

3. Lunning M, Vose J, Nastoupil L, et al. Ublituximab and umbralisib in relapsed/refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia. 

. 2019;134(21):1811-1820. doi:10.1182/ blood.2019002118

Long-lasting responses to the triplet combination of umbralisib, ublituximab, and pembrolizumab were seen in a phase 1/2 study.

Triplet Regimen Leads to Long-Term Efficacy in CLL and Richter Transformation

The addition of alectinib (Alecensa) to patients with 

positive non–small cell lung cancer (NSCLC) resistant to or intolerant of crizotinib (Xalkori) yielded survival benefits, according to results from a study presented during the 2021 World Conference on Lung Cancer.

“There have been limited data in clinical outcomes, long-term survival, and toleration with sequential therapy of first-line crizotinib followed by alectinib in clinical practice for Chinese patients with advanced 

-positive NSCLC,” said Zihua Zou, MD, lead author on the retrospective study. Zou works in the Department of Medical Oncology at the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital at the Chinese Academy of Medical Sciences and Peking Union Medical College.

Regarding the efficacy of crizotinib, the overall response rate (ORR) in patients with at least 1 radiological evaluation (n = 60) was 60% and comprised 1 complete response (CR) and 35 partial responses (PRs; 95% CI, 46.5%-72.4%). The ORR in patients with target lesions (n = 42) was 85.7%, with 1 CR and 35 PRs (95% CI, 71.5%-94.6%).

In terms of the intracranial efficacy of crizotinib, the ORR in patients with central nervous system (CNS) metastases (n = 9) was 22.2% and included 2 PRs (95% CI, 2.8%- 60.0%). The ORR in patients with measurable CNS metastases (n = 5) was 40% and comprised 2 PRs (95% CI, 5.3%-85.3%). Additionally, 1 patient with CNS-related symptoms had no improvement in symptoms.

Regarding efficacy with alectinib, the ORR in the overall population (n = 61) was 47.5%, with 2 CRs and 27 PRs (95% CI, 34.6%-60.7%). The ORR in patients with target lesions (n = 46) was 60.9% and comprised 1 CR and 27 PRs (95% CI, 45.4-74.9%). Additionally, 1 patient achieved a CR in target lesions.

In terms of the intracranial activity with alectinib, the ORR in patients with CNS metastases (n = 38) was 47.4%, with 7 CRs and 11 PRs (95% CI, 31.0%-64.2%). The ORR in patients with measurable CNS metastases (n = 19) was 68.4% and comprised 2 CRs and 11 PRs (95% CI, 43.4%-87.4%). Moreover, 9 patients with CNS-related symptoms experienced significant improvement in symptoms.

The retrospective study obtained medical records of patients with advanced 

-positive NSCLC who were treated with sequential crizotinib and alectinib at 6 centers in China. Patients could not have received intermittent systemic therapies between crizotinib and alectinib.

Combined treatment to failure was defined as the period from the start of crizotinib to the complete discontinuation of alectinib for reasons including disease progression, death, severe adverse effects (AEs), and patient preference.

Patients (n = 61) were a median age of 49 years (range, 25-81) and 4 patients were 65 years or older. There were 29 male patients. Most patients (n = 50) had an ECOG performance status (PS) of 0 or 1, but 11 patients had an ECOG PS of 2 or more. Most patients had adenocarcinoma (n = 58), were never smokers (n = 47), and had stage IV or recurrent disease with distant metastases (n = 53).

Ten patients had baseline CNS metastases, and 1 patient had CNS-related symptoms.

Reasons for crizotinib discontinuation included disease progression (n = 52), severe AEs (n = 7), and patient preference (n = 2).

Regarding baseline characteristics, patients (n = 61) were a median age of 49 years (range, 25-81) and 8 patients were 65 years or older. Additionally, ECOG PS was between 0 and 1 (n = 40) and 2 or more (n = 21).

