The American Society for Radiation Oncology (ASTRO) Annual Meeting took place in Washington, D.C., from September 29,2024 to October 2,2024. As one of the most prestigious annual events in radiation oncology, ASTRO offers a platform to share the latest advances, focusing on radiotherapy as a primary treatment for various cancers, alongside key updates in technology and basic research.

This year, much attention was drawn to the INNOVATION study, which evaluated the efficacy and safety of combining the next-generation ALK inhibitor Iruplinalkib with chemoradiotherapy (CRT) for unresectable ALK/ROS1-positive locally advanced NSCLC. Results from Part 1 were presented, demonstrating the substantial benefits of this innovative approach in enhancing the objective response rate (ORR) and extending progression-free survival (PFS). Impressively, the ORR was 86%, and the median PFS had not yet been reached, with a 12-month PFS rate of 100%.

In an exclusive interview, Dr. Linlin Wang, the Principal Investigator of the INNOVATION study from Shandong Cancer Hospital, shared her insights into the study’s innovative design, key outcomes, and their potential impact on the future treatment of NSCLC, particularly in ALK-positive cases. She also discussed the promising future for ALK-TKIs in treating this subset of patients and the upcoming research needed to further optimize treatment strategies.

Pioneering the Combination of Iruplinalkib and CRT in ALK/ROS1-Positive Unresectable NSCLC

Q1: The preliminary findings of the INNOVATION study garnered significant attention at the 2024 ELCC meeting. At ASTRO 2024, Part 1 of the study was again presented. Could you elaborate on the innovative aspects of this study and its importance for the treatment of unresectable ALK/ROS1-positive NSCLC?

Dr. Wang: At the 2024 ELCC meeting, we presented the preliminary data from the INNOVATION study, and now at ASTRO 2024, the first phase results have been shared again. These outcomes reinforce the role of ALK-TKIs in treating ALK/ROS1-positive stage III NSCLC, specifically in cases where surgery is not an option.

Over the past few years, advances in ALK-TKIs have allowed patients with advanced ALK-positive NSCLC to achieve prolonged survival. In 2023, the ALINA study showed that postoperative ALK-TKI adjuvant therapy could significantly delay disease progression in stage II-III ALK-positive NSCLC patients who were eligible for surgery. However, there is still a gap in evidence regarding the best treatment for patients with unresectable stage III disease. Currently, the standard of care for these patients includes concurrent or sequential chemoradiotherapy, followed by immunotherapy consolidation. However, studies like PACIFIC and several real-world data have revealed that patients with driver mutations such as ALK or EGFR tend to gain limited benefit from immunotherapy consolidation.

This year, studies like LAURA and POLESTAR confirmed the strong PFS results from EGFR-TKI consolidation therapy, setting a new benchmark for treating stage III EGFR-mutant NSCLC. For ALK-positive patients, small-scale real-world studies have hinted at the feasibility of ALK-TKI consolidation, but we still lack solid prospective evidence. That’s why we launched the INNOVATION study in 2022 to explore treatment options for this patient group in a more structured, forward-looking manner. The study has been progressing well, and as the follow-up data matures, we hope it will provide valuable insights for clinical treatment.

The true innovation in the INNOVATION study lies in combining the next-generation ALK inhibitor Iruplinalkib with CRT and exploring its safety and efficacy in unresectable ALK/ROS1-positive NSCLC patients. Over a median follow-up period of 17.7 months, Iruplinalkib consolidation after definitive CRT achieved an ORR of 86%, and the 12-month PFS rate reached 100%. Importantly, no patients developed grade 3 or higher pneumonitis. These results suggest that ALK-TKI consolidation can significantly improve patient outcomes without compromising safety.

Through this prospective study, we’ve demonstrated the potential for overcoming the limitations of immunotherapy consolidation in ALK-positive patients by validating the safety and efficacy of combining Iruplinalkib with CRT.

Breaking Barriers in Efficacy: Iruplinalkib and CRT Outperform Existing Approaches

Q2: The ORR for the CRT + Iruplinalkib consolidation approach reached 86%, with median PFS/TTP still not reached and a 12-month PFS rate of 100%. These results are superior to those from CRT alone, CRT combined with immunotherapy, or ALK inhibitors used independently. Furthermore, no grade 3 or higher drug-related pneumonitis was observed. What is your take on these findings?

Dr. Wang: Treating locally advanced unresectable NSCLC is particularly challenging, and radiotherapy plays an essential role in managing these patients. When designing the study, we were primarily concerned with the safety of combining ALK-TKIs with standard CRT, especially the rate of pneumonitis, which is a known complication of radiotherapy. Consequently, our primary endpoint was the occurrence of grade 3 or higher pneumonitis within 90 days post-radiotherapy, in accordance with CTCAE v5.0 criteria.

