The addition of pembrolizumab (Keytruda) to lenvatinib (Lenvima) did not significantly improve overall survival (OS) or progression-free survival (PFS) over lenvatinib alone when used in the frontline treatment of patients with unresectable hepatocellular carcinoma (HCC), missing the dual primary end points of the phase 3 LEAP-002 trial (NCT03713593).

Although a trend toward improved survival was observed with the doublet over the monotherapy, they did not reach statistical significance per the prespecified statistical plan. Notably, the median OS in the control arm was noted to be longer than what had previously been observed with single-agent lenvatinib in this disease.

Moreover, the toxicity profile observed with the doublet proved to be consistent with what has previously been reported with the regimen.

Additional data from LEAP-002 are anticipated to be shared at an upcoming medical meeting.

“Our joint clinical development program for [pembrolizumab] plus [lenvatinib] is designed to address unmet needs for some of the most challenging-to-treat types of cancer, like HCC,” Gregory Lubiniecki, MD, vice president of Global Clinical Development at Merck Research Laboratories, stated in a press release. “We remain confident in the potential of this combination based on the body of evidence we have seen to date and will continue to investigate its role across multiple types of cancer.”

The multicenter, double-blinded, active-controlled, phase 3 trial enrolled patients who were at least 18 years of age and who had a diagnosis of HCC confirmed by radiology, histology, or cytology.

 Patients were required to have Barcelona Clinic Liver Cancer (BCLC) stage C disease, or BCLC stage B disease that was not amenable to or refractory to locoregional therapy.

Patients also needed to have a Child-Pugh class A liver score, at least 1 measurable lesion per RECIST v1.1 criteria and confirmed by blinded independent central review (BICR), an ECOG performance status of 0 or 1, and a predicted life expectancy that was longer than 3 months.

A total of 794 patients were randomized 1:1 to receive intravenous (IV) pembrolizumab at 200 mg on day 1 of each 3-week cycle in combination with oral lenvatinib at 12 mg once daily in those who weighed at least 60 kg, or oral lenvatinib at 8 mg once daily in those who weighed less than 60 kg; or lenvatinib alone at either of these doses based on weight.

Treatment was continued until disease progression, intolerable toxicity, or up to 35 cycles.

The dual primary end points of the trial were PFS per BICR assessment and RECIST v1.1 criteria, and OS. Key secondary end points comprised objective response rate per BICR assessment and RECIST v1.1 criteria and duration of response.

In August 2018, the FDA approved lenvatinib monotherapy for the first-line treatment of patients with unresectable HCC based on data from the phase 3 REFLECT trial (NCT01761266), which showed that lenvatinib was noninferior but not statistically superior to sorafenib (Nexavar) in terms of OS.

 The median OS with lenvatinib was 13.6 months vs 12.3 months with sorafenib in this patient population (HR, 0.92; 95% CI, 0.79-1.06). However, lenvatinib was found to significantly improve PFS over sorafenib, at a median of 7.3 months vs 3.6 months, respectively (HR, 0.64; 95% CI, 0.55-0.75).

Single-agent lenvatinib has also been approved for the frontline treatment of patients with unresectable HCC in Europe and China, as well as for those with unresectable HCC in Japan.

Merck and Eisai provide update on phase 3 LEAP-002 trial evaluating Keytruda (pembrolizumab) plus Lenvima (lenvatinib) versus Lenvima monotherapy in patients with unresectable hepatocellular carcinoma. News release. Merck. August 3, 2022. Accessed August 3, 2022. 

Safety and efficacy of lenvatinib (E7080/MK-7902) in combination with pembrolizumab (MK-3475) versus lenvatinib as first-line therapy in participants with advanced hepatocellular carcinoma (MK-7902-002/E7080-G000-311/LEAP-002). ClinicalTrials.gov. Updated July 27, 2022. Accessed August 3, 2022. 

https://clinicaltrials.gov/ct2/show/NCT03713593

FDA approves lenvatinib for unresectable hepatocellular carcinoma. News release. FDA. August 16, 2018. Accessed August 3, 2022. 

