NSCLC: A Look at Top Abstracts From ESMO Virtual Congress 2020

NSCLC: A Look at Top Abstracts From ESMO Virtual Congress 2020

Question

Please discuss the results of PIONeeR in non-small cell lung cancer for patients who have been treated with PD-(L)1 immune checkpoint inhibitors (ICIs).¹ Do you think PD-L1–positive cell density is a potential new predictive biomarker?

Answer

The data shown are highly preliminary. It does make sense though that PD-L1–positive cell density may be associated with better response based on what we know about PD-L1 presence in tumor cells.

They are exploring over 400 potential biomarkers, both tissue- and blood-based, with analysis in the first 100 patients. At this time, results presented are biologically plausible and have been captured to a different degree in other studies (for example, the atezolizumab trials also included assessment of PD-L1 expression in immune cells). In the PIONeer study, the investigators assessed cell density of PD-L1 expression in all cell types (tumor and stroma). However, it will be premature to indicate how much better the predictive ability is, whether used on its own or to complement the current PD-L1 [tumor proportion score]. Findings reported are preliminary and we look forward to future analysis with more patients accrued.

The key question is: When a biomarker can be used for making treatment decisions? This still has to be validated to see how it performs relative to our current standard.

Question

It was determined from the LungART trial that postoperative conformal radiotherapy (PORT) for completely resected non-small cell lung cancer (NSCLC) and pN2 disease cannot be recommended as a standard of care.² Does this finding change practice, in your view?

Answer

What is the current practice? That is the question. There is quite a bit of heterogeneity of care regarding postoperative radiation in patients with N2-positive lymph nodes.

LungART is a needed study and is certainly practice changing for N2-positive NSCLC patients who have R0 resection. It provides concrete support to our current practice of not routinely administering PORT after surgery to stage III patients. At our institution, we do not administer PORT to patients who had mediastinal clearance or response to neoadjuvant systemic chemotherapy. This study provides additional evidence against PORT in patients who have documented N2 disease at the time of resection, regardless of whether preoperative chemotherapy was administered or not. It is to be noted that patients with extracapsular mediastinal nodal involvement were excluded from the study.

The study also presented concerns that for some patients, there might be increased risk for harm due to toxicities. That would contribute to the fact that even though we saw disease-free survival improvements with PORT, in the end, this didn’t translate into overall survival prolongation. We await the full details of the trial in the upcoming publication.

Question

In the CROWN trial, the researchers asserted that frontline tyrosine kinase inhibitor (TKI) lorlatinib has the potential to be a new standard of care.³ Should the strategy of “best TKI first” apply here? And, based on CROWN, do you think brain metastases will be important for patient selection?

Answer

One should define what “best TKI” in this setting refers to. The issue at hand is that the comparison of lorlatinib to crizotinib is outdated. With caveats regarding cross-trial comparison in mind (eg, heterogeneity in patients, treatments rendered), the central nervous system (CNS) response appears to be better than what we see with the second-generation ALK TKIs. However, there are side effects that can be significant despite dose reduction. It will be a case-to-case discussion with patients, potentially taking into consideration their ALK variant and/or degree of CNS involvement.

Question

In ADAURA, osimertinib was said to have superior control of central nervous system recurrence in the resected EGFRm NSCLC setting.⁴ What do the new results coming out of ESMO Virtual Congress 2020 mean for a chance at a cure in this patient group?

Answer

Unfortunately, cure is unlikely. There are also multiple questions regarding the rigor in screening patients for baseline CNS metastases prior to enrollment. Nonetheless, the CNS activity is expected/not surprising. What is important to know will be the quality-of-life impact (eg, are CNS metastases in the control arm diagnosed typically in the asymptomatic state due to surveillance screening vs symptomatic presentation?) with adjuvant osimertinib vs placebo. Overall survival data are not mature and there are lingering questions on how well the crossover will be for the control arm (ie, control patients receiving osimertinib as first-line therapy at the time of disease progression).

This update does not change overall the results of ADAURA seen in its initial report released at ASCO20 Virtual Meeting in June. The jury is still out on whether overall survival will also be improved.

Question

In an early-phase trial, the KRAS^G12C inhibitor sotorasib was shown to have a favorable safety profile as well as antitumor activity in advanced NSCLC.⁵ Do we have enough data to understand if G12C inhibitors can safely combine with immune checkpoint inhibition?

Answer

We are participating as a clinical trial site. I have personal experience and may be biased due to my familiarity with the agent and having observed firsthand the impact on our patients.

Even though the response data [are] not as impressive as other targeted therapies, its overall clinical activity (responses plus stable disease) as well as significantly better toxicity profile (relative to other targeted therapies) is very encouraging, especially as the first-in-class agent against this historically elusive drug target. Many patients thank me for discussing and enrolling them to this trial with them as their experience is significantly better compared to how they felt while on chemotherapy or immunotherapy. Many of these patients have good quality of life as their cancer is under control and the treatment regimen has manageable side effects.

However, with regards to the safety of combination with immunotherapy, I have inside information and it may not be appropriate to divulge. All I can say is that data from the clinical trial will be presented soon and there are no surprises.