Cabozantinib (Cabometyx) plus atezolizumab (Tecentriq) demonstrated promising clinical activity and a suitable safety profile as first-line therapy in patients with cisplatin- eligible and -ineligible, inoperable locally advanced or metastatic urothelial cancer (UC) and as second- or later-line therapy in those who received a prior immune checkpoint inhibitor (ICI), according to findings from the phase 1b COSMIC-021 trial presented at the 2022 ASCO Annual Meeting.

The multicenter, open-label COSMIC-021 trial (NCT03170960) is evaluating the combination of the PD-L1 inhibitor atezolizumab and the multikinase inhibitor cabozantinib in patients with locally advanced or metastatic solid tumors. This analysis included patients with inoperable locally advanced/metastatic UC with transitional cell histology and ECOG performance status (PS) of 0-1.

Among the enrolled patients, those in study cohorts 3 (C3) had no prior systemic therapy and were cisplatin ineligible. Patients in study cohort 4 (C4) were also systemic treatment–naïve but were cisplatin eligible, and study cohort 5 (C5) comprised patients who had received 1 prior immune checkpoint inhibitor (ICI), were VEGFR-TKI–naïve, and had received ≤2 lines of therapy overall.

The results showed that 1 patient in C3, 2 patients in C4, and no patients in C5 had complete responses (CRs). Partial responses (PRs) were reached by 5, 7, and 3 patients in C3, C4, and C5, respectively. The objective response rates (ORRs) were 20%, 30%, and 10%, respectively, and the disease control (CR + PR + stable disease) rates were 80%, 63%, and 61%, respectively.

“Cabozantinib plus atezolizumab demonstrated clinical activity with manageable toxicity in inoperable locally advanced or metastatic urothelial carcinoma as first-line therapy in cisplatin-based chemotherapy eligible or ineligible patients, and in second- or later-line therapy in patients who received prior ICI therapy,” said lead study author Sumanta K. Pal, MD, City of Hope Comprehensive Cancer Center.

Overall, C3 and C4 had 30 patients and C5 had 31 patients. The median ages were 74, 66, and 68 years, respectively; percentage male were 67%, 73%, and 55%, respectively; and ECOG PS 1 were 63%, 57%, and 74%, respectively (all other patients had ECOG PS 0). The lung/liver metastasis rates were 33%/17%, 40%/20%, and 58%/23%, respectively. Additionally, 30%, 43%, and 45% of patients, respectively, had ≥3 tumor sites and 67%, 70%, and 71%, of patients, respectively, had bladder as their primary tumor site.

Patients were treated with cabozantinib at 40 mg orally each day and received atezolizumab at 1200 mg IV every 3 weeks. The primary study end point was ORR per RECIST v1.1 by investigator. The secondary end point was safety, with other key end points comprising duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

The median follow-ups in cohorts 3, 4, and 5, were 27.9 months (range, 15.2-43.8), 19.1 months (range, 7.4-42), and 32.9 (range, 23-41.2). The median DORs were 7.1 months, not yet reached, and 4.1 months, respectively. At least some reduction in tumor size occurred in 74%, 62%, and 63% of patients respectively. The median PFS was 5.6, 7.8, and 3.0 months, respectively, and the median OS was 14.3, 13.5, and 8.2, months, respectively.

Regarding safety, in C3, grade 3/4 adverse events (AEs) were fatigue in 1 patient and amylase increase in 2 patients. Grade 3/4 AEs in C4 were diarrhea (1 patient), AST increase (n = 2), decreased appetite (n = 2), ALT increase (n = 3), and fatigue (n = 1). In C5, grade 3/4 AEs were decreased appetite (n = 1), ALT increase (n = 1), fatigue (n = 2), amylase increase (n = 2), and stomatitis (n = 1). There were no grade 5 treatment-related AEs across the 3 cohorts.

Cabozantinib is currently approved by the FDA for the treatment of patients with advanced RCC and also specifically for use in combination with nivolumab (Opdivo) for the first-line treatment of patients with advanced RCC. Atezolizumab is approved for single-agent use for cisplatin-ineligible and PD-L1–positive or platinum-ineligible locally advanced or metastatic UC.

Pal SK, Agarwal N, Singh P, et al. Cabozantinib (C) in combination with atezolizumab (A) in urothelial carcinoma (UC): Results from Cohorts 3, 4, 5 of the COSMIC-021 study. 

