Phase II multicohort study of atezolizumab monotherapy in multiple advanced solid cancers

Abstract

Background: The programmed death-ligand 1 inhibitor atezolizumab had shown clinical activity against several advanced malignancies.

Patients and methods: This phase II, open-label basket study (NCT02458638) was conducted in 16 main cohorts of patients aged ≥18 years with stage III or IV solid tumors. In stage I, 12 patients were enrolled into each cohort. Treatment was atezolizumab 1200 mg intravenously every 3 weeks until loss of clinical benefit or unacceptable toxicity. The primary efficacy endpoint was the non-progression rate (NPR) at 18 weeks in treated, assessable patients. NPR ≤20% was not of interest for development as monotherapy, and NPR ≥40% was defined as the threshold of benefit/success. If ≥3 patients had non-progressive disease in stage I (interim analysis), 13 additional patients could be enrolled into stage II (final analysis). Secondary efficacy and safety endpoints were also evaluated.

Results: Overall, 474 patients were enrolled and treated; 433 were included in the efficacy set. Due partly to slow recruitment because of competing trials and limited efficacy at interim analyses, enrollment was stopped early, including in cohorts that passed stage I boundaries of success. NPR was >20% in five cohorts: cervical cancer {n = 27; NPR 44.4% [95% confidence interval (CI) 25.5% to 64.7%]}; follicular/papillary thyroid cancer [n = 11; 54.5% (95% CI 23.4% to 83.3%)]; thymoma [n = 13; 76.9% (95% CI: 46.2% to 95.0%)]; gastroenteropancreatic (GEP) and lung neuroendocrine tumors [NETs; n = 24; 41.7% (95% CI 22.1% to 63.4%)], and low/intermediate grade carcinoid GEP and lung NETs [n = 12; 58.3% (95% CI 27.7% to 84.8%)]. Treatment-related adverse events occurred in 55.3% of patients overall, and at grade 3, 4, and 5 in 10.3%, 1.7%, and 0.4%, respectively.

Conclusions: Atezolizumab monotherapy was effective in the cervical cancer cohort. The interim benefit threshold was crossed in patients with follicular/papillary thyroid cancer, thymoma, and GEP and lung NETs, but recruitment was stopped before these signals could be confirmed in stage II. Safety was consistent with previous findings.

Keywords: PD-L1 checkpoint inhibitor; atezolizumab; basket study; multicohort; solid tumors.

Figure 1

Trial profile. AE, adverse event; EOS, end of study; PD, progressive disease.

Figure 2

NPR at 18 weeks by cohort at interim analysis (stage I) or final analysis (stage II) in the efficacy set. Cohort data shown in red passed the boundary of interim analysis; cohort data shown in blue did not pass the boundary of interim analysis. Cohorts for which only interim analyses are shown did not reach stage II due to low accrual or because recruitment was stopped. Interim analysis was not conducted for cohorts that were stopped before 12 eligible, assessable patients had been enrolled. CI, confidence interval; CRC, colorectal cancer; ER, estrogen receptor; GE, gastroesophageal; GEP, gastroenteropancreatic; GIST, gastrointestinal stromal tumor; HER, human epidermal growth factor receptor; HPV, human papillomavirus; MBC, metastatic breast cancer; MMR, mismatch repair; MSI-H, microsatellite instability-high; NET, neuroendocrine tumor; NPR, non-progression rate; SCLC, small-cell lung cancer.

Figure 3

Tumor response shown as change in sum of tumor diameter over time (efficacy set). The sum of the diameters of baseline target lesions is shown. Treatment discontinuation is shown at the time of the last tumor assessment carried out on or before discontinuation. CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.

Figure 3

Tumor response shown as change in sum of tumor diameter over time (efficacy set). The sum of the diameters of baseline target lesions is shown. Treatment discontinuation is shown at the time of the last tumor assessment carried out on or before discontinuation. CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.