ISSN 1933-0863 (PRINT)     ISSN 1933-0871 (ONLINE)

Home               Archives               About Us             Submission Guidelines              Editorial Board              Advertising Information               Contact Us

Lenvatinib and Pembrolizumab Combination Demonstrates Clinical
Activity in Metastatic Renal Cell Carcinoma Patients Who Received
Prior Immunotherapy

MIAMI—The combination of lenvatinib and pembrolizumab demonstrates clinical activity with a promising objective response rate (ORR) in metastatic renal cell carcinoma (mRCC) patients who progressed on prior immunotherapy. An interim analysis of the ongoing phase II clinical trial (NCT02501096) was presented by Dr. Chung-Han Lee of Memorial Sloan Kettering Cancer Center.

     A total of 33 mRCC patients who received ≤2 prior systemic therapies, including those who progressed on a prior anti–PD-1/PD-L1 therapy, were included in the analysis. Patients were treated with the combination of the oral multikinase inhibitor lenvatinib 20 mg daily and the intravenous PD-1 inhibitor pembrolizumab 200 mg every 3 weeks. The primary endpoint was ORR by week 24 of treatment. Secondary endpoints included ORR, progression-free survival (PFS), duration of response, and safety and tolerability. A majority of the patients (58%) were previously treated with nivolumab/ ipilimumab (21%) or VEGF-targeted therapy plus PD-1/PD-L1 inhibitor combi-nations. Per IMDC risk criteria, 29%, 55%, and 6% of the patients were in the favorable-, intermediate-, and poor-risk categories, respectively.

     ORR as of week 24 was 61%. The best ORR was partial response in 64% and stable disease in 30% of the population. PFS was 11.3 months (95% CI, 7.3–NE) per investigator assessment using the irRECIST v1.1 definition. From a safety and toxicity standpoint, all patients experienced at least one treatment-related adverse event (TRAE). Grade 3 or 4 TRAEs were seen in 55% of the cohort. Most frequently seen TRAEs were fatigue (49%), diarrhea (39%), dysphonia (36%), stomatitis (33%), and nausea (27%). TRAEs led to the discontinuation of lenvatinib in 21% of patients and pembrolizumab in 18% of patients. One patient died due to potentially treatment-related upper gastrointestinal bleeding.

     Dr Lee highlighted the promising activity of the lenvatinib and pembrolizumab combination in mRCC patients previously treated with immunotherapy. The adverse event profile of the combination was considered manageable. Dr Lee underscored that the clinical trial (NCT02501096) is still recruiting.

 

Updated OS Data on Tivozanib Suggest Potential Role in Refractory Setting, But FDA Still Unconvinced Pending More Results

MIAMI—Updated results from the Phase 3 TIVO-3 trial point toward a potential role for this TKI, but so far the FDA has withheld approval pending additional results on the use of tivozanib. Based on the data emerging from studies of tivozanib, there is speculation that the drug may have a role in patients previously treated with checkpoint inhibitors as well as two VEGFR-TKIs.

     As previously presented, results for the intent to treat (ITT) population showed that tivozanib significantly improved progression free survival (PFS), the study’s primary endpoint, and overall response rate (ORR) compared to sorafenib, with responses to tivozanib more durable than sorafenib. Newly presented data include the recently announced interim overall survival (OS) hazard ratio (HR) of 0.99 within the ITT population, as well as results from two prespecified subgroup analyses of patients previously treated with a checkpoint inhibitor and a VEGF-TKI, or two VEGFR-TKIs. Superior PFS and ORR, as well as OS HRs below 1, favoring tivozanib, were observed in the prespecified subgroups. Tivozanib was shown to have lower overall rates of adverse events and fewer dose interruptions and reductions versus sorafenib, indicating better patient tolerability.

     “Until the TIVO-3 trial results, limited prospective data existed to inform sequencing of treatment after checkpoint inhibitor therapy, the emergent standard of care in earlier-line treatment,” said Sumanta Pal, MD, in his presentation at IKCS. “Tivozanib’s outcomes within this population, as well as in those receiving two prior VEGF-TKIs, suggest an important potential role for tivozanib in the evolving refractory advanced RCC setting. Furthermore, tivozanib’s unique tolerability profile is potentially well suited to an advanced setting, where many are reluctant to accept higher rates of adverse events following multiple courses of therapy.” AVEO plans on completing a final OS analysis of TIVO-3 in June 2020 after a planned submission of a new drug application to the FDA in the first quarter of 2020.

 

Treatment-Free Survival With and Without Toxicity With Nivolumab and
Ipilimumab in Metastatic Renal Cell Carcinoma

MIAMI—Treatment-free survival (TFS) without toxicity, a novel way of describing disease control and toxicity during an off-treatment period, was longer in patients who received nivolumab/ipilimumab in combination versus those who received sunitinib, according to an innovative analysis of the CheckMate 214 dataset. The study was presented by Meredith M. Regan, MD of the Dana-Farber Cancer Institute.