Thirty-eight patients had CNS metastases before alectinib. For crizotinib-resistant patients, the number of patients with CNS metastases rose from 7 to 52 patients after crizotinib resistance. Moreover, 11 patients had CNS-related symptoms.

Further results with crizotinib showed that 7 patients had tumor reduction of at least 75%, 16 had tumor reduction between 51% and 75%, 13 had tumor reduction between 26% and 50%, and 6 had tumor reduction of 25% or less. With alectinib, tumor reduction occurred in 3, 13, 12, and 18 patients, respectively.

The median progression-free survival (PFS) for crizotinib-resistant patients during the stage of crizotinib (n = 52) was 15.4 months (95% CI, 11.0-19.5). Moreover, 22 patients experienced intracranial progression, 18 experienced extracranial progression, and 12 experienced intracranial plus extracranial progression.

At a median follow-up of 17.1 months, the median PFS during alectinib treatment for patients with crizotinib-resistant disease was 13.5 months (95% CI, 8.5-18.8).

Additionally, 16 patients had no rebiopsy, 12 had rebiopsy with a secondary 

mutation identified, and 8 patients had rebiopsy without a secondary 

mutations identified included G1202R (n = 4), I1171N (n = 4), L1196Q (n = 1), I1171T (n = 1), L1196M plus G1202R (n = 1), and F1174L plus G1269A plus E1210K (n = 1).

The median time to treatment failure (TTF) in the overall population during crizotinib treatment was 12.7 months (95% CI, 7.6-18.1). Additionally, 9 patients continued crizotinib after local or gradual progression.

At a median follow-up of 34.3 months, the median TTF during treatment from crizotinib to alectinib was 39.2 months (95% CI, 30.0-49.6). Nine patients continued alectinib after local or gradual progression; 33 patients discontinued treatment because of disease progression (n = 31) or AEs (n = 2).

Of the 33 patients who discontinued alectinib, 29 received at least 1 line of subsequent therapy, and 27 received other ALK tyrosine kinase inhibitors (TKIs).

mutations who received sensitive ALK TKI had a median PFS of 10.4 months vs 3.1 months in patients without a secondary 

mutation identified (95% CI, 0.016-0.389).

Subsequent ALK TKIs in patients with secondary 

mutations included lorlatinib (Lorbrena; n = 6), ceritinib (Zykadia; n = 4), brigatinib (Alunbrig; n = 1), and ensartinib (Tepmetko; n = 1). In patients without secondary 

mutations, subsequent ALK TKIs included brigatinib (n = 2), lorlatinib (n = 2), ensartinib (n = 1), and ceritinib (n = 1).

Finally, the estimated 3-year overall survival (OS) rate was 84.5% in crizotinib-resistant patients. The estimated 5-year OS rate was 66.7%. In the overall population, the estimated rates were 87.1% and 68.6%, respectively (

Grade 1/2 AEs with crizotinib in evaluable patients (n = 57) included constipation (14%), diarrhea (42.2%), nausea (47.3%), vomiting (21%), edema (43.8%), increased aminotransferase levels (40.3%), vision impairment (29.8%), and rash (10.5%). Grade 3/4 events included diarrhea (5.2%), nausea (1.7%), and increased aminotransferase levels (8.7%).

Dose interruptions occurred in 24.6% of patients (n = 14) and were most commonly due to grade 2 to 4 increased aminotransferase levels (n = 10). Dose reductions occurred in 15.8% of patients (n = 9) and were most commonly due to grade 2 to 4 increased aminotransferase levels (n = 7). Additionally, 12.3% of patients (n = 7) permanently discontinued crizotinib because of AEs; grade 3/4 increased aminotransferase levels (n = 5) and grade 3 diarrhea (n = 2) were severe AEs that led to permanent crizotinib discontinuation.

