Physician Views: If approved, will US oncologists use Keytruda with chemotherapy in first-line NSCLC?

From a strategic perspective, it was with some significance that Merck & Co. recently announced the FDA has accepted its supplementary new drug application for Keytruda to be used in combination with chemotherapy for the treatment of first-line metastatic, non-squamous, non-small-cell lung cancer regardless of PD-L1 expression (Stealing their thunder? – Merck & Co. does it again).

Last year, Keytruda was approved as monotherapy for treatment naïve NSCLC patients whose tumours express PD-L1 levels of 50 percent or greater; a population estimated to account for approximately 25 percent of the first-line market. Approval of Keytruda in combination with chemotherapy, for the label Merck is seeking, would expand the addressable market to approximately 80 percent to 85 percent of the treatment naïve population, estimate analysts at BMO Capital Markets.

However, even assuming FDA approval is granted, will oncologists use this combination with any enthusiasm?

Merck's application is based on a small, albeit impressive, dataset from the Keynote-021 (Cohort G) study. A randomised Phase II trial that enrolled 123 patients. Data were presented at last year's ESMO congress, demonstrating an overall response rate (ORR) of 55 percent for the Keytruda plus chemotherapy combination versus 29 percent for chemotherapy alone, and a median progression-free survival benefit of 13 months for Keytruda plus chemotherapy versus 8.9 months for chemotherapy.

Importantly, the two treatment arms demonstrated comparable safety profiles and the combination of Keytruda plus chemotherapy was shown to be particularly effective in PD-L1-negative patients, where it demonstrated an ORR of 57 percent versus 13 percent for chemotherapy alone. PD-L1 negative patients are estimated to account for approximately 25 percent of the first-line NSCLC market and typically show minimal therapeutic response to PD-(L)1 inhibitor monotherapy.

At six months, however, the overall survival (OS) rate in both treatment arms was 92 percent. Although Merck has noted there was extensive patient crossover in the trial; 52 percent of patients receiving chemo-monotherapy crossed over to an anti-PD-(L)1 therapy, while no patients receiving Keytruda plus chemotherapy did, these data will do little to allay concerns among key opinion leaders that using PD-(L)1 inhibitor therapy and chemotherapy in combination provides minimal or no long-term durable benefit and improvement in OS. Until more data is available, many physicians may prefer to use sequential, rather than concurrent use, of PD-(L)1 inhibitors and chemotherapy.

To better ascertain the mind-set of practising oncologists ahead of potential approval for this combination in May, we are asking US-based oncologists the following questions…

Are you based in an academic or community setting?

Academic

Community

The FDA has accepted a filing for Keytruda plus chemotherapy for treatment of metastatic or advanced, non-squamous NSCLC regardless of PD-L1 expression and with no EGFR/ALK tumour aberrations. Filing is based on data from a 123-patient, randomised Phase II study showing a 55% ORR for Keytruda/chemo versus 29% for chemo and a mPFS of 13 months for Keytruda/chemo versus 8.9 months for chemo. Six-month OS was 92% for both arms; 52% of chemo-only patients crossed over into other arm. Safety profiles for both arms were comparable.

Assuming approval of Keytruda/chemo in May, would you consider using this combo in patients who you would otherwise consider treating with chemotherapy?

No

Yes – very infrequently

Yes – infrequently

Yes – frequently

Yes – very frequently

Data shows improved response rate for Keytruda/chemo to be greatest versus chemo only in PD-L1 negative patients; an ORR of 57% for Keytruda/chemo versus 13% for chemo only. Taking into account that PD-1 inhibitor monotherapy tends to offer little benefit to these patients, and assuming approval of Keytruda/chemo in May, would you consider using this combo in PD-L1 negative patients?

No

Yes – very infrequently

Yes – infrequently

Yes – frequently

Yes – very frequently

Which of the following statements best describes your current stance on the use of Keytruda/chemotherapy for the treatment of first-line NSCLC patients based on the data submitted to FDA?

Very enthusiastic about this data and clinical profile offered by the combination; will use if approved  

Enthusiastic but need to see durability effect and OS benefit before changing treatment practice/data provides insufficient evidence to support use of concurrent pembro/chemo treatment instead of sequential use

Not enthusiastic – FDA should not approve this combination on strength of data

Do you agree with the view that if subsequent data show an OS benefit in favour of PD-1/chemo versus chemo alone, this combination will prove highly popular with oncologists as it offers a cheaper combination option versus immunotherapy plus immunotherapy combinations and physicians are extremely familiar with the toxicity profile of chemotherapy?

No

Yes – agree somewhat

Yes – agree

Yes – agree completely

Results and related analysis will 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.

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