     Dr Regan and colleagues previously defined TFS as the interval between the time point of immune checkpoint inhibitor (ICI) discontinuation and initiation of subsequent systemic treatment (J Clin Oncol. 2019 Sep 9:JCO1900345. doi:10.1200/JCO.19.00345). Development of this novel outcome measure was based on the fact that ICI-treated patients are observed to have continued benefit from treatment or develop treatment-related adverse events (TRAEs) after treatment discontinuation.

 

Incidence of Brain Metastases Is 4.5% in Asymptomatic Metastatic RCC

MIAMI—Asymptomatic brain metastases are encountered in 4.5% of asymptomatic metastatic renal cell carcinoma (mRCC) patients according to a large multi-institutional retrospective analysis of 1597 patients’ data. The study was presented by Dr. Ritesh Kotecha of Memorial Sloan Kettering Cancer Center.

     Through a collaborative effort of scientists from the Institut Gustav Roussy and Memorial Sloan Kettering Cancer Center, investigators analyzed the data of 1597 asymptomatic mRCC patients who were screened for brain metastases for inclusion in 68 clinical trials. A total of 71 patients, representing the 4.5% of the cohort, were found to have brain metastases. Per IMDC criteria, 26%, 61%, and 13% of the cohort were in favorable-, intermediate-, and poor-risk groups, respectively. A majority of the patients were treatment-naïve (32%) or had received one prior line of treatment (43%). A total of 86% of the patients had more than one extracranial metastatic site, and the most common accompanying extracranial metastatic site was lung (92%). Patients with metastatic disease at initial presentation comprised 60% of the patient population. The investigators reported a median overall survival (OS) of 10.3 months (95% CI, 7–17.9 months).

 

Living With Kidney Cancer, New Patient Magazine

The Kidney Cancer Association is launching a patient and caretaker magazine called “Living with Kidney Cancer”.  This complimentary magazine is available for you to have in your offices, waiting rooms, or to give specifically to patients. Sign-up to receive your complimentary magazines here: https://tinyurl.com/LivingWithKidneyCancer

 

William Kaelin’s 2019 Nobel Prize in Physiology Linked to
Kidney Cancer Molecular Mechanisms

William G. Kaelin Jr., MD, has won the 2019 Nobel Prize in Physiology or Medicine with two other physician-scientists for unraveling a molecular mechanism that not only is crucial to survival, but is entwined with cancer and other diseases, especially kidney cancer. Dr Kaelin is the Sidney Farber Professor of Medicine at Harvard Medical School, and an investigator at the Howard Hughes Medical

Institute.

     Dr Kaelin and his collaborators deciphered the core molecular events that explain how almost all multi-cellular animals tune their physiology to cope with varying quantities of life-sustaining oxygen in a unique signaling scheme. Their findings could lead to new therapeutics for a wide range of disorders — including cancer, cardiovascular disease, anemia, and macular degeneration. This oxygen-sensing mechanism involves the tumor-suppressor protein VHL, which is mutated in many kidney cancers, and proteins known as hypoxia inducible factors, HIF-1α and HIF-2α. Kaelin showed that HIF-2α drives certain kidney cancers and recently discovered how HIF-1α is hijacked by triple-negative breast cancers. He is developing therapeutic strategies for targeting these molecules and others implicated in cancer, such as mutated enzymes IDH1 and IDH2, with designer drugs.

 

2019 Top Stories in Oncology? Pembrolizumab Plus Axitinib for
RCC Heads the List

The pembrolizumab plus axitinib study is the renal cell carcinoma top story for 2019, according to Eric Jonasch, MD, a leading investigator on RCC trials and Professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston.

    Writing in the journal Oncology, Dr Jonasch reported: KEYNOTE-426 was a randomized phase III study designed to compare the combination of axitinib and pembrolizumab against sunitinib in patients with untreated clear cell renal cell carcinoma.1  The study demonstrated superior overall survival, response rate, and progression-free survival in patients treated with the pembrolizumab plus axitinib combination, while showing relatively low levels of toxicity. This combination also appeared to show benefit across all risk strata—good-, intermediate-, and poor-risk patients all had superior outcomes in the combination arm.

     Although the complete response rate of 6% was a bit lower than the rate seen in the CheckMate 214 study published a year earlier,2 the combination of efficacy, favorable toxicity, and benefit across all risk groups makes the combination of pembrolizumab plus axitinib a compelling choice for patients with metastatic RCC choosing a front-line therapy.

 

1. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019;380(12): 1116-1127.

2. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018; 378(14):1277-1290.   KCJ

 

Lenvatinib and Pembrolizumab Combination Demonstrates Clinical
Activity in Metastatic Renal Cell Carcinoma Patients Who Received
Prior Immunotherapy

MIAMI—The combination of lenvatinib and pembrolizumab demonstrates clinical activity with a promising objective response rate (ORR) in metastatic renal cell carcinoma (mRCC) patients who progressed on prior immunotherapy. An interim analysis of the ongoing phase II clinical trial (NCT02501096) was presented by Dr. Chung-Han Lee of Memorial Sloan Kettering Cancer Center.

     A total of 33 mRCC patients who received ≤2 prior systemic therapies, including those who progressed on a prior anti–PD-1/PD-L1 therapy, were included in the analysis. Patients were treated with the combination of the oral multikinase inhibitor lenvatinib 20 mg daily and the intravenous PD-1 inhibitor pembrolizumab 200 mg every 3 weeks. The primary endpoint was ORR by week 24 of treatment. Secondary endpoints included ORR, progression-free survival (PFS), duration of response, and safety and tolerability. A majority of the patients (58%) were previously treated with nivolumab/ ipilimumab (21%) or VEGF-targeted therapy plus PD-1/PD-L1 inhibitor combi-nations. Per IMDC risk criteria, 29%, 55%, and 6% of the patients were in the favorable-, intermediate-, and poor-risk categories, respectively.

     ORR as of week 24 was 61%. The best ORR was partial response in 64% and stable disease in 30% of the population. PFS was 11.3 months (95% CI, 7.3–NE) per investigator assessment using the irRECIST v1.1 definition. From a safety and toxicity standpoint, all patients experienced at least one treatment-related adverse event (TRAE). Grade 3 or 4 TRAEs were seen in 55% of the cohort. Most frequently seen TRAEs were fatigue (49%), diarrhea (39%), dysphonia (36%), stomatitis (33%), and nausea (27%). TRAEs led to the discontinuation of lenvatinib in 21% of patients and pembrolizumab in 18% of patients. One patient died due to potentially treatment-related upper gastrointestinal bleeding.

     Dr Lee highlighted the promising activity of the lenvatinib and pembrolizumab combination in mRCC patients previously treated with immunotherapy. The adverse event profile of the combination was considered manageable. Dr Lee underscored that the clinical trial (NCT02501096) is still recruiting.

 

Updated OS Data on Tivozanib Suggest Potential Role in Refractory Setting, But FDA Still Unconvinced Pending More Results

MIAMI—Updated results from the Phase 3 TIVO-3 trial point toward a potential role for this TKI, but so far the FDA has withheld approval pending additional results on the use of tivozanib. Based on the data emerging from studies of tivozanib, there is speculation that the drug may have a role in patients previously treated with checkpoint inhibitors as well as two VEGFR-TKIs.

     As previously presented, results for the intent to treat (ITT) population showed that tivozanib significantly improved progression free survival (PFS), the study’s primary endpoint, and overall response rate (ORR) compared to sorafenib, with responses to tivozanib more durable than sorafenib. Newly presented data include the recently announced interim overall survival (OS) hazard ratio (HR) of 0.99 within the ITT population, as well as results from two prespecified subgroup analyses of patients previously treated with a checkpoint inhibitor and a VEGF-TKI, or two VEGFR-TKIs. Superior PFS and ORR, as well as OS HRs below 1, favoring tivozanib, were observed in the prespecified subgroups. Tivozanib was shown to have lower overall rates of adverse events and fewer dose interruptions and reductions versus sorafenib, indicating better patient tolerability.

     “Until the TIVO-3 trial results, limited prospective data existed to inform sequencing of treatment after checkpoint inhibitor therapy, the emergent standard of care in earlier-line treatment,” said Sumanta Pal, MD, in his presentation at IKCS. “Tivozanib’s outcomes within this population, as well as in those receiving two prior VEGF-TKIs, suggest an important potential role for tivozanib in the evolving refractory advanced RCC setting. Furthermore, tivozanib’s unique tolerability profile is potentially well suited to an advanced setting, where many are reluctant to accept higher rates of adverse events following multiple courses of therapy.” AVEO plans on completing a final OS analysis of TIVO-3 in June 2020 after a planned submission of a new drug application to the FDA in the first quarter of 2020.

 

Treatment-Free Survival With and Without Toxicity With Nivolumab and
Ipilimumab in Metastatic Renal Cell Carcinoma

MIAMI—Treatment-free survival (TFS) without toxicity, a novel way of describing disease control and toxicity during an off-treatment period, was longer in patients who received nivolumab/ipilimumab in combination versus those who received sunitinib, according to an innovative analysis of the CheckMate 214 dataset. The study was presented by Meredith M. Regan, MD of the Dana-Farber Cancer Institute.