Grade 1/2 AEs with alectinib included constipation (39.3%), fatigue (26.8%), edema (28.6%), musculoskeletal pain (33.9%), increased creatine kinase levels (23.3%), increased aminotransferase levels (23.2%), increased total bilirubin levels (33.9%), and rash (12.5%). Grade 3/4 events included increased total bilirubin levels (1.8%).

Dose interruptions occurred in 17.8% of patients (n = 10) and were most commonly due to grade 2 to 4 increased total bilirubin levels (n = 6). Dose reductions occurred in 8.9% of patients (n = 5), most commonly due to grade 2 increased bilirubin levels (n = 2) or grade 2 increased creatine kinase levels (n = 2). Additionally, 3.6% of patients (n = 2) permanently discontinued alectinib. Grade 4 increased total bilirubin levels (n = 1) and grade 5 interstitial pneumonia (n = 1) were severe AEs that led to permanent discontinuation.

Zou Z. Clinical outcomes, long-term survival and toleration with sequential therapy of first-line crizotinib followed by alectinib in advanced ALK+NSCLC. Presented at: International Association for the Study of Lung Cancer 2021 World Conference on Lung Cancer; September 8-14, 2021; virtual.

Treatment with alectinib demonstrated survival benefit in patients with non–small cell lung cancer who have resistance to crizotinib, in a retrospective study. 

Adding Alectinib Results in Survival Benefit for Patients With Crizotinib Resistance in NSCLC

Compared with the median PFS reported in the durvalumab arm of the phase 3 PACIFIC trial (NCT02125461) in patients with stage III non–small cell lung cancer (NSCLC), the median real-world progression-free survival (PFS) with durvalumab (Imfinzi) was higher. Although challenges with real-world data collection could indicate that the real-world benefit observed is overestimated, according to findings from the PACIFIC-R trial (NCT03798535) that were presented during the 2021 ESMO Congress.

At a median follow-up of 23 months (range, 0-35.6), the median PFS was 21.7 months (95% CI, 19.2-24.5) in the full analysis set of the PACIFIC-R trial (n = 1399) compared with 16.9 months (95% CI, 13-23.9) in the durvalumab arm of the PACIFIC trial (n = 476). The 12-month PFS rates were 62.4% vs 55.7%, respectively, and the 24-month PFS rates were 48.2% vs 45%, respectively.

Moreover, the real-world efficacy of durvalumab after chemoradiation among analyzed subgroups was generally consistent with that observed in analyses of the PACIFIC trial. 

“The median real-world PFS in this study was higher than that reported in PACIFIC, [but] obviously there are methodological limits in such comparison,” lead study author Nicolas Girard, MD, PhD, a professor of respiratory medicine at Versailles Saint Quentin University and head of the Curie-Montsouris Thorax Institute, in Paris, France, said during a presentation of the data. 

On February 16, 2018, the FDA approved durvalumab for the treatment of patients with unresectable stage III NSCLC whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy.

Findings from the randomized PACIFIC trial, which led to the regulatory decision, demonstrated significant overall survival (OS) and PFS improvement with durvalumab compared with placebo in patients with unresectable stage III NSCLC. Five-year survival outcomes from the study showed that the median OS was 47.5 months (95% CI, 38.1-52.9) with durvalumab vs 29.1 months (95% CI, 22.1-35.1) with placebo (HR, 0.72; 95% CI, 0.59-0.89).3 The median PFS was 16.9 months (95% CI, 13-23.9) vs 5.6 months (4.8-7.7), respectively (HR, 0.55; 95% CI, 0.45-0.68).

The PACIFIC-R study assessed the real-world efficacy of durvalumab in patients included in an expanded access program (EAP).

The study evaluated patients with unresectable stage III NSCLC regardless of tumor PD-L1 expression. Patients could not have evidence of disease progression following definitive platinum-based chemoradiation therapy to be eligible for inclusion.

At an index date between September 2017 and December 2018, patients were started on 10 mg/kg of intravenous durvalumab every 2 weeks through the EAP.

