Results from the COSMIC-021 Phase Ib study is evaluating cabozantinib (Cabometyx®; Exelixis/Ipsen*), a multi-targeted tyrosine kinase inhibitor (TKI), in combination with atezolizumab (Tecentriq®; Genentech/Roche) in advanced solid tumors, including metastatic non-small cell lung cancer (NSCLC). Furthermore, a new analyses from pivotal Phase III Checkmate -9ER trial support the superior efficacy of cabozantinib and nivolumab (Opdivo®; Bristol-Myers Squibb) over sunitinib (Sutent®; Pfizer) in advanced renal cell carcinoma (aRCC). A new analyses from pivotal Phase III COSMIC-311 trial further support the potential of cabozantinib in radioactive iodine-refractory differentiated thyroid cancer.[1][2][3][4][5]

The results from these studies were presented at the annual meeting of the American Society of Clinical Oncology (ASCO), held June 3 – 7, 2022, in Chicago, Il.

The presented data included finding in mNSCLC, as well as established indications of advanced renal cell carcinoma (RCC) and radioactive iodine-refractory differentiated thyroid cancer (RAI-R DTC). These data demonstrated the therapeutic potential of cabozantinib as a key treatment option in a broad range of tumors.

Phase Ib COSMIC-021
Lung cancer is one of the leading causes of cancer death globally.[6] There are broadly two different groups of lung cancer – NSCLC and SCLC (small cell lung cancer). NSCLC accounts for around 80-85% of all cases. [7] The major subtypes of lung cancer include adenocarcinoma, squamous cell carcinoma and large cell carcinoma. These subtypes, which start from different types of lung cells are grouped together as NSCLC because their treatment and prognoses are often similar.

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Updated outcomes from the multicenter Phase Ib COSMIC-021 trial evaluating the combination of cabozantinib plus atezolizumab in an expanded patient population in metastatic NSCLC demonstrate encouraging clinical activity with manageable toxicity in people previously treated with an immune checkpoint inhibitor (ICI).[1]

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The investigators believe that these results lay the foundations for the potential of cabozantinib in metastatic NSCLC which is being further examined in the ongoing Phase III CONTACT-01 trial. This trial is evaluating the combination of cabozantinib plus atezolizumab versus docetaxel in patients with metastatic NSCLC previously treated with an ICI and platinum-containing chemotherapy, and topline results of the study are expected to be announced in the second half of 2022.

Standard of care
“Currently, first-line immunotherapy with or without chemotherapy is the standard of care for patients with metastatic NSCLC but there is a real need for additional effective treatment options for those patients who progress after a prior immunotherapy,” explained Santiago Ponce-Aix, M.D., Head of Drug Development Department, Institute Gustave Roussy, France, and an investigator in the COSMIC-021trial.

“These new data are encouraging as they show the potential role of cabozantinib in creating an environment which may enhance atezolizumab’s activity in kid.”

“The therapeutic potential of cabozantinib as a treatment option against a broad range of tumors including NSCLC is continuing to be evaluated and these data demonstrate our ambition to bring meaningful new treatments to patients. These latest data support the potential role of cabozantinib to positively impact treatment when paired with immunotherapy, and we will continue to evaluate cabozantinib as both a monotherapy and in combination with other innovative therapies for the most difficult-to-treat cancers,” said Dr. Howard Mayer, Executive Vice President and Head of Research and Development at Ipsen.

Exploratory analyses
An exploratory analysis will also be presented investigating the relationship between depth of response (DepOR) and clinical outcomes in CheckMate -9ER, evaluating cabozantinib in combination with nivolumab versus sunitinib in previously untreated advanced renal cell carcinoma. [2]

There were over 430,000 new cases of kidney cancer diagnosed worldwide in 2020. [8] Of these, renal cell carcinoma or RCC is the most common type of kidney cancer, accounting for approximately 90% of cases. [9][10] The disease is almost twice as common in men. Men also account for over two thirds of deaths. [9] If detected in the early stages, the five-year survival rate is high, but for patients with or late-stage metastatic RCC the survival rate is much lower, around 12%, with no identified cure for this disease.[11][12]

Inn the exploratory analyses, DepOR was defined as the best percent reduction from baseline in sum of diameters of target lesions. Overall, greater proportions of patients receiving cabozantinib plus nivolumab demonstrated deeper responses vs sunitinib. Regardless of treatment, deeper responses were generally associated with improved progression-free survival (PFS) and overall survival. [2]

Additionally, two new data analyses from the pivotal Phase III trial COSMIC-311 evaluating cabozantinib in RAI-R DTC were presented.