Articles

The addition of pembrolizumab to lenvatinib did not significantly improve overall survival or progression-free survival over lenvatinib alone when used in the frontline treatment of patients with unresectable hepatocellular carcinoma, missing the dual primary end points of the phase 3 LEAP-002 trial.

Pembrolizumab/Lenvatinib Combo Misses Survival End Points in Unresectable HCC

PD-L1 and tumor mutational burden (TMB) are established biomarkers for driving immunotherapy treatment decisions in patients with non–small cell lung cancer (NSCLC). However, their use may not be appropriate in determining therapies for all patients, according to David R. Gandara, MD, who added that emerging genetic tests seek to expand on how biomarkers are utilized in the NSCLC space.

“[PD-L1 and TMB] are both good biomarkers for immunotherapy, but they’re incomplete. They only tell a part of the story,” Gandara said.

 (ILCC), Gandara addressed two new genetic tests, the Lung Cancer Master Protocol and DetermaIO, and explained how they could eventually alter how immunotherapy treatment decisions are made in clinical practice.

, Gandara, the chief medical officer of the International Society of Liquid Biopsy, the co-director of the Center for Experimental Therapeutics in Cancer, a senior advisor to the director at UC Davis Comprehensive Cancer Center, and an adjunct clinical professor of the Translational and Clinical Research Program at the University of Hawaii Cancer Center, discussed how the Lung Cancer Master Protocol and DetermaIO could expand the use of biomarkers in NSCLC to better determine which patients would benefit most from immunotherapy.

: How could new biomarkers affect immunotherapy decisions in NSCLC, and how could they supplement what is known about PD-L1 and TMB?

: My presentation at this meeting [focused] on new predictive biomarkers for checkpoint immunotherapy in NSCLC. This is a topic of considerable interest. We do two have biomarkers that are FDA approved [as a biomarker for administering treatment] in different situations. One is immunohistochemistry for PD-L1, which is tied to many drug regimens, and the second is TMB. [However], there’s controversy about how important they are and when they should be used.

Interestingly, they are largely not overlapping. They’re independent biomarkers. Both of these markers measure the inflammatory component of the immune microenvironment. And the newer [genetic] tests—I’ll talk about two of these—also add in negative signals. In other words, what makes a tumor cold instead of hot? What makes it less likely to respond to checkpoint immunotherapy?

Could you elaborate on the first new genetic test, the Lung Cancer Master Protocol?

The first of these is a composite gene signature that we have worked on with our Lung-Map group [called] the Lung Cancer Master Protocol. [It was developed] together with Foundation Medicine, who is our partner for doing the genomics for that large project. This signature is an add-on to both PD-L1 and TMB, and it [comprises] several other genes that represent either inflammatory or cold signatures.

We have just finished what we would call a test set, where we used specimens from the Lung Cancer Master Protocol, and then most recently, [we completed] a validation set on a separate large phase 3 trial, where we have perfected this composite gene signature. This is now being submitted to another meeting for full presentation, but I previewed it [at ILCC]. It seems to be quite effective in improving the predictive signature of the other biomarkers we already have.

What is unique about the second new genetic test, DetermaIO?

The second test is called the DetermaIO, and it uses this same theme of the tumor microenvironment to develop a signature. Only in this case, it’s a 27-gene signature. This signature was developed initially for triple-negative breast cancer, where the data are already presented. What I talked about at ILCC are the initial data in NSCLC, where this signature is superior to both PD-L1 and TMB in predicting progression-free survival and overall survival. And it is now entering large, randomized trials.

These are just two examples of many different efforts that are ongoing to improve our ability to determine [which patients] benefit from checkpoint immunotherapy, whether it’s given by itself or together with chemotherapy.

How could these tests eventually affect clinical practice?

What we’re using today to assess how patients benefit from immunotherapy and what we do in day-to-day practice is going to change. We’re not necessarily going to discard other biomarkers, such as PD-L1 or TMB. But we’re going to add to them so that we’re better able to select what the best approach is [for one patient vs the next].

As one of the co-chairs of the 2022 ILCC, what is the importance this meeting?

