Jessica Skarzynski

In pretreated patients with advanced small cell lung cancer (SCLC), treatment with the combination of apatinib (Rivoceranib) and single-agent chemotherapy showed promising efficacy and was well-tolerated, data from a prospective phase 2 study (NCT03547804) presented at the 2020 World Conference on Lung Cancer (WCLC) in Singapore show.

While it accounts for around 15% of all lung cancers, SCLC is an aggressive malignancy with unsatisfactory treatment options in the second line and above, with a median progression-free survival (PFS) rate of less than 3 months, the authors noted in a poster highlighting their data.

Given this, and the lack of targeted drugs or new chemotherapeutic agents in the advanced SCLC space, researchers from The First Hospital of Jilin University, Changchun, China evaluated the efficacy and safety of the tyrosine kinase inhibitor (TKI) in combination with chemotherapy as a possible option for this patient population.

The prospective, single-center, single-arm clinical study – the initial results of which were presented at the 2019 WCLC – enrolled 31 patients from March 2018 through October 2019, 28 of which were available for response evaluation.

In addition to one of the chemotherapeutic agents, irinotecan or docetaxel, 28 patients were initially given a dose of 500 mg apatinib once daily. However, the treatment plan was adjusted to a lower dose of 250 mg once daily due to the patients’ tolerance. If patients experienced grade 3 or 4 adverse events (AEs), the apatinib dose could be further reduced to 250 mg every other day.

The primary end point was progression-free survival (PFS); secondary end points included overall survival (OS), disease control rate (DCR), objective response rate (ORR), and the amount of adverse events (AEs) experienced.

Upon this updated analysis, researchers noted an ORR of 25% (n = 7). DCR was 100%. Median PFS was 7.43 months and OS was 12.5 months.

A subgroup analysis found that patients with limited-stage disease had longer PFS compared to those with extensive-stage disease (9.17 months vs 4.33 months, 

 = .0013). Additionally, no significant differences in efficacy were seen in the subgroups of patients who received different initial doses of 500 mg versus 250 mg, or age (<60y vs ≥60y).

The most common treatment-related AEs were neutropenia, thrombocytopenia, hypertension, hand-foot syndrome, proteinuria, diarrhea, abnormal liver function and mucositis. The authors noted, however, that the incidence of grade 3-4 AEs was lower, and treatment was better tolerated when patients were given an initial dose of 250 mg apatinib plus chemotherapy.

Overall, the authors concluded, for patients with advanced SCLC, apatinib in combination with single agent chemotherapy was found to be a promising option with good tolerability, particularly at the dose of 250mg per day.

Ma K, Xu Y, Cai Y, et al. A Prospective Phase II Study of Apatinib Plus Chemotherapy for Pretreated Patients With Advanced Small Cell Lung Cancer. Presented at: 2020 World Conference on Lung Cancer Singapore. Poster FP10.05.

Articles

In pretreated patients with advanced small cell lung cancer, treatment with the combination of apatinib and single-agent chemotherapy showed promising efficacy and was well-tolerated, data from a prospective phase 2 study.

Apatinib/Chemotherapy Demonstrates Encouraging Efficacy, Tolerability in Advanced SCLC

In multiple gastrointestinal tumor types, including advanced gastric cancer, advanced metastatic microsatellite instability-high (MSI-H) or mismatch repair (MMR) colorectal cancer, and advanced biliary tract cancers, the combination of the anti-angiogenic multikinase inhibitor lenvatinib (Lenvima) plus the anti-PD-1 antibody pembrolizumab (Keytruda) demonstrated promising antitumor activity and a manageable safety profile, according to data presented at the 2021 ASCO Gastrointestinal Cancers Symposium.

The combination of the anti-angiogenic multikinase inhibitor lenvatinib (Lenvima) plus the anti-PD-1 antibody pembrolizumab (Keytruda) demonstrated promising antitumor activity and a manageable safety profile in previously treated patients with advanced gastric cancer, advanced metastatic microsatellite instability-high (MSI-H) or mismatch repair (MMR) colorectal cancer, and advanced biliary tract cancers, according to data presented at the 2021 ASCO Gastrointestinal Cancers Symposium.

Given the duo’s performance in previous phase 2 studies, the multicohort LEAP-005 study (NCT03797326) set out to evaluate the combination’s safety and efficacy in a number of solid tumor types, enrolling patients in 7 different cohorts. Data specific to the combination’s performance in patients with 3 types of gastrointestinal cancers were presented at this meeting.

