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ASCO 2024: Lung Cancer

CME

Conference to Clinic: Expert Analysis of the Top Abstracts in Lung Cancer From the 2024 Oncology Meeting in Chicago

Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™

Released: August 23, 2024

Expiration: February 22, 2025

Natasha Leighl
Natasha Leighl, MD, MMSc, FRCPC, FASCO
Zofia Piotrowska
Zofia Piotrowska, MD
CME/CE Information

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ADRIATIC: Consolidation Therapy With Durvalumab for Limited-Stage Small-Cell Lung Cancer

Zofia Piotrowska, MD:
There have been few advances in the treatment of LS-SCLC during the past few years, and at ASCO 2024, we saw exciting updates on the use of immunotherapy in this setting with the ADRIATIC trial. We think of ADRIATIC as being like the PACIFIC trial, but for small-cell lung cancer. In the setting of unresectable stage III NSCLC, the PACIFIC trial provided support for the use of durvalumab, a PD-L1 inhibitor, as consolidation after concurrent CRT with a significant improvement in PFS and OS when compared with placebo.1

Similarly, the ADRIATIC study looked at consolidation therapy with durvalumab after concurrent CRT in patients with LS-SCLC. ADRIATIC was a randomized, double-blind phase III trial that enrolled 730 patients with LS-SCLC, which was defined as stage I/II inoperable or stage III disease.2 Like the PACIFIC trial, patients enrolled on ADRIATIC completed chemotherapy and radiation before enrollment. Patients received 3-4 cycles of platinum etoposide and once-daily or twice-daily radiation, as both are considered standard options. Prophylactic cranial radiation was permitted, but both CRT and prophylactic cranial irradiation must have been completed before randomization. After completing concurrent CRT, patients were assessed for disease progression, and those who did not have disease progression were then enrolled and randomized in this study.

The 730 enrolled patients were randomized to one of 3 treatment arms, but this abstract focused on 2 of these arms. In the first arm, patients were treated with durvalumab 1500 mg every 4 weeks until PD or for up to 24 months. They were compared with patients receiving placebo. In the third arm of the study, patients received durvalumab plus the CTLA-4 inhibitor tremelimumab, but we are still awaiting those results.

The coprimary endpoints of this study were PFS and OS for durvalumab vs placebo. The secondary endpoints were PFS and OS for durvalumab plus tremelimumab compared with placebo, OS/PFS landmarks, and safety.

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ADRIATIC: Baseline Characteristics

Zofia Piotrowska, MD:
In total, 730 patients were randomized, with 264 assigned to the durvalumab group and 266 to the placebo group. Baseline characteristics and prior treatments were well balanced between the arms. The radiation schedule was once daily for 73.9% of patients in the durvalumab group and 70.3% in the placebo group, and it was twice daily for 26.1% in the durvalumab group and 29.7% in the placebo group. In addition, 53.8% of patients in each arm received prophylactic cranial irradiation.

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ADRIATIC: Overall Survival and Progression-Free Survival (Dual Primary Endpoints)

Zofia Piotrowska, MD:
This was a positive study for OS and PFS. We saw an improvement in OS with the addition of durvalumab after CRT. The median OS for durvalumab vs placebo was 55.9 months vs 33.4 months (HR: 0.73; 95% CI: 0.57-0.93; P = .0104). The 24-month and 36-month OS were 68.0% vs 58.5% and 56.5% vs 47.6%, respectively. Median PFS improved with durvalumab vs placebo with a median of 16.6 months vs 9.2 months (HR: 0.76; 95% CI: 0.61-0.95; P = .0161).

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ADRIATIC: Overall Survival Subgroup Analysis

Zofia Piotrowska, MD:
When examining OS by subgroups, the HRs indicate that all patients derived significant benefit from durvalumab. Analyzed subgroups included disease stage at diagnosis, time to randomization after concurrent CRT, prior chemotherapy regimen, and radiation schedule.

