KRAS analy­sis vaults Mer­ck­'s flag­ship Keytru­da back in­to the spot­light

The jew­el in Mer­ck’s crown — Keytru­da — just got more pre­cious.

On Thurs­day, the US drug­mak­er broke out an ex­plorato­ry analy­sis show­ing the check­point in­hibitor helped pa­tients live longer as the first line of de­fense in pa­tients with a form of non-small cell lung can­cer (NSCLC) whose tu­mors ex­pressed PD-L1, re­gard­less of KRAS sta­tus.

Jonathan Cheng Mer­ck

KRAS mu­ta­tions oc­cur in rough­ly a fifth of pa­tients di­ag­nosed with non-small cell lung can­cer, and da­ta sug­gest that these mu­ta­tions are as­so­ci­at­ed with poor re­sponse to treat­ment, not­ed Jonathan Cheng, vice pres­i­dent of on­col­o­gy clin­i­cal re­search at Mer­ck Re­search Lab­o­ra­to­ries, in a state­ment.

The ex­plorato­ry analy­sis was con­duct­ed on the KEYNOTE-042 tri­al, which pit­ted the block­buster ther­a­py Keytru­da against chemother­a­py in metasta­t­ic non­squa­mous NSCLC whose tu­mors ex­pressed PD-L1. Of the 1,274 pa­tients in the tri­al — 301 pa­tients had KRAS evalu­able da­ta (n=232 with­out any KRAS mu­ta­tion; n=69 with any KRAS mu­ta­tion, in­clud­ing n=29 with the KRAS G12C mu­ta­tion).

Keytru­da re­duced the risk of death by 58% in pa­tients with any KRAS mu­ta­tion, and by 72% in pa­tients with the KRAS G12C mu­ta­tion, ver­sus chemother­a­py, the com­pa­ny said.

For decades, sci­en­tists have scratched their heads about KRAS, the no­to­ri­ous can­cer-caus­ing pro­tein. “Some have de­scribed KRAS as the beat­ing heart of can­cer,” Dar­ryl Mc­Connell, Boehringer’s head of dis­cov­ery re­search not­ed in an in­ter­view with End­points News ear­li­er this year.

Dar­ryl Mc­Connell

KRAS’ smooth ter­rain long elud­ed ma­nip­u­la­tion, large­ly due to the ab­sence of a dis­tinct pock­et for a drug to latch on to. How­ev­er, the process of tri­al and er­ror fi­nal­ly yield­ed progress — trig­ger­ing a flock of com­pa­nies, in­clud­ing Mer­ck, Am­gen, J&J, and As­traZeneca, to en­gi­neer com­pounds de­signed to an­nex the oft’ mu­tat­ed onco­gene. Re­cent­ly, Ger­many’s Boehringer In­gel­heim en­tered the fold. An­a­lysts have been in­tox­i­cat­ed with the po­ten­tial of KRAS drugs for use in can­cer pa­tients with few op­tions at their dis­pos­al — fore­cast­ing ap­proved drugs will reap bil­lions in peak sales.

The first KRAS pock­et es­tab­lished by Am­gen for at­tack is G12C, al­though small­er ri­val Mi­rati is at the large drug­mak­er’s heels. The KRAS G12C mu­ta­tion is found in rough­ly 14% of NSCLC pa­tients and 5% of col­orec­tal can­cer pa­tients. Un­like Am­gen and Mi­rati — Boehringer’s ear­ly-stage drug is a pan-KRAS in­hibitor hits SOS1 as well as G12C. SOS1 is a pro­tein that turns KRAS from an “off” to “on” state.

Am­gen’s keen­ly watched AMGN510 made a splash at the AS­CO con­fer­ence this year af­ter a small, ear­ly study showed five out of 10 pa­tients suf­fer­ing from ad­vanced, drug-re­sis­tant NSCLC saw a par­tial re­sponse to the ex­per­i­men­tal treat­ment, in­clud­ing one who went on to achieve a com­plete re­sponse af­ter the da­ta cut­off point. In Sep­tem­ber, those da­ta were up­dat­ed at the World Con­fer­ence on Lung Can­cer. Re­searchers tracked a 54% par­tial tu­mor re­sponse, and ob­served tu­mors shrink­ing in sev­en of 13 NSCLC pa­tients.

Mean­while, en­cour­ag­ing Phase I/II da­ta em­a­nat­ing from Mi­rati’s ex­per­i­men­tal drug, MRTX849, for ad­vanced sol­id tu­mors that har­bor KRAS G12C mu­ta­tions were un­veiled in late Oc­to­ber. The lit­tle biotech has tied up with No­var­tis — and the two are look­ing at com­bin­ing the G12C drug with a ther­a­py that tar­gets SHP2, which func­tions as a key reg­u­la­tor of cell cy­cle con­trol.

Rev­o­lu­tion Med­i­cines has the same po­ten­tial com­bo in-house. Oth­er KRAS con­tenders in­clude Mod­er­na and Mer­ck’s mR­NA-5671; J&J’s col­lab­o­ra­tion with Well­spring on ARS-3248, a G12C tar­get­ed small mol­e­cule; and AZD4785, li­censed by As­traZeneca from Io­n­is — al­though the com­pound has been dis­con­tin­ued af­ter a poor show­ing in clin­i­cal tri­als.

As an onco­gene, KRAS has the po­ten­tial to ren­der nor­mal cells can­cer­ous. Akin to HRAS and NRAS, it be­longs to the RAS fam­i­ly of onco­genes and plays a key role in cell di­vi­sion, cell dif­fer­en­ti­a­tion, and apop­to­sis.

M&A: a crit­i­cal dri­ver for sus­tain­able top-line growth in health­care

2021 saw a record $600B in healthcare M&A activity. In 2022, there is an anticipated slowdown in activity, however, M&A prospects remain strong in the medium to long-term. What are future growth drivers for the healthcare sector? Where might we see innovations that drive M&A? RBC’s Andrew Callaway, Global Head, Healthcare Investment Banking discusses with Vito Sperduto, Global Co-Head, M&A.

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