Retrospective data were collected at different time points from patient’s medical records. The trial utilized a 5-year observation period to evaluate disease evolution. Overall, 1399 patients were included in the full analysis set. Patients were from 290 active clinical trial sites in 11 participating countries, including France (n = 342), Spain (n = 244), Australia (n = 165), the Netherlands (n = 155), Belgium (n = 118), Italy (n = 116), Israel (n = 92), Germany (n = 62), the United Kingdom (n = 54), Norway (n = 36), and Switzerland (n = 15).

The dual primary end point of the study was investigator-assessed PFS and OS, with key secondary end points including demographics, disease characteristics, prior therapy, PFS/OS by subgroups, and adverse effects (AEs) of special interest.

At EAP inclusion, patients were a median age of 66 years (range, 26-88) and most were 75 years or age or younger (89.6%). The majority of patients were male (67.5%), former smokers (59.5%), and had an ECOG or World Health Organization performance status of 0 (51.4%). Most patients had stage IIIB/C disease (51%) and nonsquamous histology (63.1%).

The majority of patients received concurrent chemoradiotherapy (76.6%) vs sequential chemoradiotherapy (14.3%) or other chemoradiotherapy (9.1%).

Additionally, most evaluable patients (n = 967) had PD-L1–positive disease (PD-L1 ≥1%; 72.5%).

The median time to durvalumab initiation from the end of radiation therapy was 56 days, and patients received durvalumab treatment for a median of 335 days, which translated to approximately 11 months. A proportion of patients (20.1%) received durvalumab for more than 12 months and 4.4% for more than 14 months. Finally, patients received a median of 22 durvalumab infusions; 7.1% received more than 26 infusions.

By subgroup, the data showed the median PFS was 22.4 months (95% CI, 18.7-25.5) in the PD-L1 1% or greater population vs 16.3 months (95% CI, 11.7-23.2) in the PD-L1 less than 1% population (median PFS 25.2 months [95% CI, 14-27.3] in PD-L1–inconsistent population).

The median PFS was 23.7 months (95% CI, 20.2-26.5) in patients with stage IIIA disease vs 19.2 months (95% CI, 15.8-24.2) in patients with stage IIIB/C disease. By histology, the median PFS was 25.3 months (95% CI, 22-26.9) in patients with nonsquamous NSCLC vs 14.7 months (95% CI, 12.8-19) in patients with squamous NSCLC. Finally, by chemoradiation type, the median PFS was 23.7 months (95% CI, 20.1-25.8) with concurrent chemoradiation vs 19.4 months (95% CI, 12.4-25.3) with sequential chemoradiation.

Regarding safety in the full study analysis cohort, reasons for durvalumab discontinuation included patient decision (n = 20; 1.4%), AEs (n = 233; 16.7%), completed treatment (n = 659; 47.1%), disease progression (n = 377; 26.9%), and death (n = 21; 1.5%). Other reasons for discontinuation included missing data (n = 2), unspecified reasons (n = 68), lost to follow-up (n = 3), and ongoing durvalumab treatment at the time of data extraction (n = 16). The median time from durvalumab start to treatment discontinuation was 6.1 months, 2.8 months, 12 months, 5.1 months, and 1.9 months, respectively.

Additionally, pneumonitis and interstitial lung disease (ILD) was the most common toxicity that led to treatment discontinuation among patients. The AE led to permanent discontinuation in 9.5% (n = 133) of patients and temporary interruption in 5.2% (n = 73) of patients.

Pneumonitis and ILD was observed in 17.9% (n = 250) of patients. Of these events, 4% (n = 56) were mild, 8.4% (n = 118) were moderate, 2.9% (n = 41) were severe, and 0.4% (n = 5) were life threatening or fatal.

The median time to onset of pneumonitis or ILD from durvalumab initiation was 2.5 months, and corticosteroids were required in 71.3% of events.