 40, 2022 (suppl 16; abstr 4504). doi: 10.1200/JCO.2022.40.16_suppl.4504

Articles

Cabozantinib plus atezolizumab demonstrated promising clinical activity and a suitable safety profile as first-line therapy in patients with cisplatin- eligible and -ineligible, inoperable locally advanced or metastatic urothelial cancer and as second- or later-line therapy in those who received a prior immune checkpoint inhibitor, according to findings from the phase 1b COSMIC-021 trial.

Atezolizumab Plus Cabozantinib Elicits Clinical Activity in Advanced Urothelial Cancer

The selective EGFR inhibitor CLN-081 elicited objective responses in heavily pretreated patients with non–small cell lung cancer (NSCLC) with 

 exon 20 insertions and was found to have an acceptable toxicity profile, according to data from the phase 1/2a CLN-081-001 trial (NCT04036682) presented during the 2022 ASCO Annual Meeting.

Among the 39 patients who received the agent at 100 mg twice daily, the confirmed partial response (PR) rate was 41%, the median duration of response (DOR) was over 21 months (95% CI, 8-not calculated [NC]), and the median progression-free survival (PFS) was 12 months (95% CI, 5-NC).

In the overall population (n = 73), the agent elicited a confirmed PR rate of 38.4%, with a median DOR of 10 months (95% CI, 6-NC), and a median PFS of 10 months (95% CI, 6-12). In the subset of patients who received CLN-081 at a twice-daily dose of 65 mg or less, the confirmed PR rate was 35%, with a median DOR of greater than 19 months (95% CI, 5-NC) and a median PFS of 8 months (95% CI, 5-13). In the 11 patients who received CLN-081 at a twice-daily dose of 150 mg, the confirmed PR rate was 36.4%, the median DOR was 7 months (95% CI, 4-NC), and the median PFS was 8 months (95% CI, 1-10).

“The safety profile of CLN-081 is amenable for long-term treatment [when given] at doses less than 150 mg twice daily,” Helena Alexandra Yu, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, added in a presentation on the data. “Most adverse effects [AEs] were grade 1 or 2. There was no grade 3 rash or diarrhea at doses less than 150 mg twice daily.”

The novel, irreversible, oral EGFR inhibitor possesses a unique pyrrolopyrimidine scaffold. Preclinical data have showcased that the agent has strong, broad-spectrum activity against 

exon 20 insertions. The agent also has selectivity against wild-type 

CLN-081-001 was a phase 1/2a dose-escalation and -expansion trial. The dose-escalation portion of the research utilized an accelerated titration and rolling-six design, Yu said. Moreover, the phase 1 and 2 dose-expansion cohorts enrolled additional patients at dose levels that met predefined thresholds for efficacy and tolerability.

To be eligible for participation, patients were required to have recurrent or metastatic NSCLC harboring 

 exon 20 insertion mutations that had be confirmed via local laboratory. Patients must have previously received treatment in the recurrent or metastatic setting, including a platinum-based chemotherapy regimen.

In the dose-escalation cohorts, patients were allowed to have previously received an agent that targeted 

 exon 20 insertion mutations. Notably, those who had untreated central nervous system (CNS) metastases that had been stable for at least 4 weeks before the first day of the first cycle of treatment were permitted.

Study participants received CLN-081 twice daily, at a dose level starting at 30 mg. Investigators evaluated tumor response at 6 weeks and then every 9 weeks thereafter.

At a data cutoff date of May 9, 2022, 73 patients had been enrolled across doses that ranged from 30 mg twice daily to 150 mg twice daily. However, enrollment to the group evaluating the agent at 150 mg twice daily was closed after 11 patients due to toxicity.

Of these 73 patients, 33% continue to receive CLN-081, and 67% have discontinued treatment. The most common reason for discontinuation was disease progression (61%), followed by toxicity (25%), another unspecified reason (8%), and withdrawn consent (6%).

Yu noted that those enrolled to the trial were heavily pretreated, with 44% of patients having received 2 prior lines of systemic anticancer therapy and 22% having received 3 or more prior lines of treatment. Notably, the median prior lines of therapy received was 2, with a range of 1 to 9 prior regimens received.

Thirty-six percent of patients previously received an EGFR TKI in the form of afatinib (Gilotrif) or gefitinib (Iressa; 18%), or osimertinib (Tagrisso; 18%); 4% of patients previously received poziotinib and/or mobocertinib (Exkivity). Moreover, approximately half of patients (55%) had prior immunotherapy. Notably, 38% of patients had a history of CNS involvement at baseline.

