Ryan McDonald

Findings from the phase 3 CLEAR trial (NCT02811861) showed that the addition of lenvatinib (Lenvima) to either pembrolizumab (Keytruda) or everolimus (Afinitor) led to an improvement in survival and response rates in comparison with sunitinib (Sutent) monotherapy in the first-line setting for patients with advanced renal cell carcinoma (RCC).

The results from the trial were presented during the 2021 Genitourinary Cancers Symposium and simultaneously published in 

Previously, single-agent lenvatinib and pembrolizumab have been shown to be effective in treating RCC. The combination of lenvatinib and everolimus has also been shown to induce longer PFS than single-agent everolimus as a second-line treatment option. And, as Robert J. Motzer, MD, noted, results of a recent phase 1b/2 study of lenvatinib plus pembrolizumab showed anti-tumor activity in previously treated patients with RCC.

As a result, researchers aimed to assess the safety and efficacy of lenvatinib plus pembrolizumab, as well as lenvatinib plus everolimus, versus sunitinib alone in the first-line treatment of advanced RCC.

Motzer, the Kidney Cancer Section Head, Genitourinary Oncology Service; and Jack and Dorothy Byrne Chair in Clinical Oncology at Memorial Sloan Kettering Cancer Center, presented the results of the multi-center, open-label trial during the meeting.

Patients were eligible to enroll onto the trial if they were treatment-naïve, had adequate organ function, measurable disease and presented with advanced clear-cell RCC. Patients were then stratified into 2 geographic regions — Western Europe and North America vs. rest of the world — and stratified by favorable, intermediate or poor disease risk.

The trial comprised 1069 patients who were then randomized in a 1:1:1 fashion to receive lenvatinib 20 mg oral QD plus pembrolizumab 200 mg IV Q3W (n = 355), lenvatinib 18 mg oral QD plus everolimus 5 mg oral QD (n = 357), or sunitinib 50 mg oral QD for 4 weeks on and 2 weeks off (n = 357).

PFS by IRC per RECIST v1.1 was the primary endpoint, and secondary endpoints included OS, ORR by IRC per RECIST v1.1, safety and health-related quality of life (HRQoL).

The median PFS with lenvatinib and pembrolizumab was 23.9 months (95% CI, 20.8-27.7) compared to 9.2 months (95% CI, 6-11) with single-agent sunitinib (HR, 0.39; 95% CI, 0.32-0.49; 

 < .001). The lenvatinib plus everolimus treatment arm achieved a median PFS of 14.7 months (95% CI, 11.1-16.7) compared to the 9.2 months in the sunitinib arm (HR, 0.65; 95% CI, 0.53-0.8; 

The PFS benefit extended across all patient subgroups in both the lenvatinib and pembrolizumab and lenvatinib and everolimus treatment arms.

A median OS was not reached in any of the three treatment arms; however, the data indicated the endpoint was significantly longer in the lenvatinib and pembrolizumab arm compared to the sunitinib arm (HR, 0.66; 95% CI, 0.49-0.88; 

 = .005). Motzer noted that there was no observed OS benefit in the lenvatinib and everolimus treatment arm over sunitinib alone (HR, 1.15; 95% CI, 0.88-1.5; 

ORR was higher in both the lenvatinib plus pembrolizumab (71%; 95% CI, 66.3-75.7) and lenvatinib plus everolimus (53.5%; 95% CI, 48.3-58.7) treatment arms compared to sunitinib (36.1%; 95% CI, 31.2-41.1). Of note, Motzer mentioned the “high complete response rate” of 16.1% in the lenvatinib plus pembrolizumab arm.

Patients in the lenvatinib plus pembrolizumab arm achieved the longest median DOR at 25.8 months (95% CI, 22.1-27.9), compared to 16.6 months (95% CI, 14.6-20.6) in the lenvatinib plus everolimus arm and 14.6 months (95% CI, 9.4-16.7) in the sunitinib arm.