The gastric cancer cohort1 enrolled 31 patients (87% male) with metastatic or unresectable gastric cancer who had received at least 2 prior lines of therapy. More than half (58%) of the patients were 65 years old or younger, and 71% had a PD-L1 combined positive score (CPS) of 1.

Patients received lenvatinib 20 mg once daily plus pembrolizumab 200 mg every 3 weeks for up to 35 cycles (approximately 2 years) of pembrolizumab or until disease progression, unacceptable toxicity, or consent withdrawal. In patients who experienced a clinical benefit, treatment with lenvatinib could continue beyond 2 years.

Overall response rate (ORR) and safety were the primary endpoints of the study, with secondary endpoints including disease control rate (DCR; which included complete response [CR], partial response [PR], and stable disease [SD]), duration of response (DOR), progression-free survival (PFS), and overall survival (OS)).

While 19 patients (61%) discontinued treatment, at the time of data reporting, the ORR was 10% (95% CI, 2-26). One patient had a CR (3%), 2 had a PR (6%), and 12 patients (39%) had SD, leading to a DCR of 48% (95% CI, 30.67). Median PFS was 2.5 months (95% CI, 1.8-4.2) and median OS was 5.9 months (95% CI, 2.6-8.7), however, median DOR was not reached (range, 2.1+ to 2.3+ months).

Follow-up imaging was done every 9 weeks for 54 weeks, then every 12 weeks until week 102, and every 24 weeks beyond that. In a presentation on the data, lead author Hyun Cheol Chung, MD, noted the antitumor activity findings of this cohort.

“Among 26 patients who completed at least one baseline tumor assessment, 50% had a decrease from baseline in the size of their target lesions, and 15% of patients showed a decreased tumor size of more than 30%,” said Chung.

In terms of safety, 90% of patients experienced treatment-related AEs, 13 (42%) of whom experienced grade 3-5 AEs. One patient died as a result of a treatment-related hemorrhage. Immune-mediated AEs were less frequent, found in 8 patients (26%), and included hypothyroidism (n = 5), hyperthyroidism (n = 2), and pneumonitis (n = 1). There were no infusion-related reactions.

Overall, Chung concluded, “In patients with advanced gastric cancer who failed 2 prior lines of therapy, lenvatinib plus pembrolizumab demonstrated promising antitumor activity and a manageable safety profile. Based on these data, enrollment in the gastric cancer cohort has been expanded to 100 patients.”

Given pembrolizumab’s approval in both the first-line treatment of patients with unresectable or MSI-H or MMR deficient colorectal cancer, as well as for patients who have progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan, the colorectal cancer cohort examined the combination therapy this patient population

Similar to the gastric cancer cohort, 32 patients received lenvatinib 20 mg once daily plus pembrolizumab 200 mg every 3 weeks for the same amount of time, noting that treatment with lenvatinib could continue beyond 2 years in patients who saw clinical benefit with it. In a presentation of the data, lead author Carlos Gomez-Roca, MD, noted that the median age of all participants was 56 years, and 91% of patients (n=29) received 2 prior lines of therapy.

The study’s primary endpoints were ORR and safety, with secondary endpoints including DCR, DOR, PFS, and OS. The median time from first dose to data cutoff was 10.6 months (range, 5.9-13.1 months).

At data cutoff, the ORR was 22% (95% CI, 9-40), and the DCR was 47% (95% CI, 29-65). Median PFS was 2.3 months (95% CI, 2.0-5.2) and median OS was 7.5 months (95% CI, 3.9-NR). Median DOR was not reached (2.1+-10.4+).

Safety data found that grade 3-5 treatment-related AEs occurred in 16 (50%) pts. Three patients discontinued treatment as a result of treatment-related AEs, including a grade 2 ischemic stroke (n = 1), grade 3 increased liver transaminases (n = 1), and grade 5 intestinal perforation (n = 1).

Overall, the authors noted, lenvatinib plus pembrolizumab showed promising antitumor activity and a manageable safety profile in patients with previously treated, advanced non–MSI-H/pMMR colorectal cancer, leading researchers to expand enrollment in the colorectal cohort to 100 patients.

 included 31 patients with metastatic and/or unresectable disease with progression after 1 prior line of therapy. The treatment schedule was the same as in the gastric and colorectal cancer cohorts, with primary endpoints of ORR and safety. Secondary endpoints included the combined DCR, DOR, PFS and OS.