In 2020, over 580,000 new cases of thyroid cancer were diagnosed worldwide.[13] Thyroid cancer is the ninth most commonly occurring cancer globally and incidence is three times higher in women than in men, with the disease representing one in every 20 cancers diagnosed among women.[13] While cancerous thyroid tumors include differentiated, medullary and anaplastic forms, differentiated thyroid cancer (DTC) makes up about 90 to 95% of cases.[14][15]

Differentiated thyroid cancer is typically treated with surgery, followed by ablation of the remaining thyroid tissue with radioactive iodine (RAI), but approximately 5 to 15% of cases are resistant to RAI treatment.[16] Patients who develop RAI-R DTC have a poor prognosis with an average estimated survival of three to five years.[17]

One analysis of he pivotal Phase III trial COSMIC-311 showed outcomes for pre-specified subgroups based on the baseline histology subtypes of papillary and follicular thyroid cancers, with results demonstrating cabozantinib to maintain superior efficacy versus placebo irrespective of histology subtype.[3]

Median PFS was 9.2 months for cabozantinib versus 1.9 months for placebo in the papillary thyroid cancer (PTC) subgroup (HR 0.27 95% CI, 0.17-0.43) and 11.2 months versus 2.5 months in the follicular thyroid cancer (FTC) subgroup (HR 0.18 95% CI, 0.10-0.31). The overall response rate (ORR) was 15% for cabozantinib versus 0% for placebo in the PTC subgroup and 8% versus 0% in the FTC subgroup.[3]

Another analysis will be presented related to outcomes for prespecified subgroups who received prior lenvatinib (Lenvima®; Eisai) and/or sorafenib (Nexavar®; Bayer) treatment.

The data from this analysis showed cabozantinib maintained its PFS versus placebo irrespective of prior  treatment with lenvatinib and/or sorafenib. [4]

The analyses showed a median PFS across the different groups included 16.6 months for cabozantinib versus 3.2 months for placebo in prior sorafenib (no lenvatinib) (HR 0.13, 95% CI 0.06–0.26), 5.8 months versus 1.9 months in prior lenvatinib (no sorafenib) (HR 0.28, 95% CI 0.16-0.48), and 7.6 months versus 1.9 months in prior sorafenib and lenvatinib (HR 0.27, 95% CI 0.13– 0.54). [4]

The safety profile identified in COSMIC-021, CheckMate -9ER and COSMIC-311 was consistent with that previously observed for cabozantinib both in monotherapy and in combination therapy.

* Note: Cabozantinib (Cabometyx®) is Exelixis’ lead oncology drug. Under agreement with Ipsen, signed in 2016, Exelixis will have exclusive commercialization rights for current and potential future cabozantinib indications in the United States, Canada and Japan. Ipsen will have exclusive commercialization rights in the rest of the world, including the European Union (EU) and the United Kingdom.

Clinical trials
Study of Cabozantinib in Combination With Atezolizumab to Subjects With Locally Advanced or Metastatic Solid Tumors – NCT03170960
A Study of Nivolumab Combined With Cabozantinib Compared to Sunitinib in Previously Untreated Advanced or Metastatic Renal Cell Carcinoma (CheckMate 9ER) – NCT03141177
A Study of Cabozantinib Compared With Placebo in Subjects With Radioiodine-refractory Differentiated Thyroid Cancer Who Have Progressed After Prior Vascular Endothelial Growth Factor Receptor (VEGFR) -Targeted Therapy – NCT03690388

Highlights of prescribing information
Cabozantinib (Cabometyx®; Exelixis/Ipsen)[Prescribing information]
Atezolizumab (Tecentriq®; Genentech/Roche)[Prescribing information]
Nivolumab (Opdivo®; Bristol-Myers Squibb)[Prescribing Information]
Sunitinib (Sutent®; Pfizer)[Prescribing Information]
Lenvatinib (Lenvima®; Eisai)[Prescribing information]
Sorafenib (Nexavar®; Bayer) [Prescribing Information]

Summary of Product Characteristics (EU)
Cabozantinib (Cabometyx®; Exelixis/Ipsen)[SmPC]