Additional data showed that the median time on study was 11 months, and the median time to response with CLN-081 was 1.5 months.

Yu shared additional data on 3 patients who had CNS target lesions at baseline before study entry. One patient was 69 years of age and had initially presented with early-stage disease; this patient had undergone surgical resection and had received adjuvant chemotherapy. One year later, he experienced CNS recurrence. “A large right frontal lobe lesion was resected and radiated,” Yu said. “A separate asymptomatic cerebellar lesion was growing prior to study entry. By cycle 6, there was a decrease from 19 mm to 10 mm and decreased enhancement.”

The second patient, who has received at least 1 year of treatment and continues to receive the agent, achieved stable disease with CLN-081, both intracranially and systemically. The third patient experienced disease progression at cycle 3.

Most toxicities were grade 1 or 2 in severity, and dose reductions and discontinuations were uncommon at doses below 150 mg. Notably, no grade 3 or higher rash or diarrhea was noted in those who received doses of less than 150 mg. Four patients experienced treatment-emergent pneumonitis; this occurred in 1 patient who received the agent at 65 mg twice daily, 2 patients who received it at 100 mg twice daily, and 1 patient who received it at 150 mg twice daily. Notably, however, these cases were noted to be asymptomatic (n = 1) or cofounded by comorbid medical illness (n = 3).

“Enrollment into the phase 2b portion of the study is planned for the second half of this year and there are prespecified cohorts that plan to enroll patients with active untreated CNS metastases and those who have progressed on prior EGFR exon 20 therapies,” Yu concluded.

Yu HA, Tan DSW, Smit EF, et al. Phase (ph) 1/2a study of CLN-081 in patients (pts) with NSCLC with EGFR exon 20 insertion mutations (ins20). 

. 2022;40(suppl 16):9007. doi:10.1200/JCO.2022.40.16_suppl.9007

The selective EGFR inhibitor CLN-081 elicited objective responses in heavily pretreated patients with non–small cell lung cancer with EGFR exon 20 insertions and was found to have an acceptable toxicity profile, according to data from the phase 1/2a CLN-081-001 trial.

CLN-081 Produces Antitumor Activity With Acceptable Safety in Heavily Pretreated EGFR Exon 20 Insertion+ NSCLC

Adagrasib led to early onset and deep responses translating to encouraging survival as a single agent in previously treated patients with 

G12C–mutated non–small cell lung cancer (NSCLC), according to results from cohort A of the phase 1/2 KRYSTAL-1 trial (NCT03785249) presented at the 2022 ASCO Annual Meeting.

At the meeting, Alexander I. Spira, MD, PhD, FACP, co-director of Virginia Cancer Specialists Research Institute, director of the Thoracic and Phase I Program, and clinical assistant professor at Johns Hopkins School of Medicine, presented data as of October 15, 2021, from the registrational phase 2 cohort A study, which was simultaneously published in the 

After a median follow-up of 12.9 months, the objective response rate (ORR) was 43% (95% CI, 33.5%-52.6%) among the 112 patients with measurable disease at baseline, which included 1 complete response (CR; 1%) and 47 partial responses (PRs; 42%). There were 41 patients with stable disease (SD; 37%) and 6 with progressive disease (5%) for a DCR of 80% (n = 89; 95% CI, 70.8%-86.5%). There were no differences in ORR by subgroup in exploratory analyses.

“Responses appear to be deep, with 75% of responders having a greater than 50% tumor reduction,” Spira said.

Moreover, the median time to response with the KRASG12C inhibitor was 1.4 months (range, 0.9-7.2) and median duration of response was 8.5 months (95% CI, 6.2-13.8).

Spira noted that as of the data cut-off, treatment is ongoing in half of patients who experienced a response (n = 24) and 33% (n = 16) have maintained their response.

Lastly, the median progression-free survival (PFS) was 6.5 months (95% CI, 4.7 to 8.4), with 6- and 12-month PFS rates of 52% and 29%, respectively. Similarly, the median OS was 12.6 months (95% CI, 9.2-19.2), with 6- and 12-month OS rates of 71% (95% CI, 61.1-78.3) and 51% (95% CI, 40.9-60.0), respectively.

