In an exclusive BioPharma APAC interview, Professor Benjamin Solomon, a distinguished Medical Oncologist at the Peter MacCallum Cancer Centre, Australia, and Principal Investigator of the groundbreaking ALINA study, shares key insights into the challenges of managing lung cancer in Asia. Discussing the pivotal Phase II results of the ALINA trial, Prof. Solomon delves into the potential implications for clinical practice, especially in the context of Asia where over 50% of trial participants were enrolled. Furthermore, he provides a preview of the Asia-specific results to be unveiled at ESMO Asia, offering a glimpse into the future of lung cancer treatment and the evolving role of targeted therapies.

Lung cancer has a significant impact on the Asian population, being both the most common cancer and the leading cause of cancer mortality in the region. Could you provide some insights into the specific challenges and nuances of managing lung cancer in Asia, and how these factors influenced the design and conduct of the ALINA trial?

Lung cancer is the leading cause of cancer related death in Asia and around the world. While many patients with lung cancer have been smokers, a large proportion of patients have never smoked. In these patients, molecular testing can identify oncogenic drivers, including mutations in EGFR and gene rearrangements involving ALK.

 ALK gene rearrangements are found in about 5% of patients with non-small cell lung cancer.

For patients who present with early-stage ALK positive NSCLC, recurrence rates remain high despite surgery and adjuvant cisplatin-based chemotherapy has modest efficacy and significant toxicity. The ALINA trial was designed to see if alectinib, a highly effective treatment for patients with advanced ALK+ NSCLC, could improve outcomes compared to chemotherapy when given after surgery in patients with early stage (Stage IB-IIIA) resectable ALK+NSCLC.

The ALINA trial has shown remarkable results with a 76% reduction in disease recurrence or death for people with ALK-positive early-stage non-small cell lung cancer. How do you envision these findings impacting the current landscape of lung cancer treatment in Asia, especially considering that more than 50% of the trial participants were from the region?

The ALINA trial indicates that adjuvant alectinib is a new and highly effective treatment option for patients with resected ALK+ NSCLC both in terms of reduced risk for recurrence or death but also through its effects on preventing intracranial recurrence. The latter is important as brain metastases are frequent and a cause of significant morbidity in patients with advanced ALK+ NSCLC.

The results of the study are consistent across subgroups including Asian patients who comprised approximately 55% of the study population. Given this it is expected that adjuvant alectinib would be a highly effective alternative to chemotherapy in the Asian region and around the world.

As the Principal Investigator of the ALINA trial, you and your team will be unveiling the Asia-specific results at ESMO Asia. Could you provide a preview of what these results reveal about the potential implications for clinical practice, and how this data may address the current limitations in treatment options for ALK-positive early-stage NSCLC?

The results of the Asian subgroup representing 140 patients enrolled in five Asian regions (comprising about 55% of the study population) are consistent with those of the entire study. The study endpoints of disease free survival (HR 0.39) and CNS disease free survival (HR 0.24) in patients with stage IB-IIIA were both positive in favour of alectinib compared with chemotherapy. Alectinib was well tolerated. Follow up remains immature for this cohort with relatively few patients having more than 36 months follow up.

In terms of clinical implication, these data highlight the importance of testing patients with resected NSCLC for ALK rearrangements and in patients found to have ALK rearrangements in their tumours adjuvant alectinib should be provided as an option for patients. 

Your work has led to regulatory approvals for first, second, and third generation ALK TKIs, defining new standards of care in the population with ALK-positive lung cancer. How do you see the field of lung cancer treatment evolving in the coming years, and what role do targeted therapies like ALK TKIs play in shaping this evolution?

The field has rapidly progressed since the identification of ALK rearrangements on lung cancer in 2007 by Dr Mano and colleagues from Japan. In the years that have followed we have seen approval for the first in class ALK TKI crizotinib in 2011 and subsequently second and third generation ALK inhibitors. These targeted treatments have transformed outcomes for patients with advanced ALK+ NSCLC, changing median survivals from 1-2 years prior to crizotinib to median survival in excess of 5 years in the era of second and third generation ALK TKIs.

The ALINA trial for the first time indicates that the effects of these highly effective targeted therapies in the advanced setting extend to the early-stage setting. In the years that follow we will find out if the benefit in DFS translates to an effect in improving OS as has been the case with Adjuvant Osimertinib for resected EGFR mutation positive NSCLC. There remain many additional questions to explore these include:

• What is the optimal duration of therapy?
• Is there a role for intensification of therapy potentially with the combination of chemotherapy and alectinib?
• Can ctDNA identify minimal residual disease?
• Is there a role for neoadjuvant therapy with ALK TKIs?

With your extensive involvement in global clinical trials and leadership roles, how do you perceive the collaborative efforts in advancing research and treatment strategies for lung cancer on a global scale? Are there unique challenges or opportunities that arise when conducting trials with a focus on the Asia-Pacific region?

Collaborative efforts are essential to drive research forward particularly when it comes to clinical trials. This is illustrated nicely in the ALINA trial in a subset of lung cancers where 257 patients with resectable ALK+ NSCLC were enrolled from 26 countries, with more that 50% of patients coming from Asia. This collaborative effort not only increases the pace of accrual and improves timelines to completion of trials but also ensures global representation and therefore applicability of the study findings. 

Within many countries in Asia delays in reimbursement and access to treatments remain problematic. And while these provide opportunities for clinical trials to provide access to new therapies – global policy and co-operation between governments and pharma are needed to improve access to important and potentially life saving treatments.

As a clinician-scientist, you have significantly contributed to improving outcomes for patients with lung cancer. Looking ahead, what do you believe are the most promising areas of research and innovation in lung cancer treatment, and how can these advancements be translated into meaningful improvements in patient care?

Translating the advances made in advanced disease to the early-stage where treatments can have even bigger impacts and possibly provide the opportunity for cure is an area of great excitement. While this has been demonstrated for immunotherapy in the neoadjuvant and adjuvant setting it has also been demonstrated for targeted therapies with EGFR and ALK inhibitors in the ADAURA and ALINA studies. It will be exciting to see how these treatments can be further optimised in terms of optimal duration and opportunities for risk-based intensification or deintensification in future studies. 

The role of targeted therapies in locally advanced disease is currently under exploration in the LAURA study (Osimertinib) and HORIZON-1 study(alectinib).

Circulating tumour DNA is emerging as a powerful tool for detection of minimal residual disease, prognostication, and monitoring of efficacy of therapies and identification of mechanisms of acquired resistance. It is expected that ctDNA will become incorporated into routine clinical care for these applications.

Finally further gains in advanced disease with targeted therapies are likely to come from new strategies or combinations to address or prevent acquired resistance and to target drug tolerant persister cells.