As a consequence of the COVID-19 pandemic, the 2020 World Congress in Lung Cancer (WCLC), planned to be held live in Singapore in August, was postponed and moved to a fully virtual event that was held on 28 – 31 January 2021. Below are snapshots from some of the trials presented during the Presidential Symposium and oral abstract sessions.

• Lung Cancer Screening Supported by the Taiwan TALENT Trial

Evidence from multiple lung cancer screening trials (NLST, NELSON, MILD) has shown that low-dose computed tomography (LDCT) screening leads to early diagnosis of lung cancer and can reduce mortality in patients with a history of smoking. Lung cancer in never-smokers, a distinct disease with differences in genomic profiles and patterns of progression, is a rising worldwide threat, especially in East Asia. Interesting data from the Taiwan Lung Cancer Screening in Never Smoker Trial (TALENT)¹ confirmed the effectiveness of LDCT screening in high-risk never-smokers. In Taiwan, 53% of lung cancers occur among never-smokers. Among 12,011 enrolled participants, the lung cancer detection rate was 2.6%, which is higher than in the US NLST (1.1%) and the NELSON trial (0.9%); furthermore, 96.5% of lung cancers were confirmed as stage 0–I. The study also revealed a higher prevalence of lung cancer in participants with, versus without, a family history of the disease (3.2% versus 2.0%, respectively), especially in those with a first-degree relative (3.3%). The study indicates that LDCT screening for high-risk never-smokers is feasible and that family history of lung cancer may increase the risk of the disease.

• Neoadjuvant Atezolizumab May Benefit Patients With Early-Stage NSCLC

The primary analysis of the Lung Cancer Mutation Consortium 3 (LCMC3)² – a large, phase II trial (n=181) of neoadjuvant atezolizumab monotherapy followed by resection in patients with untreated, resectable non-small-cell lung cancer (NSCLC; stage IB–IIIB) – showed a major pathologic response (≤10% viable tumor cells) of 21%, and a pathologic complete response rate of 7%, in evaluable patients (EGFR- and ALK- negative). The study demonstrated that 43% of patients had downstaging following atezolizumab treatment and 19% had upstaging. The majority of patients underwent surgery after two neoadjuvant cycles of atezolizumab, and 88% had surgery within a 20-day protocol window, an earlier and narrower timescale compared with previous neoadjuvant chemotherapy trials. Complete resection (R0) rates were high (92%), with low peri-operative morbidity and mortality rates. The regimen was well tolerated, with no new safety signals. In addition, immature survival data suggest that neoadjuvant atezolizumab may have a survival advantage compared with historical data. The investigators concluded that that the study supports the ongoing phase III IMpower 030 study of atezolizumab combined with platinum-based chemotherapy.

• New Data on Sotorasib Activity in KRAS^G12C NSCLC

The KRAS^G12C mutation is a key oncogenic driver that occurs in 13% of patients with lung adenocarcinoma. Sotorasib is a highly selective irreversible, first-in-class inhibitor KRAS^G12C that recently showed durable clinical benefit in the phase I CodeBreak 100 trial.³ New results from the NSCLC cohort of the registrational phase II CodeBreaK 100 trial,⁴ which included 124 evaluable heavily pre-treated patients (including platinum-based therapy and PD1/L1 inhibitors) with advanced KRAS^G12C-mutated NSCLC, showed that sotorasib (960 mg once daily) resulted in early, deep and durable responses, validating the results from the phase I trial. The overall response rate was 37.1%, the median duration of response was 10 months, and the median progression-free survival (PFS) was 6.8 months. Treatment-related adverse events were reported as being generally mild and manageable. Tumor responses were observed across different biomarker subgroups, including patients with negative or low PD-L1 expression and those with STK11 mutations. A confirmatory phase III CodeBreaK 200 trial is currently enrolling.

• Trastuzumab Deruxtecan Promising for Patients With HER2-Overexpressing NSCLC

The ongoing phase II DESTINY-Lung01 trial is evaluating trastuzumab deruxtecan (T-DXd), a novel antibody–drug conjugate, in two cohorts of patients with advanced non-squamous NSCLC: patients whose tumors overexpress HER2; or those that contain a HER2-activating mutation. Previously, T-DXd activity has been shown in patients with heavily pre-treated, HER2-mutated NSCLC⁵ (confirmed overall response rate [ORR]: 61.9%). In the interim analysis⁶ of T-DXd in the HER2-overexpressing cohort (49 patients), the ORR confirmed by independent central review was 24.5%. Median duration of response was 6.0 months and disease control rate was 69.4%. Estimated median PFS was 5.4 months. While the safety profile of T-DXd was generally manageable, there were 8 cases (16.3%) of drug-related interstitial lung disease (ILD). Dose interruption, reduction, and treatment discontinuation were reported in 53.1%, 34.7%, and 22.4% of patients, respectively. The results provide preliminary evidence of antitumor activity in this patient population, although ILD was noted as a serious risk factor. Enrolment to an additional lower-dose cohort is ongoing to further understand the safety and efficacy profile of
T-DXd.

• High Response Rates With Lurbinectedin Plus Irinotecan Combination in Relapsed Small Cell Lung Cancer

In June 2020, lurbinectedin monotherapy was granted accelerated approval by the US Food and Drug Administration for the treatment of patients with metastatic small-cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy. Results from the phase Ib/II trial⁷ of lurbinectedin and irinotecan combination in patients with SCLC after failure of first-line therapy (≤2 prior lines of therapy; n=21) demonstrated an ORR of 62% and a median PFS of 6.2 months. Notably, antitumor activity was significant in patients with platinum-resistant disease (ORR: 50%; PFS: 4.8 months), and in the third-line setting (ORR: 38%; PFS: 4.2 months). Although the safety profile was reported as being transient and manageable, with mainly hematological abnormalities, fatigue, and diarrhea, dose reductions and dose delays were required in 52.4% and 28.6% of patients, respectively, and 33.3% required red blood cell transfusions. The study population is being expanded to further explore the combination of lurbinectedin plus irinotecan in relapsed SCLC. As noted by the discussant of the trial, it will be important to test the combination in a larger phase III trial.

References

1. Yang P, et al. WCLC 2020; Abstract PS01.02.
2. Lee J, et al. WCLC 2020; Abstract PS01.05.
3. Hong DS, et al. N Engl J Med. 2020;383:1207–1217.
4. Li B, et al. WCLC 2020; Abstract PS01.07.
5. Smit EF, et al. ASCO 2020; Abstract 9504.
6. Nakagawa K, et al. WCLC 2020; Abstract OA04.05.
7. Ponce-Aix S, et al. WCLC 2020; Abstract OA11.04.