The development:

In October 2022, Dostarlimab met its primary endpoint of Objective Response Rate (ORR) in a head-to-head trial against Pembrolizumab (KEYTRUDA, Merck) in NSCLC (vide PERLA trial – a global, randomized, double-blind phase II trial of 243 patients).

Read more: https://www.grgonline.com/post/grg-health-competitive-intelligence-ci-perspectives-and-opinions-october-2022

Opening thoughts:

Dostarlimab – an asset that GlaxoSmithKline (GSK) obtained by acquiring Tesaro, is proving dependable in sundry trials.

This is probably a blessing since the GSK – Tesaro transaction has had more than its fair share of headlines…..and the price tag (USD5.1 billion) was not even at the top of that list!

However, a lot more must be done by GSK to ensure smooth sailing.

Thankfully, Dostarlimab -gxly injection (TSR-042, brand name JEMPERLI) is a key asset that has always remained in the spotlight, mostly for the right reasons.

Asset Outline:

Profile – Dostarlimab-gxly injection (TSR-042, brand name JEMPERLI) is a humanized monoclonal antibody (IgG4 isotype) PD-1 inhibitor that targets the mismatch repair deficiency mutation (dMMR). Dostarlimab is particularly interesting since the dMMR mutation occurs in multiple indications (including breast, endometrial, uterine, prostate, rectal). Besides, dMMR tumors may also develop Microsatellite Instability (or MSI)
Potential – Dostarlimab’s potential is believed to be high; the asset was a healthy influencer (besides the oral PARP inhibitor Niraparib (brand name Zejula) and the TIM-3 mAb Cobolimab) that drove GSK to acquire Tesaro
Performance – Since 2021, Dostarlimab is approved across the EU and the United States for recurrent or primary advanced dMMR endometrial cancer that has progressed on or following prior therapy with a Platinum-containing regimen. The initial approval was granted based on preliminary results vide GARNET trial or NCT02715284 since indication – specific therapies were unavailable for patients
Asset Spotlight:

Past achievement – Dostarlimab was in further trials when it took centerstage (worldwide) in July/August 2022
o Claim to fame – Dostarlimab took centerstage because of its celebrated, outstanding results (100% remission of disease) in a subgroup of patients who had dMMR rectal cancer (all either Stage II or III disease)

o Claim specs – The study conducted at Memorial Sloan Kettering Cancer Center (MSKCC), New York (United States), intravenously dosed these patients with Dostarlimab every three weeks for a duration of six months

Relevance – Since the current SOC for rectal cancer is neoadjuvant Chemoradiotherapy (CRT) followed by Surgery and adjuvant chemotherapy, the celebration for Dostarlimab’s performance is understandable

Recent achievement – In October 2022, Dostarlimab announced a landmark in NSCLC
o Claim to fame – Dostarlimab met its primary endpoint (ORR) in NSCLC (vide Open label, Double blind PERLA trial)

o Claim specs – The study put Dostralimab head-to-head against Pembrolizumab (KEYTRUDA, Merck)

Relevance – Since Dostarlimab went head-to-head against KEYTRUDA which is widely regarded as a top intervention, evaluating Dostarlimab’s performance in detail is likely to establish its standing as one more promising option and/or a challenger.

Next steps – Hopefully, future data will show not just ORR but survival benefit too. This would help to clarify the extent of Dostarlimab’s advantage in a key indication vis-à-vis an established gamechanger (KEYTRUDA).

This is going to be relevant since ORR alone might not be accurately reflecting survival advantage.

The CI angle:

What generates interest –
o PERLA: GSK already has Zejula (which competes with the better – established LYNPARAZA, Astra Zeneca) in pharmacies. Now, with Dostarlimab meeting its primary endpoint in PERLA and progressing further in the COSTAR Lung trial - comprising patients with advanced NSCLC who progressed in spite of prior anti-PD-L1 therapy and chemotherapy, GSK’s future as an oncology player looks promising, currently

What generates anxiety –
dMMR Rectal cancer:

Trial span: The widely lauded rectal cancer study was constrained by the (low) number of patients and a single trial institution
Durability of response: Evidence of durable response can emerge after these patients are followed for at least three years to assess (the absence of) recurrence
Price point (and affordability): Given the trial results (and the cost of Tesaro’s acquisition), Dostarlimab is likely to be available at a steep price
Ø Reportedly, the nine doses of Dostarlimab that are required over a six-month period cost USD99,000 (INR 77 lakh). Such a price tag will adversely affect uptake, especially in the third world where future disease burden is likely to surpass the first world

Ø Further, third world markets are likely to be characterized by late diagnosis (poor prognosis), low per capita income, and poor penetration of insurance

NSCLC:

The PERLA study included first-line patients (N = 243) with metastatic nonsquamous NSCLC and no known sensitizing EGFR, ALK or receptor tyrosine kinase-1 mutation, BRAF V600E mutation, or other genomic mutation for which an approved targeted therapy is available. How this affects Dostarlimab’s promise remains to be seen especially since the phase 2 PERLA study is not likely to enable any drug applications. Further, development plans for Dostarlimab in frontline NSCLC remain unclear
Self-sufficiency:

Tesaro reportedly developed Zejula by licensing Astra Zeneca’s technology platform! This is not unusual in the industry but how it will affect Dostarlimab, GSK’s oncology outlook, and GSK’s tech-specific self-sufficiency remains to be seen
Closing Opinion:

The Tesaro portfolio is proving useful for GSK, representing promise in the medium term. However, all assets report a subset-specific disease focus besides lacking synergies with established interventions.

GRG Health’s CI engagements have also revealed that there is a lack of adequate awareness and engagement even for proven assets like ZEJULA. This is concerning.

Further, GSK seems to lack a coherent strategy ever since the loss of its Respiratory assets – it would be worrying if an erstwhile, established leader in respiratory diseases relies more on M&A than either organic evolution or balanced development for the way forward.

The collective effect of such concerns is probably reflected in the consistently low share price of GSK.

In view of the above and the potential crowding of the PD-1/L1 space, GSK should aggressively focus on generating robust, broad-based data across indications to firmly establish its portfolio in oncology at the earliest.