The median time from first dose to data cutoff was 9.5 months (range, 3.1-11.9), with 16 patients remaining on treatment at data cutoff. There were 3 (10%) PRs and 18 (58%) SDs. ORR was 10% (95% CI, 2-26), and DCR was 68% (95% CI, 49-83). Median DOR was 5.3 months (range, 2.1+ to 6.2). Median PFS was 6.1 months (95% CI, 2.1-6.4) and median OS was 8.6 months (95% CI, 5.6 to NR).

In terms of safety, 30 patients (97%) experienced treatment-related AEs, 15 (48%) of whom had grade 3-4 AEs. In a presentation on the findings, lead author Luis Villanueva, MD, noted that the most frequent treatment-related AEs included hypertension (42%), dysphonia (39%), diarrhea (32%), fatigue (32%), and nausea (32%).

“Fourteen patients (45%) experienced immune-mediated AEs, including hypothyroidism (n=11, 36%), hyperthyroidism (n=2, 6%), and hepatitis (n=2, 6%).” One patient (3%) had an infusion-related reaction, and two patients (6%) discontinued treatment due to treatment-related AEs of myocarditis and pyrexia (n = 1 each). There were no treatment-related deaths.

Based on these findings, Villanueva concluded, enrollment in the biliary tract cancer cohort has been expanded to 100 patients.

1. Chung HC, Lwin Z, Gomez-Roca C, et al. LEAP-005: A phase II multicohort study of lenvatinib plus pembrolizumab in patients with previously treated selected solid tumors: Results from the gastric cancer cohort. Presented at: 2021 ASCO Gastrointestinal Cancers Symposium. Abstract 230.

2. Gomez-Roca C, Yanez E, Im S, et al. LEAP-005: A phase II multicohort study of lenvatinib plus pembrolizumab in patients with previously treated selected solid tumors—Results from the colorectal cancer cohort. Presented at: 2021 ASCO Gastrointestinal Cancers Symposium. Abstract 94.

3. Villanueva L, Lwin Z, Chung HC, et al. Lenvatinib plus pembrolizumab for patients with previously treated biliary tract cancers in the multicohort phase II LEAP-005 study. Presented at: 2021 ASCO Gastrointestinal Cancers Symposium. Abstract 321.

In multiple gastrointestinal tumor types, the combination of the anti-angiogenic multikinase inhibitor lenvatinib plus the anti-PD-1 antibody pembrolizumab demonstrated promising antitumor activity and a manageable safety profile, according to data presented at the 2021 ASCO Gastrointestinal Cancers Symposium. 

Lenvatinib/Pembrolizumab Deemed Safe and Effective in Select GI Cancers

Higher doses of telomerase inhibitor imetelstat demonstrated better overall survival, spleen response, and symptom response in patients with myelofibrosis (MF) who are relapsed after or refractory to (R/R) therapy with Janus kinase (JAK) inhibitors in the phase 2 IMbark study (MYF2001; NCT02426086), according to findings presented at the 2020 American Society of Hematology Annual Meeting.

The randomized, single-blinded study evaluated the efficacy of 2 doses of intravenous imetelstat: 4.7 mg/kg compared to 9.4 mg/kg, both every 3 weeks, and found dose-related clinical benefits in symptom response and improvement in overall survival (OS) in the higher-dose arm.

“No matter what clinical benefit one looks at, whether it's survival, symptom response, spleen response, progression free survival, clinical improvement, transfusion independence, reduction in bone marrow fibrosis, or reduction in the fraction of driving mutations, there was superiority at the high dose or the active arm of this treatment with imetelstat in this very advanced JAK inhibitor-failure patient population,” said John Mascarenhas, MD, associate professor of medicine at the Icahn School of Medicine at Mount Sinai, in a presentation on the study at ASH.

The dose-related improvement in OS in the higher dose arm was further supported by analyses of IMbark with closely matched real world controls (Kuykendall et al EHA 2019 # PS1456).

The intent-to-treat (ITT) analysis Mascarenhas presented at ASH specifically evaluated the association between overall survival and spleen response, symptom response, and fibrosis improvement, and set out to explore the prognostic pretreatment baseline characteristic factors on survival.

The co-primary endpoints of spleen response and symptom response rates were measured by spleen volume reduction (SVR) of 35% or more and a total symptom score (TSS) reduction of 50% or more at Week 24, respectively. OS was a key secondary endpoint, and analysis of OS was performed based on a database lock in April 2020, and the median follow-up was 41.7 months (range 0.2, 49.2). Bone marrow fibrosis was assessed by central pathologist.