Girard and coauthors noted that the real-world PFS benefit is likely overestimated because:

Germany and the United Kingdom did not collect data on early deaths (n = 50) that occurred prior to study enrollment,

RECIST criteria for tumor assessment is heterogenous across countries,

Assessments for progression in the real-world setting may not be completed as frequently or consistently as in clinical trials, and

The COVID-19 pandemic could have resulted in fewer hospital visits for patients.

“The future read outs of OS will provide further insight into the effectiveness of this regimen,” concluded Girard.

Girard N, Smit HJM, Sibille A, et al. PACIFIC-R real-world study: treatment duration and interim analysis of progression-free survival in unresectable stage III NSCLC patients treated with durvalumab after chemoradiotherapy. Presented at: 2021 ESMO Congress; September 16-21, 2021; virtual. Abstract 1171MO.

FDA approves durvalumab after chemoradiation for unresectable stage III NSCLC. News release. FDA. February 16, 2018. Accessed September 21, 2021. 

Spigel DR, Faivre-Finn C, Gray JE, et al. Five-year survival outcomes with durvalumab after chemoradiotherapy in unresectable stage III NSCLC: an update from the PACIFIC trial. 

. 2021;39(suppl 15):8511. doi:10.1200/JCO.2021.39.15_suppl.8511

Compared with the median PFS reported in the durvalumab arm of the phase 3 PACIFIC trial in patients with stage III non–small cell lung cancer, the median real-world progression-free survival with durvalumab was higher.

In Unresectable Stage III NSCLC, Real-World PFS Benefit Reported With PACIFIC Regimen

During a presentation a the 2021 World Conference on Lung Cancer Zihua Zou, MD said: “There has been limited data in clinical outcomes, long-term survival, and toleration with sequential therapy of first-line crizotinib [Xalkori] followed by alectinib [Alecensa] in clinical practice for Chinese patients with advanced 

-positive NSCLC.” The treatment strategy was explored in a retrospective study.

Regarding the efficacy of crizotinib, the overall response rate (ORR) in patients with at least 1 radiological evaluation (n = 60) was 60% and comprised 1 complete response (CR) and 35 partial responses (PRs; 95% CI, 46.5%-72.4%). The ORR in patients with target lesions (n = 42) was 85.7% and comprised 1 CR and 35 PRs (95% CI, 71.5%-94.6%). Additionally, 2 patients achieved a CR in target lesions, but had a non-CR, non–progressive disease in non-target lesions.

In terms of the intracranial efficacy of crizotinib, the ORR in patients with central nervous system (CNS) metastases (n = 9) was 22.2% and comprised 2 PRs (95% CI, 2.8%-60.0%). The ORR in patients with measurable CNS metastases (n = 5) was 40% and comprised 2 PRs (95% CI, 5.3%-85.3%). Additionally, 1 patient with CNS-related symptoms had no improvement in symptoms after treatment with crizotinib.

Regarding efficacy with alectinib, the ORR in the overall population (n = 61) was 47.5% and comprised 2 CRs and 27 PRs (95% CI, 34.6%-60.7%). The ORR in patients with target lesions (n = 46) was 60.9% and comprised 1 CR and 27 PRs (95% CI, 45.4-74.9%). Additionally, 1 patient achieved a CR in target lesions, but had a non-CR, non–progressive disease in non-target lesions.

In terms of the intracranial activity with alectinib, the ORR in patients with CNS metastases (n = 38) was 47.4% and comprised 7 CRs and 11 PRs (95% CI, 31.0%-64.2%). The ORR in patients with measurable CNS metastases (n = 19) was 68.4% and comprised 2 CRs and 11 PRs (95% CI, 43.4%-87.4%). Moreover, 9 patients with CNS-related symptoms experienced significant improvement in symptoms after alectinib treatment.