Nearly all patients in each treatment arm – lenvatinib plus pembrolizumab (96.9%), lenvatinib plus everolimus (97.7%) and sunitinib (92.1%) – experienced any treatment-related adverse event (TRAE). Patients in the lenvatinib plus pembrolizumab (67.3%) and lenvatinib plus everolimus (69.3%) treatment arms were more likely than the sunitinib arm (49.7%) to experience TRAEs that led to dose reductions. Of note, Motzer highlighted that the number of patients needing to have lenvatinib discontinued in either treatment arm was 18.5% and 16.1%, respectively. Moreover, the discontinuation rate of both drugs in the lenvatinib plus pembrolizumab arm was 9.7%.

Motzer noted the safety profiles of both combinations were consistent with each drugs’ known safety profile and were manageable as needed for dose modifications.

“These results support lenvatinib plus pembrolizumab as a potential first-line treatment for patients with advanced RCC,” he concluded.

Motzer RJ, Porta C, Eto M, et al. Phase 3 trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) or everolimus (EVE) versus sunitinib (SUN) monotherapy as a first-line treatment for patients (pts) with advanced renal cell carcinoma (RCC) (CLEAR study). 

. 2021; 39(suppl6):269. doi: 10.1200/JCO.2021.39.6_suppl.269.

Motzer RJ, Alekseev B, Rha S.-Y., et al. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. Published online February 13, 2021. 

Articles

Findings from the phase 3 CLEAR trial showed that the addition of lenvatinib to either pembrolizumab or everolimus led to an improvement in survival and response rates in comparison with sunitinib monotherapy in the first-line setting for patients with advanced renal cell carcinoma.

Two Lenvatinib Combos Induce Survival Benefit Over Sunitinib in Advanced RCC

In patients with relapsed/refractory small cell lung cancer (SCLC) who did not receive previous checkpoint inhibitor therapy, the addition of the anti–fucosyl-GM1 monoclonal antibody, BMS-986012 to nivolumab (Opdivo) demonstrated promising results, a presented at the 2020 World Conference on Lung Cancer on updated phase 1/2 data show.

Moreover, the combination induced a greater response to therapy than nivolumab alone.

“This shows the response rate in 11 out of 29 patients, or 38%, had a full RECIST response,” Neal Ready, MD, PhD, a medical oncologist at Duke Cancer Institute, said during a pre-recorded presentation of the data. “This compares favorably with the historical response rate of 12% reported for nivolumab monotherapy in a similar setting.”

This first-in-human, dose-escalation and expansion trial enrolled a total of 29 patients (median age, 65 years; range, 46-79) with relapsed/refractory SCLC. More than half (52%) of the study population were men, all participants were White and a significant number of participants (76%) were current or former smokers. To be enrolled, each patient had to have received at least 1 prior platinum-based treatment; however, no previous treatment with immunotherapy was permitted.

In the first part of the trial, patients received 360 mg nivolumab IV every 3 weeks with either 400 mg BMS-986012 every 3 weeks (n = 8) or 1000 mg BMS-986012 (n = 8). The dose-escalation study determined that the combination with 400 mg BMS-986012 was the ideal dose and an additional 13 patients were enrolled. The safety of the drug combination was the primary end point of the study. Additional key end points included response rate (RR), duration of response (DOR) and progression-free survival (PFS).

“We saw the typical immune-related toxicity of nivolumab with some additional toxicity related to the anti–fucosyl-GM1 antibody,” said Ready. “They were primarily dermatologic with pruritis being the most prominent side effect. The pruritis typically started while the drug was being infused, was typically grade 1 or grade 2, and often improved over time.”

Other any grade adverse events (AEs) related to treatment included dry skin (28%), fatigue (28%), and hypothyroidism (17%). Two patients from the 400 mg arm and 3 patients from the 1000 mg arm discontinued receiving the combination because of toxicities.

Grade 3-4 treatment-related AEs included 1 case each of diarrhea, pancreatitis, increased lipase levels, dehydration, and hepatic failure.

Of note, Ready said, a patient treated at Duke received 56 cycles of combination therapy over a 38-month period.