     Dr Regan and colleagues previously defined TFS as the interval between the time point of immune checkpoint inhibitor (ICI) discontinuation and initiation of subsequent systemic treatment (J Clin Oncol. 2019 Sep 9:JCO1900345. doi:10.1200/JCO.19.00345). Development of this novel outcome measure was based on the fact that ICI-treated patients are observed to have continued benefit from treatment or develop treatment-related adverse events (TRAEs) after treatment discontinuation.

 

Incidence of Brain Metastases Is 4.5% in Asymptomatic Metastatic RCC

MIAMI—Asymptomatic brain metastases are encountered in 4.5% of asymptomatic metastatic renal cell carcinoma (mRCC) patients according to a large multi-institutional retrospective analysis of 1597 patients’ data. The study was presented by Dr. Ritesh Kotecha of Memorial Sloan Kettering Cancer Center.

     Through a collaborative effort of scientists from the Institut Gustav Roussy and Memorial Sloan Kettering Cancer Center, investigators analyzed the data of 1597 asymptomatic mRCC patients who were screened for brain metastases for inclusion in 68 clinical trials. A total of 71 patients, representing the 4.5% of the cohort, were found to have brain metastases. Per IMDC criteria, 26%, 61%, and 13% of the cohort were in favorable-, intermediate-, and poor-risk groups, respectively. A majority of the patients were treatment-naïve (32%) or had received one prior line of treatment (43%). A total of 86% of the patients had more than one extracranial metastatic site, and the most common accompanying extracranial metastatic site was lung (92%). Patients with metastatic disease at initial presentation comprised 60% of the patient population. The investigators reported a median overall survival (OS) of 10.3 months (95% CI, 7–17.9 months).

 

Living With Kidney Cancer, New Patient Magazine

The Kidney Cancer Association is launching a patient and caretaker magazine called “Living with Kidney Cancer”.  This complimentary magazine is available for you to have in your offices, waiting rooms, or to give specifically to patients. Sign-up to receive your complimentary magazines here: https://tinyurl.com/LivingWithKidneyCancer

 

William Kaelin’s 2019 Nobel Prize in Physiology Linked to
Kidney Cancer Molecular Mechanisms

William G. Kaelin Jr., MD, has won the 2019 Nobel Prize in Physiology or Medicine with two other physician-scientists for unraveling a molecular mechanism that not only is crucial to survival, but is entwined with cancer and other diseases, especially kidney cancer. Dr Kaelin is the Sidney Farber Professor of Medicine at Harvard Medical School, and an investigator at the Howard Hughes Medical

Institute.

     Dr Kaelin and his collaborators deciphered the core molecular events that explain how almost all multi-cellular animals tune their physiology to cope with varying quantities of life-sustaining oxygen in a unique signaling scheme. Their findings could lead to new therapeutics for a wide range of disorders — including cancer, cardiovascular disease, anemia, and macular degeneration. This oxygen-sensing mechanism involves the tumor-suppressor protein VHL, which is mutated in many kidney cancers, and proteins known as hypoxia inducible factors, HIF-1α and HIF-2α. Kaelin showed that HIF-2α drives certain kidney cancers and recently discovered how HIF-1α is hijacked by triple-negative breast cancers. He is developing therapeutic strategies for targeting these molecules and others implicated in cancer, such as mutated enzymes IDH1 and IDH2, with designer drugs.

 

2019 Top Stories in Oncology? Pembrolizumab Plus Axitinib for
RCC Heads the List

The pembrolizumab plus axitinib study is the renal cell carcinoma top story for 2019, according to Eric Jonasch, MD, a leading investigator on RCC trials and Professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston.

    Writing in the journal Oncology, Dr Jonasch reported: KEYNOTE-426 was a randomized phase III study designed to compare the combination of axitinib and pembrolizumab against sunitinib in patients with untreated clear cell renal cell carcinoma.1  The study demonstrated superior overall survival, response rate, and progression-free survival in patients treated with the pembrolizumab plus axitinib combination, while showing relatively low levels of toxicity. This combination also appeared to show benefit across all risk strata—good-, intermediate-, and poor-risk patients all had superior outcomes in the combination arm.

     Although the complete response rate of 6% was a bit lower than the rate seen in the CheckMate 214 study published a year earlier,2 the combination of efficacy, favorable toxicity, and benefit across all risk groups makes the combination of pembrolizumab plus axitinib a compelling choice for patients with metastatic RCC choosing a front-line therapy.

 

1. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019;380(12): 1116-1127.

2. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018; 378(14):1277-1290.   KCJ

 

Vol 17, No 3    2019

The Official Journal of the Kidney Cancer Association

Home      Archives      About Us      Submission Guidelines         Editorial Board       Advertising Information      Contact Us