All 107 enrolled patients (59 in 9.4 mg/kg arm, n=48 in 4.7 mg/kg arm) were included in the ITT analysis.

As of February 2020, median OS was 28.1 months in the 9.4 mg/kg arm (95% CI 22.8-31.6) and 19.9 months in the 4.7 mg/kg arm (95% CI 17.1-33.9). Similar results were observed when sensitivity analyses accounted for confounding factors of subsequent therapies, including stem cell transplantation and dose escalation from 4.7 mg/kg to 9.4 mg/kg. At 24 months, 57.9% of patients were alive in the high-dose arm, compared to 42% in the low-dose arm.

Lower risk of death was also found to significantly correlate with improved bone marrow fibrosis in the high-dose arm, according to Mascarenhas. “Bone marrow fibrosis reduction of at least one grade was associated with the hazard ratio of .37 for death, suggesting a reduction in risk of death and improvement in survival for patients who had an associated survival in patients who had an associated improvement in bone marrow fibrosis, and this also trended for patients who had stability in bone marrow fibrosis over the treatment period.”

Patients who achieved symptom response also exhibited a trend of longer OS compared to patients who did not achieve symptom response or who had no assessment (HR=0.79, 95% CI 0.41-1.51). Thirty-two percent of patients in the high-dose arm had a total symptom score reduction of 50% or more, compared to 6.3% in the low-dose arm.

A similar trend was seen for patients who achieved spleen response at Week 24 (HR=0.46, 95% CI 0.11-1.92). “If you look at patients who had even a 10% or greater reduction in spleen volume with imetelstat treatment at the 9.4 milligram per kilogram arm, half the patients attained this, versus 19% in the low dose arm,” Mascarenhas said.

Of the 57 patients with available bone marrow data, 19 (33%) had ≥1 degree of bone marrow fibrosis improvement, and saw significantly longer OS than those who had worsening bone marrow fibrosis (HR=0.36, 95% CI 0.13-0.96 p=0.04.

Irrespective of treatment dose, Mascarenhas and his colleagues identified several baseline disease characteristic factors as prognostic for survival. Pretreatment DIPSS high risk, ECOG performance status, transfusion dependency, higher baseline neutrophils, lower baseline Hb and platelet values all correlated with an increased risk of death according to the researchers.

“Myelofibrosis is a serious and life-threatening myeloproliferative neoplasm. Patients who are relapsed after or refractory to JAK inhibitor therapy have a dismal overall survival that ranges between 13 and 16 months,” Mascarenhas explained.

These data, however, show dose-related improvement in OS in this patient population, highlighting the need for further clinical studies, which Mascarenhas hinted at with a look at the upcoming phase three IMpact study (IMpactMF, NCT04576156) which is expected to be open for screening and enrollment in the first quarter of 2021.

Wang M, Rossi JM, Munoz J, et al. Favorable Overall Survival with Imetelstat Treatment Correlates with Other Clinical Benefits in Intermediate 2 or High-Risk Myelofibrosis Relapsed/Refractory to Janus Kinase Inhibitor. Presented at: 2020 ASH Annual Meeting and Exposition. Abstract 53.

Higher doses of telomerase inhibitor imetelstat demonstrated better overall survival, spleen response, and symptom response in patients with myelofibrosis who are relapsed after or refractory to therapy with Janus kinase inhibitors in the phase 2 IMbark study.

Overall Survival in High-Risk Myelofibrosis Improved With High-Dose Imetelstat

Patients with hormone receptor (HR)-positive, HER2-negative breast cancer experienced significant benefit when treated with neoadjuvant chemotherapy (NACT) with intense dose-dense epirubicin (Ellence), paclitaxel (Taxol), and cyclophosphamide (Cytoxan) (iddEPC), according to a secondary end point review, presented during the 

As well as comparing iddEPC to weekly paclitaxel and liposomal doxorubicin (PM) in patients with high-risk early breast cancer, the GeparOcto trial (NCT02125344) examined the addition of carboplatin in patients with triple negative breast cancer (TNBC).

In an earlier readout, the primary end point of pathological complete response was found to be comparable in all groups, including TNBC and high-risk early breast cancer subgroups (pCR; ypT0/is ypN0).

In the review presented at ESMO, researchers reported on the secondary end points of invasive disease-free survival (iDFS) and overall survival (OS).