Patients (n = 61) were a median age of 49 years (range, 25-81) and 4 patients were 65 years or older. Overall, 29 patients were male and 32 were female. Most patients (n = 50) had an ECOG performance status (PS) of 0 or 1, but 11 patients had an ECOG PS of 2 or greater. Most patients had adenocarcinoma (n = 58), were never smokers (n = 47), and had stage IV or recurrent disease with distant metastases (n = 53).

Ten patients had baseline CNS metastases and 1 patient had CNS-related symptoms.

Regarding baseline characteristics before the initiation of alectinib, patients (n = 61) were a median age of 49 years (range, 25-81) and 8 patients were aged 65 years or older. Additionally, ECOG PS were between 0 and 1 (n = 40) and 2 or more (n = 21).

 mutation identified, and 8 patients had rebiopsy without a secondary 

 mutations identified included G1202R (n = 4), I1171N (n = 4), L1196Q (n = 1), I1171T (n = 1), L1196M plus G1202R (n = 1), and F1174L plus G1269A plus E1210K (n = 1).

Of the 33 patients who discontinued alectinib, 29 received at least 1 line of subsequent therapy, and 27 received other ALK TKIs.

 mutations who received sensitive ALK TKI had a median PFS of 10.4 months vs 3.1 months in patients without a secondary 

 mutation identified (95% CI, 0.016-0.389).

 mutations included lorlatinib (n = 6), ceritinib (n = 4), brigatinib (n = 1), and ensartinib (n = 1). In patients without secondary 

 mutations, subsequent ALK TKIs included brigatinib (n = 2), lorlatinib (n = 2), ensartinib (n = 1) and ceritinib (n = 1).

Finally, the estimated 3-year overall survival (OS) rate was 84.5% in crizotinib-resistant patients. The estimated 5-year OS rate was 66.7%. In the overall population, the estimated rates were 87.1% and 68.6%, respectively.

Regarding safety, grade 1/2 AEs with crizotinib in evaluable patients (n = 57) included constipation (14%), diarrhea (42.2%), nausea (47.3%), vomiting (21%), edema (43.8%), increased aminotransferase (40.3%), vision impairment (29.8%), and rash (10.5%). Grade 3/4 events included diarrhea (5.2%), nausea (1.7%), and increased aminotransferase (8.7%).

Dose interruptions occurred in 24.6% of patients (n = 14) and were most commonly because of grade 2 to 4 increased aminotransferase (n = 10). Dose reductions occurred in 15.8% of patients (n = 9) and were most commonly because of grade 2 to 4 increased aminotransferase (n = 7). Additionally, 12.3% of patients (n = 7) permanently discontinued crizotinib because of AEs; grade 3/4 increased aminotransferase (n = 5) and repeated grade 3 diarrhea (n = 2) were severe AEs that led to permanent crizotinib discontinuation.

Grade 1/2 AEs with alectinib included constipation (39.3%), fatigue (26.8%), edema (28.6%), musculoskeletal pain (33.9%), increased creatine kinase (23.3%), increased aminotransferase (23.2%), increased total bilirubin (33.9%), and rash (12.5%). Grade 3/4 events included increased total bilirubin (1.8%).

Dose interruptions occurred in 17.8% of patients (n = 10) and were most commonly because of grade 2 to 4 increased total bilirubin (n = 6). Dose reductions occurred in 8.9% of patients (n = 5) and were most commonly because of grade 2 increased total bilirubin (n = 2) or grade 2 increased creatine kinase (n = 2). Additionally, 3.6% of patients (n = 2) permanently discontinued alectinib because of AEs. Grade 4 increased total bilirubin (n = 1) and grade 5 interstitial pneumonia (n = 1) were severe AEs that led to permanent alectinib discontinuation.

 secondary mutation is the main resistance mechanism of alectinib,” Zou of the Department of Medical Oncology at the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital at the Chinese Academy of Medical Sciences and Peking Union Medical College, concluded. “Different efficacy in subsequent ALK-TKI between patients with and without 

 secondary mutation further emphasized the importance of rebiopsy to guide targeted therapy more precisely.”