The investigators further evaluated efficacy among 33 patients with treated, stable central nervous system (CNS) metastases. The intracranial ORR was 33% (n = 11; 95% CI, 18%-52%), which included 5 CRs (15%) and 6 PRs (18%). There were 17 patients with SD (52%) for a DCR of 85% (n = 28; 95% CI, 68%-95%). The median intracranial PFS was 5.4 months (95% CI, 3.3-11.6).

Treatment-related adverse events (TRAEs) of any grade occurred in 113 patients (97%), of which 50 (43%) were grade 3/4 in severity. The most frequent any-grade TRAEs were diarrhea (63%), nausea (62%), vomiting (47%), fatigue (41%), ALT increase (28%), blood creatinine increase (26%), AST increase (25%), and decreased appetite (24%). Two grade 5 events occurred: cardiac failure and pulmonary hemorrhage.

TRAEs led to dose reductions in 60 patients (52%), interruptions in 71 (61%), and discontinuation in 8 (7%).

Commenting on the presentation, Sukhmani Kaur Padda, MD, of the Samuel Oschin Cancer Center at Cedars-Sinai Medical Center, noted: “I am curious about a lower optimal starting dose. We talk about this all the time as it relates to targeted therapy… Co-mutations may help further delineate sequencing of therapeutics in 

Adagrasib, formerly MRTX849, is a covalent inhibitor that irreversibly and selectively binds KRAS G12C. “We know that 

G12C mutations act as oncogenic drivers and occur in about 14% of patients with non–small cell lung cancer, predominantly adenocarcinoma,” Spira explained. “About 27% to 42% of these patients will have CNS metastases at diagnosis. Adagrasib…was optimized for desired properties of a 

G12C inhibitor, including a long half-life, about 23 hours, dose-dependent pharmacokinetics, and CNS penetration.”

In the first-in-human trial of the agent, 15 patients with 

G12C–mutated NSCLC demonstrated an ORR of 53.3%, a median DOR of 16.4 months, and a median PFS of 11.1 months. “As previously reported, clinical activity with adagrasib has been shown in various 

G12C–mutated solid tumors, including of course non–small cell lung, colorectal, pancreatic, ovarian, endometrial, and other GI cancers,” Spira said.

Therefore, in the multicohort KRYSTAL-1 trial, investigators are assessing adagrasib as monotherapy or in combination with other therapies in patients with advanced solid tumors harboring a 

In the registrational phase 2 cohort A study, 116 patients with NSCLC previously treated with platinum-based chemotherapy and anti–PD-1/L1 therapy received 600 mg oral adagrasib twice daily. Investigators aimed to evaluate ORR, DCR, PFS, OS, and safety.

Key eligibility criteria included patients with NSCLC who harbored a 

G12C mutation, unresectable or metastatic disease, and prior treatment with a PD-1/L1 inhibitor in combination or in sequence with chemotherapy. Those with treated, stable CNS metastases were allowed on the trial.

Median age was 64 years (range, 15-89). Most patients were women (56%), White (84%), had an ECOG status of 1 (84%), were former smokers (86%), and had received prior platinum-based therapy and checkpoint inhibitor therapy (98%).

“Based on these data, the [new drug application] for adagrasib has been accepted and is under review for accelerated approval in the US, and the [marketing authorization applications] has been recently submitted to the European Medicines Agency,” Spira said, adding that the phase 3 KRYSTAL-12 trial (NCT04685135), designed to evaluate adagrasib monotherapy versus docetaxel in previously treated patients with 

Spira AI, Riely GJ, Gadgeel SM, et al. KRYSTAL-1: activity and safety of adagrasib (MRTX849) in patients with advanced/metastatic non-small cell lung cancer (NSCLC) harboring a KRAS G12C mutation. 

. 2022;40(suppl 16):9002 doi:10.1200/JCO.2022.40.16_suppl.9002

Jänne PA, Riely G, Gadgee SM, et al. Adagrasib in non–small-cell lung cancer harboring a 

Adagrasib led to early onset and deep responses translating to encouraging survival as a single agent in previously treated patients with KRAS G12C–mutated non–small cell lung cancer, according to results from cohort A of the phase 1/2 KRYSTAL-1 trial.

Pipeline Report: June 2022 | Articles

Atezolizumab Plus Cabozantinib Elicits Clinical Activity in Advanced Urothelial Cancer

CLN-081 Produces Antitumor Activity With Acceptable Safety in Heavily Pretreated EGFR Exon 20 Insertion+ NSCLC

Adagrasib Elicits Deep and Durable Responses in Pretreated KRAS G12C–Mutant NSCLC