ILCC is quite different from most other thoracic malignancy meetings. It’s what I would call a think tank in that it has a group of lung cancer experts and a sophisticated audience, so we can discuss [clinical] controversies. This meeting is known for having panel discussions and audience response devices so that we can gauge, before and after a session, how much everybody has learned from each other.

There are many case-based panels, where we put these concepts [into practice]. We present a case and then ask, [for example], ‘What tests would you order?’ And then based on these tests, ‘What treatment would you deliver?’ It’s a one-of-a-kind meeting in thoracic malignancies.

PD-L1 and tumor mutational burden are established biomarkers for leveraging immunotherapy in non–small cell lung cancer; however, their use may not be appropriate in determining treatment decisions for all patients.

Novel Biomarker Testing Could Enhance Immunotherapy Treatment Decisions in NSCLC

The FDA has deferred action on the biologics license application (BLA) seeking the approval of tislelizumab (BGB-A317) as a second-line treatment in patients with unresectable or metastatic esophageal squamous cell carcinoma (ESCC), citing the inability to conduct required inspections in China because of travel restrictions associated with COVID-19.

Action on the application will be deferred until those inspections are completed, according to a press release issued by BeiGene. Although a new anticipated action date has not been announced, the BLA remains under review.

 in September 2021, and had a decision date of July 12, 2022, under the Prescription Drug User Fee Act. The application was supported by data yielded from the phase 3 RATIONALE-302 trial (NCT03430843), which showed that treatment with tislelizumab (n = 256) resulted in a 30% reduction in the risk of death vs chemotherapy (n = 256) in this patient population (HR, 0.70; 95% CI, 0.57-0.85; 

The median overall survival (OS) with tislelizumab was 8.6 months (95% CI, 7.5-10.4) vs 6.3 months (95% CI, 5.3-7.0) with chemotherapy.

“We are working with our partner, Novartis, to facilitate the required inspections and bring tislelizumab to patients with second-line esophageal cancer in the United States following regulatory approval,” John V. Oyler, co-founder, chairman, and chief executive officer of BeiGene, stated in a press release.

The open-label, randomized, multicenter, phase 3 trial enrolled patients with histologically confirmed ESCC who had advanced or metastatic disease and who had experienced disease progression within 6 months of definitive chemoradiation, neoadjuvant, or adjuvant treatment.

To be eligible for enrollment, patients were required to be at least 18 years of age, have an ECOG performance status of 0 or 1, at least 1 measurable lesion per RECIST v1.1 criteria, and acceptable hematologic, renal, and coagulation function.

Patients could not have previously received PD-1/PD-L1 therapies, nor could they have active brain or leptomeningeal metastasis, active autoimmune disease, or other previous malignancies within 2 years before randomization on the trial.

Study participants were randomized 1:1 to receive intravenous (IV) tislelizumab at 200 mg once every 3 weeks or investigator’s choice of single-agent paclitaxel, docetaxel, or irinotecan. Specifically, IV paclitaxel was given once every 3 weeks at doses ranging from 135 mg/m2 to 175 mg/m2 or at once-weekly doses ranging from 80 mg/m2 to 100 mg/m2. Docetaxel was administered at 75 mg/m2 once every 3 weeks, and irinotecan was given at 125 mg/m2 on days 1 and 8, every 21 days.

Treatment was administered until progressive disease, intolerable toxicity, or withdrawal for other reasons. Patients were permitted to continue to receive tislelizumab after disease progression per investigator discretion.

Key stratification factors included region (Asia [excluding Japan] vs Japan vs Europe/North America), performance status (0 vs 1), and selected chemotherapy (paclitaxel vs docetaxel vs irinotecan).

The primary end point of the trial was OS in the intention-to-treat population, and a key secondary end point was OS in the subset of patients with a PD-L1 TAP of 10% or higher. Other secondary end points included PFS, ORR, and DOR per investigator assessment and RECIST v1.1 criteria in both populations, as well as safety and tolerability.

