Working Together Works

LQ: Although in 2021 a number of precision therapy options are available for non-small cell lung cancer (NSCLC) patients, late-stage disease mortality rates are still considerably high. From a clinician’s standpoint, what important unmet needs remain in this field?

FC: The lack of curative solutions represents the biggest unmet need. Existing targeted therapies are only transiently effective; eventually, most tumor cells will acquire drug resistance, with many patients experiencing relapse leading to poor clinical outcomes.

LQ: Is addressing resistance part of your focus at Loxo/Lilly? And, as a pathologist by training, which types of diagnostic tools do you view as clinically valuable?

NS: Yes, the development of therapy resistance is a very real concern. At Loxo/ Lilly, we seek to predict the likely mechanisms of resistance to a given drug so that we can develop molecules to overcome those prior to their clinical manifestation. Identifying resistance when it occurs is a challenge and liquid biopsy could be an effective tool to help us identifying early resistance onset. Unfortunately, the use of liquid biopsy is still limited in clinical practice globally, mainly for access reasons. We must therefore democratize availability and enable widespread use while ensuring optimal technical performance. Moreover, both tissue sequencing and liquid biopsy should occur locally in hospital pathology laboratories rather than being sent out. This would have benefits beyond simply timely identifying resistance – for example, it would encourage closer collaboration between oncologists and pathologists and reduce operational barriers to testing.

FC: In my opinion, liquid biopsy testing will increase dramatically, driven by its growing range of applications: diagnosis, biomarker detection, prediction of treatment response, and assessment of relapse risk. Liquid biopsy is already being progressively used in gene fusion testing – although sensitivity remains an issue – and to predict patient response to immunotherapy. Another advantage of the liquid biopsy approach is that it helps avoid invasive procedures – good news for the patient. There is no doubt that this method is changing the way we do things; in fact, I hope it signals an end to traditional approaches focused entirely on tissue collection!

NS: That said, such a novel diagnostic makeup will equally require experts with appropriate training in running and interpreting solid and liquid biopsy tests. Pathologists can add real value by providing the oncologists with not just a meaningless list of genomic variants, but also the associated clinical interpretation – the “so what.” By training residents and pathologists to become partners in diagnosis, we will get better outcomes. This is especially important in smaller community practices, where oncologists see many tumor types and cannot keep up with current advances. We must all push for pathology to become integral to clinical patient management. If we don’t, the field will become irrelevant; if we do, it has a bright future – and patients will benefit.

LQ: I agree, and I would also like to highlight that liquid biopsy enables us to speed up the diagnostic workflow. But is getting a fast diagnosis important for clinical outcomes?

FC: It’s extremely important. Slow test turnaround times may result in patients’ having to wait weeks prior to commencing therapy. This is both psychologically difficult for the patient and clinically undesirable for disease management.

NS: Yes; patients do better when treated with the best possible drugs at the earliest possible times. If a genomic diagnosis is not provided in a timely manner, patients default to chemotherapy/immunotherapy – which may not be the best treatment option for them.

LQ: Targeted therapies alone cannot yet provide a cure for lung cancer patients. What is the potential of combination therapies?

FC: First, we need to understand how to safely combine these different drugs; we don’t yet know enough about possible toxicities. Nevertheless, some combinations of precision therapy and chemotherapy seem promising and may be more effective than monotherapies. Immunotherapy combinations are also generating exciting data and combinations of targeted therapies are beginning to show promise. Once we understand combination-related toxicities, combination therapy is likely to become an important option – but, at present, I think we still need to know more about their likely safety and side effects.

NS: When using the newer, more selective targeted therapies, I think resistance is more of a problem than toxicity. Investigating combinations of targeted therapies therefore makes sense – but we should pursue development of second-generation therapies at the same time. We are currently learning and will continue to learn how we can manage resistance by combining TKI inhibitors with other therapeutic approaches.

LQ: Precision in oncology has been supported by the active participation of companies, such as Lilly and Thermo Fisher, who develop new therapies and novel diagnostic tools. What else should the corporate sector do to ensure that lung cancer patients benefit from advanced therapies and diagnostics?

FC: Continuous medical education remains a key need; in my opinion, many pathologists and clinicians need a change in mentality. Physicians, for example, often focus on delivering a specific treatment when they should be focusing on correctly diagnosing and staging disease. That is fundamental because, once the disease is correctly diagnosed and staged, treatment decisions can be streamlined and assisted by guidelines. But if we are to change these attitudes, we must invest more in education – that is, educating people not on the best drug to use, but on the best methodology to use when selecting the most appropriate drug.

NS: Another area that could benefit from attention is reimbursement. Current payment models are intended to reward high-quality cancer care, but do not similarly emphasize genomic testing. Recently, U.S. Oncology Network presented a retrospective analysis at ASCO showing that only ~50 percent of eligible patients with NSCLC are appropriately screened for relevant genomic biomarkers (1). That’s crazy! In the end, it’s about getting clinicians and pathologists to work together effectively.

LQ: Thank you both for sharing your perspective and thoughts! I completely agree that we need more education-oriented initiatives to ensure that the diagnostics bar is set higher. Additionally, notwithstanding potential side effects, it seems that combinational therapies will have a huge impact on diagnostics. Predicting the impact of such a treatment regimen will require a comprehensive, multiplexed genomic test approach – definitively outpacing single-biomarker testing and making it obsolete. In any case, all of us – from frontline physicians to pharma and medical device companies – must collaborate to ensure the community thoroughly understands that the impact of targeted therapies will only be unleashed upon the full embrace of the advanced diagnostic molecular testing paradigm. In this context, the simplicity and speed of liquid biopsies may be a gamechanger. There’s still much to do – but we are on the right track!