Zou Z. Clinical outcomes, long-term survival and toleration with sequential therapy of first-line crizotinib followed by alectinib in advanced ALK+NSCLC. Presented at: International Association for the Study of Lung Cancer 2021 World Conference on Lung Cancer; September 8-14, 2021; virtual. Abstract P45.15.

Retrospective research suggests a survival benefit with frontline Sequential crizotinib followed by alectinib in ALK-positive non–small cell lung cancer.

Sequential Therapy With Crizotinib Followed by Alectinib May Improve Survival in ALK+ NSCLC

In the phase 3 HERO trial of relugolix (Orgovyx) versus standard of care leuprolide (Lupron) in men with advanced prostate cancer, relugolix failed to significantly delay onset of castration resistance, according to a presentation given during the American Urological Association 2021 Annual Meeting.

At 48 weeks, the castration resistance–free survival (CRFS) rate was 74.3% (95% CI, 68.6%-79.2%) with relugolix vs 75.3% (95% CI, 66.7%-81.9%) with leuprolide in the metastatic disease cohort (n = 434; HR, 1.03; 95% CI, 0.68-1.57; 

 = .84). Similar CRFS rates were observed in the overall modified intention-to-treat population (mITT; n = 1074).

A post-hoc, stepwise, multivariate Cox regression analysis showed that the baseline characteristics of prostate-specific antigen (PSA) of 20 or higher (

 < .0001), and former or current smoker (

 = .0284) were associated with a CRFS event.

Additionally, all patients were under the castration threshold of less than 50 ng/dL at the time of their CRFS event except for 2 treated with leuprolide who died without attaining castration.

“Results suggest that low testosterone levels on [androgen deprivation therapy] ADT are not a driver of early castration resistance,” said lead study author Fred Saad, MD, FRCS, professor and chairman of urology, director of Genitourinary Oncology, the Raymond Garneau Chair in Prostate Cancer Research, director of clinical research, and director of the Molecular Oncology Research Laboratory in Prostate Cancer, at the University of Montreal Hospital Center, during a virtual presentation of the data.

ADT, consisting of gonadotropin-releasing hormone (GnRH) agonists or antagonists, remains the cornerstone of treatment for patients with prostate cancer, Saad explained.

Relugolix is a first-in-class, oral, highly selective GnRH receptor antagonist that was approved by the FDA in December 2020 for use in adult patients with advanced prostate cancer.

, in which 96.7% of patients treated with relugolix had suppression of testosterone to castrate levels vs 88.8% with leuprolide.

Relugolix was also associated with a 54% lower risk of major adverse cardiovascular effects compared with leuprolide.

This analysis of the HERO trial sought to further characterize the efficacy profile of relugolix in the context of CRFS, a clinically relevant indicator of disease progression and a prespecified secondary end point, in the mITT population and the metastatic disease population.

Patients enrolled on the HERO trial were randomized 2:1 to receive 120 mg of oral relugolix once daily after a single loading dose of 360 mg, or leuprolide injections every 12 weeks for 48 weeks.

Patients were stratified by geographic region, the presence or absence of metastatic disease, and age.

CRFS was defined as the time from the date of the first dose of treatment to the date of confirmed PSA progression per the Prostate Cancer Clinical Trials Working Group 3 criteria while castrated or death from any reason, whichever occurred earlier.

In the mITT population, 717 patients received relugolix and 357 received leuprolide. In the metastatic cohort, 290 patients received relugolix vs 144 who received leuprolide.

Baseline patient and clinical characteristics were similar between the mITT and metastatic disease populations.

Overall, most patients were aged 75 years or younger with a median age of 71 years. Most patients were European. Additionally, most patients had bone only metastasis at the time of study entry vs lymph node only, visceral only, or multiple sites of metastasis.