Across the treatment arms, the median age of patients was 62.5 years (range, 35-86), with most patients under the age of 65 years. The majority of patients in the investigative and control arms, respectively, were male (84.8% vs 84.0%), Asian (78.5% vs 80.9%), from Asia (78.5% vs 79.3%), had an ECOG performance status of 1 (74.2% vs 76.6%), former or current smokers (73.4% vs 75.0%), had metastatic disease at study entry (98.0% vs 92.2%), and received prior radiotherapy (66.0% vs 63.7%) or platinum-based chemotherapy (97.3% vs 98.4%).

 showed that the 12-month OS rate achieved with tislelizumab was 37.4% (95% CI, 31.4%-43.4%) vs 23.7% (95% CI, 18.5%-29.3%) with chemotherapy.

In patients with a PD-L1 tumor area positivity (TAP) of 10% or higher, tislelizumab (n = 89) was found to significantly improve OS over chemotherapy (n = 68), with a median OS of 10.3 months (95% CI, 8.5-16.1) and 6.8 months (95% CI, 4.1-8.3), respectively (HR, 0.54; 95% CI, 0.36-0.79; 

 = .0006). Tislelizumab (n = 116) also provided survival benefits over chemotherapy (n = 140) in those with a PD-L1 TAP of less than 10% (HR, 0.82; 95% CI, 0.62-1.09).

The median PFS in the tislelizumab and chemotherapy arms was 1.6 months (95% CI, 1.4-2.7) and 2.1 months (95% CI, 1.5-2.7), respectively (HR, 0.83; 95% CI, 0.67-1.01), although PFS Kaplan-Meier curves began to separate at about 3 months in favor of the immunotherapy. The estimated 6-month PFS rates in the investigative and control arms are 21.7% and 14.7%, respectively; the estimated 12-month rates are 12.7% and 1.9%, respectively.

Moreover, tislelizumab elicited an ORR of 20.3% (95% CI, 15.6%-25.8%) vs 9.8% (95% CI, 6.4%-14.1%) with chemotherapy (odds ratio, 2.39; 95% CI, 1.42-4.01). Of those who responded to treatment in the immunotherapy arm, 2.0% achieved a complete response, 18.4% experienced a partial response, and 26.6% had stable disease. Just under half, or 45.3%, had progressive disease. The median DOR with tislelizumab was 7.1 months (95% CI, 4.1-11.3) vs 4.0 months (95% CI, 2.1-8.2) with chemotherapy.

Fewer patients who received the immunotherapy reported treatment-related adverse effects (TRAEs) than those who were given chemotherapy, at 73.3% and 93.8%, respectively. The TRAEs that were most frequently experienced with tislelizumab were increased aspartate aminotransferase (11.4%), anemia (11.0%), and hypothyroidism (10.2%).

Fewer grade 3 or higher TRAEs were reported with tislelizumab vs chemotherapy, at 18.8% and 55.8%, respectively. Serious TRAEs were experienced by 14.1% of those who received tislelizumab vs 19.6% of those given chemotherapy. Moreover, 6.7% vs 13.8% of patients in the investigative and control arms, respectively, discontinued treatment.

BeiGene provides regulatory update on the US biologics license application (BLA) for PD-1 inhibitor tislelizumab in 2L ESCC. News release. BeiGene. July 14, 2022. Accessed July 14, 2022. 

BeiGene announces US FDA acceptance of biologics license application for tislelizumab in esophageal squamous cell carcinoma. News release. BeiGene, Ltd. September 13, 2021. Accessed July 14, 2022. 

Shen Li, KatoK, Kim S-B, et al. Tislelizumab versus chemotherapy as second-line treatment for advanced or metastatic esophageal squamous cell carcinoma (RATIONALE-302): a randomized phase III study. 

. Published online April 20, 2022. doi:10.1200/JCO.21.01926

The FDA has deferred action on the biologics license application seeking the approval of tislelizumab as a second-line treatment in patients with unresectable or metastatic esophageal squamous cell carcinoma, citing the inability to conduct required inspections in China because of travel restrictions associated with COVID-19.

IO - Immuno-Oncology - July 2022 Issue | Special Issues

Pembrolizumab/Lenvatinib Combo Misses Survival End Points in Unresectable HCC

Novel Biomarker Testing Could Enhance Immunotherapy Treatment Decisions in NSCLC

FDA Defers Action on BLA for Tislelizumab in Second-Line Esophageal Squamous Cell Carcinoma