Here, patients who were randomized to treatment less than 14 days after completing concurrent CRT had a better OS HR than those who were randomized 14-27 days after completion of concurrent CRT and those who were randomized 28 days or more after concurrent CRT (HR: 0.47 vs 0.59 vs 0.90). This is similar to findings from the PACIFIC trial in NSCLC, which revealed that patients who began immunotherapy within 14 after concurrent CRT experienced better outcomes compared with those who initiated treatment later (HR: 0.33 vs 0.70, respectively).3 Although it remains unclear whether this observation is because these were the patients who did best with chemotherapy and radiation and were fit and able to start treatment, it is a notable finding.

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ADRIATIC: Progression-Free Survival Subgroup Analysis

Zofia Piotrowska, MD:
Similarly, when examining PFS by various subgroups, patients across all subgroups benefited from durvalumab treatment.2

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ADRIATIC: Safety

Zofia Piotrowska, MD:
There were no unexpected safety signals observed in this study.2 Approximately 16% of patients in the durvalumab arm and 10% in the placebo arm experienced adverse events (AEs) leading to treatment discontinuation. As anticipated, immune-related AEs were more prevalent in the durvalumab arm. Pneumonitis or radiation pneumonitis, which can occur after chemotherapy and radiation, was a concern. There is always a worry that adding immunotherapy may increase the risk of pneumonitis. However, the incidence was comparable, with 38% in the durvalumab arm and 30% in the placebo arm, most of which were low grade, but approximately 3% were grade 3/4.

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ADRIATIC: Most Frequent Adverse Events

Zofia Piotrowska, MD:
If we examine the breakdown of different AEs, the frequency of radiation pneumonitis was similar across the 2 arms, with 22.9% in the durvalumab arm and 23.4% in the placebo arm. Other AEs observed were consistent with those typically seen with immunotherapy and in various aspects of lung cancer patient care.

When considering pneumonitis as being separate from radiation-related pneumonitis, the incidence of drug-related pneumonitis was relatively low, at 10.7% in the durvalumab arm and 6.0% in the placebo arm. However, in clinical practice, distinguishing between radiation pneumonitis and immunotherapy-related pneumonitis can be challenging. The key takeaway from this study is that both types of pneumonitis can occur in patients who receive concurrent CRT followed by immunotherapy, and this necessitates careful monitoring.

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ADRIATIC: Clinical Implications

Zofia Piotrowska, MD:
The results of the ADRIATIC trial led to a standing ovation at the plenary session at ASCO 2024, and these are exciting results for patients with limited-stage disease, an area where we have not seen progress in a long time. Any improvement in OS is commendable, but we are seeing an impressive 22-month improvement in OS. ADRIATIC is bringing immunotherapy, a treatment previously reserved for those with extensive-stage disease, to patients with LS-SCLC.

The consensus at ASCO was that ADRIATIC is a practice-changing study. Everyone has been eager to see an advance in the care of patients with LS-SCLC. Pending regulatory approval, we anticipate that concurrent CRT followed by durvalumab treatment given until disease progression or for up to 2 years will become a standard of care for patients with LS-SCLC.

Natasha Leighl, MD, MMSc, FRCPC, FASCO:
The results of the ADRIATIC study have immediate clinical impact. This phase III study demonstrated significant OS and PFS improvement over placebo, with no new AEs identified. Of interest, durvalumab was only associated with a small increase in radiation pneumonitis, reported in 38.0% and 30.2% of patients, respectively, a minor increase that is manageable with current treatment strategies. This study represents a significant advancement in clinical practice and supports the use of checkpoint inhibitors in patients with SCLC, especially when administered as consolidation therapy during early-stage disease. Durvalumab is the first and only immunotherapy to demonstrate a survival benefit in LS-SCLC and should become the new standard of care in this setting.

Which of the following findings was reported from the phase III ADRIATIC trial comparing durvalumab vs placebo as consolidation therapy in patients with LS-SCLC without progressive disease (PD) following standard-of-care concurrent chemoradiotherapy (CRT)?

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