In Part 1, patients underwent consolidation therapy with Iruplinalkib following CRT. As long as no more than two out of eight patients developed grade 3 or higher pneumonitis, we could proceed to Part 2, which utilized a “sandwich” design. In this phase, patients first received induction therapy with Iruplinalkib, followed by concurrent CRT, and then consolidation therapy with Iruplinalkib afterward. This phase enrolled 22 patients to further evaluate the incidence of pneumonitis and confirm the safety of the regimen.

In Part 1, among the seven ALK-positive patients and one ROS1-positive patient, none developed grade 3 or higher pneumonitis, and no one had to reduce the dose or discontinue Iruplinalkib due to pneumonitis. The most notable grade 3-4 adverse events related to Iruplinalkib were one case of elevated creatine phosphokinase and one case of hypercholesterolaemia. These findings reinforce the safety and tolerability of Iruplinalkib as a treatment option.

In terms of efficacy, comparing the results of the INNOVATION study with historical data:

• Durvalumab consolidation after CRT: median PFS of 11.3 months
• ALK-TKI consolidation after CRT: median PFS not yet reached, median follow-up of 15.7 months
• CRT alone: ORR of 45.1%, median TTP of 14.6 months, 12-month TTP rate of 60.8%
• ALK-TKI alone: ORR of 71.8%, median TTP of 17.8 months, 12-month TTP rate of 68.8%
• INNOVATION (CRT + Iruplinalkib consolidation): ORR of 86%, median PFS/TTP not reached, median follow-up of 17.7 months, 12-month PFS/TTP rate of 100%.

These comparisons suggest that the combination of Iruplinalkib and CRT offers considerable advantages in improving ORR and extending PFS, potentially shifting the current treatment paradigm for unresectable stage III ALK-positive NSCLC. We are eager to enroll more patients and gather more long-term data to further validate this treatment’s effectiveness and safety.

Given the positive results, we’re also exploring the possibility of chemo-free treatment strategies for these patients. ALK-TKIs alone have already shown remarkable efficacy in treating advanced NSCLC. For locally advanced cases, we are considering the potential safety of combining radiotherapy with targeted therapies. The safety data from the INNOVATION study provides a good reference for concurrent ALK-TKI and radiotherapy treatment, and we’re optimistic about future applications of chemo-free strategies in clinical settings.

Looking Ahead: Precision and Individualized Treatment with ALK-TKIs

Q3: With the progress of the INNOVATION study, the future of ALK-TKI treatment in locally advanced ALK/ROS1-positive NSCLC is becoming clearer. What do you see as the future research directions for Iruplinalkib?

Dr. Wang: The positive results from the INNOVATION study suggest that ALK-TKIs, like Iruplinalkib, could be a viable treatment option for unresectable, locally advanced ALK/ROS1-positive NSCLC. Looking ahead, future research will likely explore combining Iruplinalkib with other therapies, such as anti-angiogenic treatments, to further improve survival outcomes and quality of life for patients with ALK-positive lung cancer.

In addition, there has been significant progress in the perioperative use of ALK-TKIs. For example, the ALINA study showed that adjuvant alectinib significantly reduced the risk of recurrence or death in early-stage ALK-positive NSCLC. The ALNEO study, presented at WCLC, demonstrated promising neoadjuvant results, with 39% of patients achieving a major pathological response (MPR) and 17% reaching a complete pathological response (pCR) without grade 3 or higher adverse events. The feasibility and safety of neoadjuvant ALK-TKI therapy were further supported by the NAUTIKA1 study. Research into the use of Iruplinalkib in the perioperative setting is ongoing, and we eagerly await the results.

There are still many unanswered questions about the optimal use of ALK-TKIs in treating both locally advanced and perioperative ALK-positive NSCLC. How do we best combine ALK-TKIs with local treatments like surgery or radiotherapy? How long should patients remain on ALK-TKI therapy? What criteria should guide drug selection? What are the resistance mechanisms that develop during early-stage ALK-TKI treatment, and how will they affect subsequent therapies? As more research is conducted, we expect to gain clearer answers to these questions.

For Iruplinalkib’s future development, the identification of predictive biomarkers will be crucial. Research in this area will help us personalize treatment strategies and further optimize outcomes for patients.

Note: Data from different studies cannot be directly compared. The information presented here is intended to highlight developments in the field.

References:

1. 2024 ASTRO poster 61456.

Dr. Linlin Wang, Chief Physician, Postdoctoral Fellow in Oncology, PhD Supervisor Director of the Third Thoracic Radiotherapy Department, Shandong Cancer Hospital Director of the Cadre Healthcare Office Taishan Scholar Youth Expert of Shandong Province Recipient of the 12th Shandong Youth Science and Technology Award Board Member of the Chinese Society of Clinical Oncology (CSCO) Standing Committee Member of the Second Youth Council of the Chinese Anti-Cancer Association Executive Member of the Lung Cancer Committee of the China Health Promotion Foundation Chairman of the Youth Council of the Shandong Society of Clinical Oncology Deputy Director of the Lung Cancer Branch of the Shandong Anti-Cancer Association Deputy Director of the Palliative Medicine Branch of the Shandong Medical Association