At cutoff, Ready also noted, there was an impressive median DOR of 26.4 months (95% CI, 4.4 months-not reached [NR]). In fact, 4 patients remained on study therapy at data cutoff.

The median OS among all patients in the study was 18.7 months (95% CI, 8.2-NR) and the median PFS was 2.1 months (95% CI, 1.4-9.9).

“These results are promising, although in a small sample size,” Ready said. “The aggregate goals of anti–fucosyl-GM1 monoclonal antibody will be studied in an upcoming randomized phase 2 trial in which patients will receive a combination of carboplatin and etoposide and nivolumab, with or without the anti–fucosyl-GM1 monoclonal antibody. Enrollment is planned to start in early 2021.”

Chu Q, Leighl N, Surmont V, et al. Clinical Activity of BMS-986012, an Anti–Fucosyl-GM1 Monoclonal Antibody, Plus Nivolumab in Small Cell Lung Cancer. Presented at: 2020 World Conference on Lung Cancer; January 28-31, 2021; Virtual. Abtract FP03.03.

In patients with relapsed/refractory small cell lung cancer who did not receive previous checkpoint inhibitor therapy, the addition of the anti–fucosyl-GM1 monoclonal antibody, BMS-986012 to nivolumab demonstrated promising results in a phase 1/2 study. 

BMS-986012 Combined With Nivolumab Demonstrates Preliminary Efficacy in Relapsed/Refractory SCLC

The addition of pembrolizumab (Keytruda) and trastuzumab (Herceptin) to the combination cisplatin plus capecitabine was able to effectively treat HER2-positive advanced gastric and gastroesophageal junction (GEJ) cancer, regardless of PD-L1 expression in the phase 1b/2 PANTHERA trial (NCT02901301), according to updated clinical and molecular findings presented during the 2021 ASCO Gastrointestinal Cancers Symposium.

The study results also showed that alterations to the 

 pathway in patients with HER2 amplifications were associated with a statistically significant improved duration of survival in patients.

At a median follow-up of 18.2 months, patients who were administered the triplet therapy regimen (n = 43; median age, 63 years; 76.6% male) achieved a median overall survival (OS) of 19.3% (95% CI, 16.5-NR) and a median progression-free survival (PFS) of 8.6 months (95% CI, 7.2-16.4). The regimen also conferred an overall response rate (ORR) of 76.7% (95% CI, 61.4-88.2) and disease control rate (DCR) of 97.7% (95% CI, 87.7-99.9).

“Clinical parameters including PD-L1 expression were not related to survival,” Sun Young Rha, MD, PhD, a medical oncologist in the Division of Medical Oncology at Yonsei Cancer Center in Seoul, South Korea, said in a recording of the presentation.

As a result, Rha said the researchers decided to evaluate the genomic profiling of patients using targeted next-generation sequencing (NGS).

The phase 1 portion of the trial indicated that the recommended dosing schedule for the phase 2 portion of the trial should be delivered to the patient every 3 weeks with 200 mg of pembrolizumab via IV on day 1, 6 mg/kg of trastuzumab on day 1, 1000 mg/m2 of capecitabine twice a day (BID) on days 1 through 14, and 80 mg/m2 of cisplatin on day 1.

The primary end point of the phase 2 portion of the trial, per RECIST v1.1, was ORR. Additional secondary end points were PFS, OS, duration of response, safety, and predictive biomarker analysis by targeted NGS. At the time of data cutoff (Aug. 31, 2020), 6 patients had completed 2 years of treatment without any disease progression and 3 remained on treatment.

At baseline, more than half of the patients (72.1%) had not received a gastrectomy. Of the organs where the disease progressed to, the most frequent included the lymph nodes (83.7%), liver (48.8%) and peritoneum (25.6%). Using Combined Positive Score (CPS) at baseline to identify PD-L1 protein expression, 39.5% of patients had a CPS of < 1%, 48.8% had a CPS of ≥ 1%, 11.6% had a CPS of ≥ 10% and 11.6% of patients did not undergo a primary tumor PD-L1 status at diagnosis. Using an ImmunoHistoChemistry test, 69.8% of patients had a score of 3+ (indicating a presence of HER2) at baseline and the remaining patients had a score of 2+ (indicating borderline presence of HER2).