In the mITT population, testosterone values at the time of CRFS events with relugolix were 0 ng/dL to 10 or less ng/dL (n = 33), 10 ng/dL to 20 or less ng/dL (n = 43), 20 ng/dL to 30 or less ng/dL (n = 7; plus 1 death), 30 ng/dL to 40 or less ng/dL (n = 1), 40 ng/dL to 50 or less ng/dL (n = 3), or above 50 ng/dL (n = 0). In the leuprolide group, testosterone values were 0 ng/dL to 10 or less ng/dL (n = 22; plus 4 deaths), 10 ng/dL to 20 or less ng/dL (n = 13; plus 1 death), and above 50 (2 deaths).

Last testosterone values after CRFS events during treatment with relugolix were 0 ng/dL to 10 or less ng/dL (n = 36), 10 ng/dL to 20 or less ng/dL (n = 39), 20 ng/dL to 30 or less ng/dL (n = 7), 30 ng/dL to 40 or less ng/dL (n = 1), 40 ng/dL to 50 or less ng/dL (n = 1), or above 50 ng/dL (n = 4). In the leuprolide group, testosterone values were 0 ng/dL to 10 or less ng/dL (n = 27), 10 ng/dL to 20 or less ng/dL (n = 11), 20 ng/dL to 30 or less ng/dL (n = 1), and above 50 (n = 3).

Regarding safety, the frequencies of adverse effects (AEs) were similar for relugolix vs leuprolide in the metastatic disease cohort, and no new safety signals were observed.

In the metastatic disease cohort, 94.2% of men treated with relugolix and 89.6% of men treated with leuprolide experienced at least 1 AE.

The AEs reported in at least 5% of patients treated with relugolix included hot flush (n = 146; 50.3%), fatigue (n = 67; 23.1%), arthralgia (n = 47; 16.2%), constipation (n = 45; 15.5%), hypertension (n = 34; 11.7%), nausea (n = 32; 11.0%), diarrhea (n = 29; 10.0%), back pain (n = 28; 9.7%), weight gain (n = 26; 9.0%), nasopharyngitis (n = 24; 8.3%), peripheral edema (n = 23; 7.9%), asthenia (n = 21; 7.2%), musculoskeletal pain (n = 21; 7.2%), insomnia (n = 20; 6.9%) , urinary tract infection (n = 20; 6.9%), extremity pain (n = 19; 6.6%), increased alanine aminotransferase (ALT; n = 18; 6.2%), and urinary incontinence (n = 18; 6.2%).

The AEs reported in at least 5% of patients treated with leuprolide included hot flush (n = 66; 45.8%), fatigue (n = 29; 20.1%), arthralgia (n = 13; 9.0%), constipation (n = 22; 15.3%), hypertension (n = 14; 9.7%), nausea (n = 10; 6.9%), diarrhea (n = 7; 4.9%), back pain (n = 22; 15.3%), weight gain (n = 13; 9.0%), nasopharyngitis (n = 5; 3.5%), peripheral edema (n = 13; 9.0%), asthenia (n = 10; 6.9%), musculoskeletal pain (n = 8; 5.6%), insomnia (n = 11; 7.6%) , urinary tract infection (n = 6; 4.2%), extremity pain (n = 10; 6.9%), increased ALT (n = 4; 2.8%), and urinary incontinence (n = 8; 5.6%).

1. Saad F, George DJ, Cookson MS, et al. Relugolix vs leuprolide effects on castration resistance-free survival from the phase 3 HERO study in men with advanced prostate cancer. Presented at: 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Abstract MP24-07.

2. FDA approves relugolix for advanced prostate cancer. News release. FDA. December 18, 2020. Accessed September 11, 2021. 

3. Shore ND, Saad F, Cookson MS, et al. Oral relugolix for androgen-deprivation therapy in advanced prostate cancer. 

2020;382(23):2187-2196. doi:10.1056/NEJMoa2004325

In the phase 3 HERO trial of relugolix versus standard of care leuprolide in men with advanced prostate cancer, relugolix failed to significantly delay onset of castration resistance.