Immunotherapy Finds a Role in Frontline Small Cell Lung Cancer and Mesothelioma

Checkpoint inhibitors have failed to improve progression-free survival (PFS) and overall survival (OS) as second-line therapy and maintenance therapy in small cell lung cancer (SCLC), but this class of agents continue to show encouraging activity worthy of a paradigm shift up front.

The frontline role with immunotherapy has extended to patients with mesothelioma, as well. 

“SCLC and mesothelioma have been difficult cancers to treat, and immunotherapy has not made an impact until very recently, where, in the first-line setting, we have improved outcomes and new standards of care for the treatment of SCLC and mesothelioma,” said Naiyer A. Rizvi, MD, Price Family ​Professor of ​Medicine, director of Thoracic Oncology, and co-director of Cancer Immunotherapy at Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, said in a presentation during the 5th Annual International Congress on Immunotherapies in Cancer^™.

The first robust trial that demonstrated the potential for immunotherapy up front was the phase 3 IMpower133 trial. In the trial, patients with extensive-stage SCLC were randomized 1:1 to 1200 mg of intravenous atezolizumab (Tecentriq) plus carboplatin or etoposide for four 21-day cycles, or placebo plus carboplatin or etoposide followed by maintenance atezolizumab and placebo, respectively.

At a median follow-up of 13.9 months, the median PFS was 5.2 months in the atezolizumab arm vs 4.3 months in the placebo arm (HR, 0.77; 95% CI, 0.62-0.96; P = .017).¹ The 6-month PFS rate was 30.9% in the atezolizumab arm vs 22.4% in the placebo arm. The 12-month PFS rates were 12.6% and 5.4%, respectively. 

At a median follow-up of 22.9 months, the median OS was 12.3 months with atezolizumab vs 10.3 months with placebo (HR, 0.76; 95% CI, 0.60-0.95; P = .0154).² The 18-month OS rates were 34.0% and 21.0%, respectively. The 24-month OS rates were 22.0% and 16.8%, respectively. 

The median duration of response (DOR) was 4.2 months in the atezolizumab arm vs 3.9 months in the placebo arm (HR, 0.70; 95% CI, 0.53-0.92). However, more than half of patients in the placebo arm experienced ongoing response in the atezolizumab arm at last follow-up (n = 7 vs n = 18, respectively).

In the subgroup analysis, all patients except those with brain metastases (HR, 1.07; 95% CI, 0.47-2.43) derived benefit from atezolizumab.

“IMpower133 is really the first study in over 20 years to really show a meaningful improvement in OS vs standard of care in first-line SCLC. These data led to the adoption of chemotherapy plus immunotherapy as a first-line standard of care for extensive-stage SCLC,” said Rizvi.

These data were recapitulated in findings from the phase 3 CASPIAN trial, said Rizvi. In the trial, patients with extensive-stage SCLC were randomized 1:1:1 to 1500 mg of durvalumab (Imfinzi) plus etoposide every 3 weeks for up to 4 cycles, etoposide every 3 weeks for up to 6 cycles, or durvalumab plus 75 mg of tremelimumab plus etoposide for up to 4 cycles, followed by durvalumab, optional prophylactic irradiation, and durvalumab, respectively. 

At over 2 years of follow-up, the median OS was 12.9 months in the durvalumab/etoposide arm vs 10.5 months in the etoposide arm (HR, 0.75; 95% CI, 0.62-0.91; P = .0032). The 24-month OS rates were 22.2% and 14.4% respectively.³ 

The median PFS was 5.1 months in the durvalumab/etoposide arm vs 5.4 months in the etoposide arm (HR, 0.80; 95% CI, 0.66-0.96). The 24-month PFS rates were 11.0% and 2.9%, respectively.

“The trial was not powered to compare durvalumab plus chemotherapy vs durvalumab plus tremelimumab plus chemotherapy, but these 2 arms did perform fairly similarly, and both did perform similarly to chemotherapy alone,” said Rizvi.