More than half of the patients (56.6%) experienced a more than 50% reduction in tumor burden. Patients with HER2 which was amplified (22 months) by NGS had a statistically significant longer median PFS than those without an amplified HER2 (7.7 months) (

=.0275). The same was determined in patients with altered RTK/RAS pathways (median PFS, 13.8 months) vs. patients with wild-type RTK/RAS (4.9 months; 

“In summary first-line triplet regimen pembrolizumab, trastuzumab, and chemotherapy showed promising efficacy based on HER2 amplification by NGS regardless of PD-L1 status in advanced gastric cancer,” concluded Rha. “Correlative biomarkers found from our study need to be validated through ongoing trials.”

Rha SY, Lee C-K, Kim HS, et al. A multi-institutional phase Ib/II trial of first-line triplet regimen (Pembrolizumab, Trastuzumab, Chemotherapy) for HER2-positive advanced gastric and gastroesophageal junction cancer (PANTHERA Trial): Molecular profiling and clinical update. Presented at: 2021 ASCO Gastrointestinal Cancers Symposium; January 15-17, 2021; Virtual. Abstract 218.

The addition of pembrolizumab and trastuzumab to the combination cisplatin plus capecitabine was able to effectively treat HER2-positive advanced gastric and gastroesophageal junction cancer, regardless of PD-L1 expression in the phase 1b/2 PANTHERA trial.

Pembrolizumab/Trastuzumab Regimen Effective in Treating HER2-Positive Advanced Gastric, GEJ Cancer

Patients with radiation-associated breast angiosarcoma may have an effective treatment option with the combination of oral paclitaxel with encequidar (oPac+E), according to study results presented during the 2020 San Antonio Breast Cancer Symposium.

The researchers assessed activity, safety and tolerability of oPac 205 mg/m2 plus E 12.9 mg once daily for 3 consecutive days weekly in patients with unresectable cutaneous angiosarcoma. The primary outcome of the study was tumor response to therapy every 6 weeks.

From August 2018 to May 2020, 7 patients (median age, 66 years; range, 49-76) were diagnosed with breast cutaneous angiosarcoma. All patients had previously been diagnosed with breast cancer and received a mastectomy and radiotherapy and/or adjuvant chemotherapy.

Three patients (43%) achieved a complete response on the combination, and also achieved stable disease (43%). One patient achieved a partial response to therapy. Forty-three percent of patients crossed over to receive curative surgical resection.

The combination was generally well tolerated, with grade 3 treatment-related adverse events (TRAEs) occurring in 5 patients. The most common grade 3 TRAEs included fatigue (2 cases), diarrhea, dyspnea, dehydration, pneumonitis and neutropenia (one case each). Three patients needed dose reductions, however there were no treatment discontinuations as a result of AEs. No patient deaths have been reported to date.

The authors concluded that the combination may be an effective oral treatment for patients with radiation-associated breast angiosarcoma, with limited toxicities, which could offer patients the potential to avoid intravenous chemotherapy at a hospital.

Ravi V, Wagner M, Chen TWW, et al. A phase 2 study of oral paclitaxel and encequidar (oPac+E) in the treatment of cutaneous angiosarcoma: The breast angiosarcoma subgroup. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11; 2020; Virtual. Poster PS13-05.

Patients with radiation-associated breast angiosarcoma may have an effective treatment option with the combination of oral paclitaxel with encequidar.

Ryan McDonald | Authors

Articles

Two Lenvatinib Combos Induce Survival Benefit Over Sunitinib in Advanced RCC

BMS-986012 Combined With Nivolumab Demonstrates Preliminary Efficacy in Relapsed/Refractory SCLC

Pembrolizumab/Trastuzumab Regimen Effective in Treating HER2-Positive Advanced Gastric, GEJ Cancer

Oral Paclitaxel Plus Encequidar Produces Responses as Treatment of Radiation-Associated Breast Angiosarcoma