To achieve these findings, a total of 961 patients were first stratified by breast cancer subtype:

HR+/HER2- versus HER2-/HR- versus HER2+/HR+/-

Ki67 at baseline (less than or equal to 20% versus greater than 20%), and

lymphocyte-predominant breast cancer (LPBC)

Patients were then separated into two groups and received either nine cycles of intensified dose dense epirubicin (150 mg/m2) followed by paclitaxel (225 mg/m2) followed by cyclophosphamide (2000 mg/m2), every two weeks, or weekly paclitaxel (80 mg/m2) plus liposomal doxorubicin (20 mg/m2) for 18 weeks.

Patients with TNBC also received carboplatin (AUC 1.5) weekly.

In both treatment arms, patients with HER2+ breast cancer additionally received trastuzumab (Herceptin) (6 [loading dose 8]mg/kg every two weeks) and pertuzumab (420 [840]mg every three weeks) concurrently with each paclitaxel and carboplatin cycle.

Adjuvant locoregional and endocrine therapy were administered according to German national guidelines.

Between December 2014 and June 2016, a total of 945 patients started receiving treatment (iddEPC, n=470; PM(Cb), n=475).

Investigators planned to evaluate both secondary end points as time-to-event end points, with iDFS to be performed at 169 events to detect a hazard ratio (HR) of 0.65 with 80% power. However, due to the COVID-19 pandemic, follow-up analysis was performed at 162 events, to detect the HR of 0.65, with only 2% less power than initially planned, according to lead author Andreas Schneeweiss, MD.

After a median follow-up of 47 months, 162 iDFS events were reported, the majority of which were distant relapses (47 in the iddEPC versus 51 in the PM(Cb) arm) and invasive locoregional relapses (18 versus 24).

Additionally, 79 deaths were reported (41 in the iddEPC arm and 38 in the PM(Cb) arm).

Overall, investigators found no difference in iDFS (HR PM(Cb) to iddEPC, 1.16; 95% CI, 0.85-1.59; 

=.3357) or OS (HR, 0.90; 95% CI, 0.58-1.40; 

=.6371) between both arms. Four-year iDFS was 81.9% following iddEPC versus 79.7% in PM(Cb), while OS after 4 years was 90.6% and 90.3% respectively.

In the subgroup of HR+/HER2- breast cancer, iDFS was significantly longer for iddEPC (4-year iDFS 62.5% with PM vs.77.9% with iddEPC; HR, 2.11; 95% CI, 1.08-4.10; 

 =0.0284), which indicated a benefit in OS (4-year OS 80.1% vs. 94.7%; HR, 3.26; 95% CI, 1.06-10.00; 

There was no significant difference in survival in HER2+ or TNBC.

In an exploratory analysis, researchers found that in patients with a higher likelihood of relapse following neoadjuvant chemotherapy based on their CPS-EG score, those with HR+/HER2- breast cancer were 3.5 times more likely to experience an iDFS event following weekly PM(Cb) compared to those who received iddEPC.

Despite the lack of evidence of improved survival following NACT with iddEPC or PM(Cb) in any group, patients with HR+/HER2- breast cancer had a better iDFS with treatment with iddEPC, which Schneeweiss said supports the idea that neoadjuvant chemotherapy could have an additional effect in patients with luminal-like, HER2-negative breast cancer. These benefits could be possibly due to the inclusion of cytotoxic agent cyclophosphamide.

“Cyclophosphamide might play an important role in adjuvant treatment of patients with high risk, HR+/HER2- breast cancer, maybe due to an immunogenic long-term effect, not indicated by pCR and CPS-EG score,” said Schneeweiss.

Schneeweiss A, Möbus V, Tesch H, et al. Survival analysis of the randomized phase III GeparOcto trial comparing neoadjuvant chemotherapy (NACT) of iddEPC versus weekly paclitaxel, liposomal doxorubicin (plus carboplatin in triple-negative breast cancer, TNBC) (PM(Cb)) for patients (pts) with high-risk early breast cancer (BC). Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract 160O.

Patients with HR-positive, HER2-negative breast cancer experienced significant benefit when treated with neoadjuvant chemotherapy with intense dose-dense epirubicin, paclitaxel, and cyclophosphamide.

Jessica Skarzynski | Authors

Articles

Apatinib/Chemotherapy Demonstrates Encouraging Efficacy, Tolerability in Advanced SCLC

Lenvatinib/Pembrolizumab Deemed Safe and Effective in Select GI Cancers

Overall Survival in High-Risk Myelofibrosis Improved With High-Dose Imetelstat

Significant Benefit Observed in HR+/HER2- Breast Cancer With Dose-Dense iddEPC