Therapy Focus - First-Line Lung Cancer Is An Opdivo Vs. Keytruda Showdown

| About: Merck & (MRK)

New data from early studies of checkpoint inhibitors in non-small cell lung cancer emerged at Asco, but none represented the results that the oncology field is awaiting most eagerly.

This accolade is reserved for the outcome of the phase III studies of Merck & Co’s (NYSE:MRK) Keytruda and Bristol-Myers Squibb’s (NYSE:BMY) Opdivo in first-line NSCLC therapy that will likely determine how the most commercially important cancer indication divides up among competing agents. Other immunotherapies are waiting in the wings, but the initial battle hinges on the breadth of the possible NSCLC label that Opdivo and Keytruda might boast (see table below).

The Bristol and Merck drugs are both approved as second-line therapies in NSCLC, but Keytruda is indicated only for those patients whose tumour cells express PD-L1. Opdivo has no such restriction, and – with no need to conduct a companion test – has so far captured the lion’s share of NSCLC patients. In other respects the two agents are considered interchangeable, despite minor differences in efficacy and dosing schedules.

Up the chain

With these agents already established as the second-line standard, the next change in the field is expected to be a move to first-line therapy. This will be determined by the outcome of the Keynote-024 study of Keytruda, which is due imminently, and the Checkmate-026 trial of Opdivo, expected in November.

The two studies are very similar and test the drugs against platinum-based chemotherapy in the subgroup of patients who are “strong” expressers of PD-L1 – about 25% of patients. With Merck having already lost its first-mover checkpoint inhibitor advantage, the group's lead in first-line NSCLC could be a chance to even the balance against Bristol.

However, any advantage might be short-lived. This is because Bristol's study has a statistical design allowing all-comers to be tested if an initial benefit in "high PD-L1 expressors" is shown. Merck's Keynote-025 is recruiting only PD-L1-high patients.

Clearly an additional advantage can come from better efficacy. Later studies test the drugs in combination with first-line chemotherapy and/or in broader groups based on PD-L1 expression.

Signs

But what of the data in first-line therapy emerging at Asco? One closely watched presentation concerned Keynote-021, a multi-cohort phase I/II study of Keytruda plus platinum-doublet chemotherapy, immunotherapy or EGFR-targeted therapy.

In one cohort 24 patients who received Alimta, carboplatin and Keytruda as a front-line treatment followed by Alimta/Keytruda for up to two years achieved an objective response rate (ORR) of 71%. Furthermore, those with the highest level of PD-L1 expression showed a 75% ORR.

Pooled data from Checkmate-012, a phase Ib study of Opdivo and Yervoy, were also presented. Here the combination achieved an ORR of 39% to 47%, depending on dose. ORR averaged 57% in PD-L1-positive patients and reached 92% in the highest (≥50%) PD-L1 expressers. In patients who tested PD-L1-negative the ORR for the combination regimen was just 15%.

This combination is being assessed in the phase III Checkmate-227 trial, which has a projected completion date of January 2018. But competition in the NSCLC market looms, and a review by EP Vantage shows 23 phase III studies under way with PD-1/PD-L1 inhibitors.

Selected late-stage immuno-oncology trials in non-small cell lung cancer

Project/company

Enrolment

Study name

Trial ID

Data

Opdivo

(Bristol-Myers Squibb)

535

Checkmate-026

NCT02041533

Nov 2016

1,980

Checkmate-227

NCT02477826

Jan 2018

500

Checkmate-078

NCT02613507

May 2018

Keytruda (Merck & Co)

305

Keynote-024

NCT02142738

Jun 2016

570

Keynote-189

NCT02578680

Sep 2017

1,240

Keynote-042

NCT02220894

Feb 2018

560

Keynote-407

NCT02775435

Mar 2018

Tecentriq (Roche)

1,200

IMpower150

NCT02366143

Jan 2017

1,225

Oak

NCT02008227

Jun 2017

400

IMpower110

NCT02409342

Apr 2018

Durvalumab (AstraZeneca)

730

Arctic

NCT02352948

Feb 2017

702

Pacific

NCT02125461

May 2017

350

Caural

NCT02454933

Aug 2018

800

Nepture

NCT02542293

Oct 2018

Avelumab (Merck KGaA/Pfizer)

420

Javelin Lung 100

NCT02576574

Aug 2017

650

Javelin Lung 200

NCT02395172

Oct 2017

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The first threat is likely to come from Roche’s (OTCQX:RHHBY) Tecentriq, which is under review for second-line use in PD-L1 expressers, with a PDUFA date of October 19. A more direct threat could come in the form of Pfizer (NYSE:PFE)/Merck KGaA’s (OTCPK:MKGAY) avelumab, which is being studied in the first-line indication in the Javelin lung 100 study.

AstraZeneca (NYSE:AZN) has a number of phase III studies under way with durvalumab, though earlier this year it made a decision that, irrespective of their outcome, it would not file this project as monotherapy, instead seeking to build an immuno-oncology franchise based on the combination with tremelimumab. Its first study of this combination in PD-L1-negative third line-patients reads out in early 2017.

Either way, any lead that Keytruda will have thanks to its earlier data readout is likely to be short lived.

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