Oncologist feedback from our Physician Views snap-poll last week indicates that Merck & Co.'s Keytruda/chemotherapy combination is a new, practice-changing, standard of care in first-line non-small-cell lung cancer (see Physician Views Poll Results: Oncologists proclaim a resounding win for Merck & Co.'s practice changing Keynote-189 data ).
An equally important consideration is the potential future role of Bristol-Myers Squibb's Opdivo/Yervoy combination . Data presented at the recent AACR annual meeting showed a significant progression-free survival benefit over chemotherapy in patients with higher rates of tumour mutation burden (TMB); a result that simultaneously raises the prospect of TMB as a new prospective biomarker for patient selection.
To better understand how these data may impact future clinical practice, we are snap-polling US and EU5-based oncologists - in collaboration with Medefield MedePolls - with the following questions…
Initial results from the CheckMate-227 trial show the combination of Opdivo (nivolumab) and low-dose Yervoy (ipilimumab) reduced the risk of disease progression or death by 42% versus chemotherapy (hazard ratio=0.58) in first-line metastatic non-small-cell lung cancer patients with high tumour mutational burden (TMB) - defined as ≥10 mutations/megabase. Progression-free survival (PFS) benefit was observed regardless of PD-L1 expression levels (HR of 0.62 in patients with PD-L1 ≥1% and 0.48 in patients with PD-L1 <1%) and in both squamous and non-squamous patients (HRs of 0.63 and 0.55, respectively).
Based on an early descriptive analysis, an encouraging overall survival benefit was observed with the combination of Opdivo and Yervoy versus chemotherapy in patients with high TMB (a 21% reduction in risk of death/HR=0.79).
The Grade 3-4 treatment-related adverse event rate with Opdivo and Yervoy was 31% versus 36% with chemotherapy.
How clinically compelling are these data?
CheckMate-227 enrolled 1739 patients in total, of which 1004 (58%) were evaluable for TMB analyses. Of all TMB-evaluable patients, 444 (44%) had TBM ≥10 mut/Mb, including 139 patients randomised to receive Opdivo plus Yervoy and 160 patients randomised to chemotherapy.
Given that less than 10% of all patients enrolled in CheckMate-227 had TBM ≥10 mut/Mb and were randomised to receive Opdivo plus Yervoy, do these data validate TMB as an independent and reliable biomarker in first-line NSCLC that can be used as an alternative to PD-L1 IHC?
No, but promising nevertheless
Do you think the combination of Opdivo and Yervoy should be approved on the strength of these data and the size of the patient cohort?
Assuming the combination of Opdivo/Yervoy is approved, to what extent would the requirement to test for TMB limit utilisation?
When we polled oncologists last week, an overwhelming majority of respondents (over 95%) said that new data showing the combination of Keytruda and chemotherapy significantly improved PFS and overall survival in first-line metastatic non-squamous NSCLC patients - irrespective of PD-L1 status - was practice changing and should be considered the new standard-of-care therapy.
To what extent will the broad efficacy benefit of the Keytruda/chemotherapy combination and requirement to test for both PD-L1 and TMB limit in order to identify patients best suited for treatment with Opdivo/Yervoy limit the potential use of Opdivo/Yervoy (based on initial data from CheckMate-227) to squamous patients?
Results and related analysis will shortly be published for FirstWord Pharma PLUS subscribers to read, with the opportunity for non-FirstWord Pharma PLUS subscribers to purchase these findings. To be notified when poll results and analysis become available, please click here .
As always, FirstWord would very much like to receive your feedback  and suggestions. Note: FirstWord Polls are powered by Medefield MedePolls, a fast-turnaround service to conduct instant polls of up to five questions with guaranteed samples that include physicians from dozens of specialties and over 100 markets. To conduct this poll with a different audience, or an entirely different poll, contact us at firstname.lastname@example.org .