ViewPoints: All eyes on ASCO

Some key themes to watch in Chicago early next month, following publication of conference abstracts on Wednesday.

Lung cancer remains a key focus

Competitive positioning of immunotherapies in first-line non-small-cell lung cancer will again be a prominent feature, with focus sharpening on the treatment of patients with squamous histology.

Merck & Co. announced earlier this month that it has already filed a Keytruda/chemotherapy combination for accelerated approval based on data from the Keynote-407 trial; confirming this combination met its interim overall response rate (ORR).

Abstract #105 shows an ORR of 58.4 percent for Keytruda/chemotherapy versus 35 percent for chemotherapy alone. It has been suggested that results from a second interim analysis, which would include progression-free survival (PFS) and overall survival (OS), data may be available prior to ASCO.

Roche's IMPower-131 trial shares a similar design, and the combination of Tecentriq and chemotherapy has already met its PFS endpoint. More data will be disclosed in a late breaking abstract nearer the meeting.

See KOL Views Results: Tecentriq’s IMpower131 readout nice start but leading oncologist says more evidence needed to change habits in squamous NSCLC

Incremental updates are expected from Bristol-Myers Squibb's CheckMate-227 trial, which is assessing the combination of Opdivo and Yervoy in both squamous and non-squamous NSCLC patients.

See KOL Views Results: Keytruda is new standard in NSCLC but CheckMate-227 is useful starting point for TMB, says leading medical oncologist and Physician Views Poll Results: Oncologists see early promise in Bristol-Myers Squibb's latest lung cancer data

Initial data from the '227 trial for Opdivo and Opdivo plus Yervoy in combination with chemotherapy in patients with PD-L1 expression of <1 percent will also be presented. Abstract #9001 indicates a hazard ratio of 0.74 (0.68 in non-squamous patients) and while comparisons to Merck's Keynote-189 dataset are limited, these results may silence the suggestion that Opdivo is an inferior PD-1 inhibitor to Keytruda, note analysts.

New disclosures in abstract #9002 - the subject of which is Roche's IMPower-150 trial - drew a cautious assessment from analysts. Those at Morgan Stanley said an interim OS analysis suggests that Tecentriq may not be superior to Avastin in this trial; in first-line non-squamous patients, Tecentriq plus chemotherapy showed a non-significant HR of 0.88 versus Avastin plus chemotherapy, although the triple combination of Tecentriq, Avastin and chemotherapy did demonstrate a significant OS HR of 0.78 versus Avastin plus chemotherapy.

Analysts at Credit Suisse noted "although the Tecentriq and Keytruda trials are not directly comparable we expect physicians will compare this to the HR of 0.49 shown in Keynote-189," adding "we believe with this OS data it will be difficult for Roche to compete against Keytruda in this population."

Physician Views Poll Results: Oncologists proclaim a resounding win for Merck & Co.'s practice changing Keynote-189 data

Merck will also look to enhance its leading position in the first-line market with data from Keynote-042 (Keytruda monotherapy in patients with PD-L1 expression >1% expression), which is another late-breaker. Merck disclosed this study met its OS primary endpoint last month.

The next-generation

Merck KGaA has been touting M7824 - a PD-L1 antibody with a chemical linked to two molecules of TGF-beta trap - for some time.

See Spotlight On: Merck KGaA offers an alternative approach to the PD-(L)1 rat-race and Spotlight On Interview: Merck KGaA's R&D renaissance – FirstWord discusses immuno-oncology aspirations with global head of R&D Luciano Rossetti

Data presented previously was mixed; and in very sick, heavily treated patients; but new results (abstracts #9017 and #3007) show clear efficacy and tolerability in second-line NSCLC and HPV associated cancers.

Lung cancer data is particularly impressive, wrote analysts at Bernstein, and validates Merck's aspirations for the compound in this tumour type; showing an ORR of 25 percent in PD-(L)1 naïve patients, 40.7 percent in PD-L1 positive patients and 71.4 percent in PD-L1 high patients. This suggests M7824 could compete with established PD-(L)1 inhibitors in first-line patients, with its efficacy potentially enhanced by combination use with chemotherapy, they add.

Loxo's target for success

Selected for 'best of show' status at ASCO, initial disclosure of data for Loxo's RET inhibitor Loxo-292 had an immediate impact on the company, sending its share price up 18 percent after the close on Wednesday.

In 32 patients with RET alterations, LOXO-292 showed an ORR of 69 percent including a 65 percent ORR in NSCLC. While this data "is well above expectations, where investors were expecting an ORR of no more than 50 percent," noted analysts at Morgan Stanley, LOXO-292 did underperform Blueprint Medicine's data for BLU-667 in medullary thyroid cancer patients.

ViewPoints: Blueprint lays down a promising marker in RET duel

That said, Loxo management has already confirmed that as a result of a later data cut-off (April versus use of data with a January cut-off in the abstract), results for LOXO-292 will improve when presented next month.

Bristol and Lilly’ cytokine bets in focus

Bristol-Myers Squibb paid a lot of money upfront for a piece of Nektar Therapeutics' NKTR-214 in February; hopeful that it can be combined with its own immunotherapies Opdivo and Yervoy (ViewPoints: Is Bristol-Myers Squibb’s mega-deal for NKTR-214 a steal?)

However, a virtual overnight collapse in research around PD-(L)1 and IDO inhibitor combinations - following a negative readout from Incyte and Merck’s ECHO-301 study - has heightened uncertainty levels around immuno-oncology combinations; particularly those being studied in small single-arm trials.

This, and super-high expectations for NKTR-214, partially explain why shares in Nektar fell after the close on Wednesday.

Also contributing was the fact that new abstracts contain older data for the combination of Opdivo and NKTR-214, which were collected before the February abstract deadline. On its fourth quarter earnings call, management disclosed updated response rates of 64 percent for first line melanoma, 71 percent in first line RCC, and 60 percent in first and second line NSCLC; results broadly in line with data presented at SITC last year but in slightly larger patient cohorts.

Eli Lilly’s recent acquisition of ARMO Biosciences looks an increasingly sensible deal; lead asset AM0010 - a pegylated version of IL-10 - showed a response rate of 41 percent in 26 NSCLC patients when combined with either Keytruda or Opdivo, including a 33 percent ORR in 12 patients with PD-L1 expression levels <1 percent.     

See also - ViewPoints: Eli Lilly makes a billion-dollar bet on cytokines to join the I/O club

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