In an exploratory analysis, tumor mutational burden was not shown to be predictive of an improvement in OS for durvalumab plus or minus tremelimumab/etoposide vs etoposide alone, indicating that the marker should not be used to select patients for treatment.⁴ 

Despite the progress that has been made, there is room for improvement, said Rizvi, who cited the phase 3 SKYSCRAPER-02 trials as 1 study that could push the needle further.

In SKYSCRAPER-02, patients will be randomized to 1:1 to 1200 mg of atezolizumab plus chemotherapy plus 600 mg of tiragolumab every 3 weeks for 4 cycles or atezolizumab plus placebo in the same schedule, followed by atezolizumab/tiragolumab or atezolizumab/placebo, respectively. 

Mesothelioma

Immunotherapy has also been subject to research in mesothelioma, explained Rizvi, who pointed to the phase 3 CheckMate 743 trial, where patients with malignant pleural mesothelioma will be randomized 1:1 to 3 mg/kg of nivolumab (Opdivo) every 2 weeks plus 1 mg/kg of ipilimumab (Yervoy) every 6 weeks or cisplatin or carboplatin plus pemetrexed for 6 cycles.

Initial results from CheckMate 743 demonstrated a median PFS of 6.8 months with chemotherapy vs 7.2 months with chemotherapy (HR, 1.00; 95% CI, 0.82-1.21). The 24-month PFS rates were 16% and 7%, respectively.⁵ 

OS data, when broken down by subtype, revealed a significant improvement with the combination vs chemotherapy in patients with non-epithelioid tumors, at 18.1 months vs 8.8 months, respectively (HR, 0.46; 95% CI, 0.31-0.68). The 24-month OS rates were 38% and 8%, respectively. 

In epithelioid tumors, the median OS was 18.7 months with the combination vs 16.5 months with chemotherapy (HR, 0.86; 95% CI, 0.69-1.08). The 24-month OS rates were 42% and 33%, respectively.  

“These data are really meaningful, supporting immunotherapy only as first-line therapy [in mesothelioma],” said Rizvi.

Additionally, although OS favored the combination vs chemotherapy, irrespective of PD-L1 expression, patients who had greater than 1% expression derived more benefit from the combination (HR, 0.69) vs those with PD-L1 expression less than 1% (HR, 0.94).

The response rates were comparable in the combination and chemotherapy-alone arm, at 40% and 43%, respectively. The median DOR was 11.0 months and 6.7 months, respectively. At 2 years, 32% of patients in the combination arm were still in response vs 8% in the chemotherapy-alone arm. 

References

1. Horn L, Mansfield AS, Szczęsna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379(23):2220-2229. doi:10.1056/NEJMoa1809064.
2. Liu SV, Horn L, Mok T, et al. IMpower133: Characterisation of long-term survivors treated first-line with chemotherapy ± atezolizumab in extensive-stage small cell lung cancer. Ann Oncol. 2020;31(suppl 4):S974-S987. doi:10.1016/annonc/annonc290 
3. Paz-Ares LG, Dvorkin M, Chen Y, et al. Durvalumab ± tremelimumab + platinum-etoposide in first-line extensive-stage SCLC: updated results from the phase III CASPIAN study. J Clin Oncol. 2020;38(suppl 15):9002. doi:10.1200/JCO.2020.38.15_suppl.9002
4. Goldman JW Garassino MC, Franks A, et al. Durvalumab ± tremelimumab + platinum-etoposide in 1L ES-SCLC: characterization of long-term clinical benefit and tumor mutational burden in CASPIAN. Ann Oncol. 2020;31(suppl 4):S1212-S1213. doi:10.1016/j.annonc.2020.08.2328
5. Bass P, et al. First-line nivolumab + ipilimumab vs chemotherapy in unresectable malignant pleural mesothelioma: CheckMate 743. Presented at: 16th World Conference on Lung Cancer; September 6-9; Denver, CO. Abstract 3.