Reference
[1] Neal JW, Santoro A, Viteri S, Ponce Aix S, Fang B, Lim FL, Gentzler RD, Goldschmidt JH, et al. Cabozantinib (C) plus atezolizumab (A) or C alone in patients (pts) with advanced non–small cell lung cancer (aNSCLC) previously treated with an immune checkpoint inhibitor (ICI): Results from Cohorts 7 and 20 of the COSMIC-021 study. J Clin Oncol 40, 2022 (suppl 16; abstr 9005) | DOI 10.1200/JCO.2022.40.16_suppl.9005
[2] Suárez C, Choueiri TK, Burotto M, Powles T, Bourlon MT, Shah AY, Tomita Y, et al. Association between depth of response and clinical outcomes: exploratory analysis in patients with previously untreated advanced renal cell carcinoma (aRCC) in CheckMate 9ER. J Clin Oncol 40, 2022 (suppl 16; abstr 4501)| DOI 10.1200/JCO.2022.40.16_suppl.4501
[3] Capdevila J, Robinson B, Sherman SI, Jarząb B, Lin CC, Vaisman F, Hoff A, et al. Cabozantinib versus placebo in patients (pts) with radioiodine-refractory (RAIR) differentiated thyroid cancer (DTC) who have progressed after prior VEGFR-targeted therapy: outcomes in prespecified subgroups based on histology subtypes. J Clin Oncol 40, 2022 (suppl 16; abstr 6081) | DOI 10.1200/JCO.2022.40.16_suppl.6081
[4] Hernando J, Capdevila J, Robinson B, Sherman SI, Jarząb B, Lin CC, Vaisman F, Hoff A et al. Cabozantinib (C) versus placebo (P) in patients (pts) with radioiodine-refractory (RAIR) differentiated thyroid cancer (DTC) who have progressed after prior VEGFR-targeted therapy: outcomes in prespecified subgroups based on prior VEGFR-targeted therapy. J Clin Oncol 40, 2022 (suppl 16; abstr 6083) | DOI 10.1200/JCO.2022.40.16_suppl.6083
[5] Pal SK, Agarwal N, Singh P, Necchi A, McGregor BA, Hauke RJ, Powles T, et al. Cabozantinib (C) in combination with atezolizumab (A) in urothelial carcinoma (UC): Results from Cohorts 3, 4, 5 of the COSMIC-021 study. J Clin Oncol 40, 2022 (suppl 16; abstr 4504) | DOI 10.1200/JCO.2022.40.16_suppl.4504
[6] World Health Organization: GLOBOCAN 2020 – Lung Cancer: Estimated cancer incidence, mortality and prevalence worldwide. Online. Last accesses on June 2, 2022. Available from:
[7] What is Lung Cancer? American Cancer Society. Online. Last accessed on June 2, 2022.
[8] Kidney Cancer Factsheet. GLOBOCAN 2020. Online. Last accessed on June 2, 2022.
[9] Kidney Cancer. Mayo Clinic. Online. Last accessed on June 2, 2022.
[10] Infographic: Kidney Cancer. Mayo Clinic. Online. Last accesses on June 2, 2022.
[11] Survival rates for kidney cancer. American Cancer Society. Online. Last accesses on June 2, 2022. Accessed: May 2022. Available:
[12] Orlin, I et al., Renal cell carcinomas epidemiology in the era of widespread imaging. Journal of Clinical Oncology. 2019; 37:15
[13] Sung. H et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal For Clinicians. doi: 10.3322/caac.21660..
[14] Cancer.Net. ASCO. Thyroid Cancer: Introduction. Last accessed: May 2022. Available at: https://www.cancer.net/cancer- types/thyroid-cancer/introduction.
[15] Chen D. et al. Innovative analysis of distant metastasis in differentiated thyroid cancer. Oncol Lett 19: 1985-
1992, 2020. doi: 10.3892/ol.2020.11304
[16] Worden F. Treatment strategies for radioactive iodine-refractory differentiated thyroid cancer. Ther Adv Med Oncol. 6:267–279. doi: 10.1177/1758834014548188.
[17] Fugazzola L. et al. 2019 European Thyroid Association Guidelines for the Treatment and Follow-Up of Advanced Radioiodine-Refractory Thyroid Cancer. Eur Thyroid J. 2019;8:227–245. doi: 10.1159/000502229.

Featured image: Annual meeting of the American Society of Clinical Oncology (ASCO); Ipsen booth. Photo courtesy: © 2018 – 2022 Sunvalley Communication / Evan Wendt. Used with permission.

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