Spotlight On: What happened at ASCO this weekend...

Your one-stop shop for all the key takeaways from this year’s annual meeting of the American Society of Clinical Oncology (ASCO). We will be publishing further analysis of the key presentations throughout the week.

ASCO goes virtual

In response to the COVID-19 pandemic this year’s ASCO was a fully virtual affair. 

When we snap-polled oncologists in late March there was some concern this could dilute the meeting’s impact on clinical practice. Time will tell if this sentiment proves accurate; we will be polling oncologists in the next few weeks to gauge how ASCO 2020 was received by the physician community.  

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AstraZeneca’s ADAURA study steals the show 

AstraZeneca’s Tagrisso is the standard of care therapy for first-line metastatic EGFRm non-small-cell lung cancer (NSCLC) and compelling data presented at ASCO suggest it should be used to treat patients with earlier-stage disease whose tumours can be surgically removed, potentially adding billions of dollars to peak sales.

In patients with stage II-IIIa EGFRm NSCLC Tagrisso was shown to reduce the risk of disease recurrence or death by 83% and showed a 79% reduction in the overall study population which included patients with stage Ib disease, suggesting that a broad label will be sought by AstraZeneca.

Some commercialisation challenges lie ahead despite these impressive data. Disease free survival is a surrogate endpoint and some oncologists will want to see Tagrisso’s effect on overall survival before they prescribe. 

Around 30% of NSCLC patients are diagnosed before metastasis occurs but the required presence of an EGFR mutation reduces the number of new patients to approximately 3000 a year in the US, AstraZeneca estimates. Testing for EGFR mutations in earlier-stage patients is also less commonplace than in those with metastatic disease. 

AstraZeneca can also bask in the glow of yet more positive data for Enhertu, the HER2-targeted antibody drug conjugate (ADC) it paid a pretty penny to in-license co-development rights for from Daiichi Sankyo last year.

Already approved as a later line treatment for HER2 positive breast cancer, Enhertu has shown further promise as a potential therapy for HER2 positive NSCLC, gastric and colorectal cancer.

See also - KOL Views Results: Leading oncologist sees 1L potential from Enhertu in HER2-positive breast and gastric cancer

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Immunotherapy continues to expand its reach

Merck KGaA and Pfizer’s PD-L1 inhibitor Bavencio (avelumab) has struggled to carve out sales in a crowded immunotherapy market, but results from the JAVELIN Bladder 100 study show that it improved overall survival by 7.1 months versus best supportive care when used as a first-line maintenance treatment for advanced bladder cancer. 

A more pronounced effect was seen in patients who tested positive for PD-L1 but impressive data in all comers will likely see these results considered practice changing, experts have previously told FirstWord. Approximately 80% of patients with advanced bladder cancer respond to chemotherapy and would be eligible for treatment with Bavencio, though uptake (if approved) will also depend on the outcome of ongoing studies evaluating other immunotherapy agents in the first-line setting.

See also - ASCO20: Merck KGaA, Pfizer's Bavencio "cures" some patients with gestational trophoblastic tumours

Elsewhere, Merck & Co.’s Keytruda looks well placed to become a new standard of care first-line treatment for microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) unresectable or metastatic colorectal cancer, based on impressive progression free survival data presented at ASCO including confirmation that 40% of patients who received Keytruda were disease free 40 months later.

The KEYNOTE-177 study is yet to confer an overall survival benefit but KOLs are already enthusiastic about using Keytruda in the approximate 5% of biomarker-positive patients as a second-line treatment, following its US approval in this indication three years ago. Feedback from experts suggests some off-lable use in first-line patients is already occurring in MSI-H positive patients, despite the broader trend in CRC to hold immunotherapy back to the second-line as most patients respond to initial chemotherapy.

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JNJ-4528 hoping to ‘out’-manoeuvre  bb2121

Additional follow-up data from the Phase Ib/II CARTITUDE-1 trial continued to suggest that JNJ-4528 (formerly LCAR-B38M) from Legend Biotech and Johnson & Johnson may have best-in-class efficacy, but what really stood out is a safety profile that could differentiate it from competing anti-BCMA CAR-T cell therapies like bb2121 from bluebird bio and Bristol Myers Squibb.

Mark Wildgust, vice president of global medical affairs at Janssen’s oncology unit, said he is particularly excited about the low rate of severe cytokine release syndrome (CRS) seen with JNJ-4528, as only two (7%) of 29 patients experienced grade 3 or worse, with a median time to onset of seven days.

“This is different than other CAR-T cells and even bispecifics, and is indicative of the slow expansion of [JNJ-4528] cells,” he noted, adding that cytokine release not peaking until seven days later “offers the opportunity to explore outpatient dosing in some patients.” This could further differentiate the programme from bb2121, which is further ahead in the race to market despite a recent ’refusal to file’ letter issued by the FDA due to questions on manufacturing.

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Bristol Myers Squibb outlines its 1L NSCLC pitch

The FDA stole a little of Bristol Myers Squibb’s thunder by approving the combination of Opdivo (nivolumab) and Yervoy (ipilimumab) plus limited chemotherapy for front-line treatment of NSCLC on May 26, more than two months ahead of the PDUFA date and a couple of days before the CheckMate-9LA data – the basis for the label expansion request – were presented.

The findings themselves were not terribly exciting, as they had already been top-lined when the abstract was revealed on May 14 and subsequently revealed in fuller detail when the new label was revealed earlier in the week. Thus, the full dataset simply reiterated an encouraging overall survival improvement (15.6 months versus 10.9 months for chemotherapy alone) that comes with a notable uptick in serious adverse events.

One question that oncologists will struggle with is teasing out how much benefit Yervoy is bringing to the table, a consequence of the CheckMate-9LA trial not having an Opdivo plus chemotherapy arm, and balancing it against the added toxicities – or if they will even bother to do so given how comfortable they have become with prescribing Merck & Co.’s Keytruda (pembrolizumab) in front-line NSCLC.

See also - KOL Views: I/O combos for 1L NSCLC in spotlight at ASCO – contenders or pretenders?

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Roche hopes its TIGIT will rule them all

Roche presented updated data from its CITYSCAPE trial of anti-TIGIT antibody tiragolumab in combination with Tecentriq (atezolizumab) in patients with NSCLC. While the updated results didn't include any groundbreaking changes relative to an abstract release last month, it did give Roche the opportunity to plead its case for the competitiveness of its TIGIT antibody, as well address outstanding investor questions from the initial disclosure. (See ViewPoints: Roche's TIGIT debut fails to curb investor appetites)

The CITYSCAPE data for tiragolumab have looked more promising than available results from its competitors, most notably Merck & Co.'s MK-7684. Roche has noted that it sees a definite benefit for its antibody via the incorporation of an intact Fc domain- but some, though not all, of its competitors have taken the same approach, complicating any conclusions about why tiragolumab may be overperforming in its checkpoint synergy.

"I think this speaks to the value of running a randomised study rather than trying to use historical or cross-study comparisons," said Ira Mellman, Genentech's VP of research oncology. Roche's CITYSCAPE data represent the only placebo-controlled trial from the drug class thus far.

Roche was also able to address the two biggest outstanding questions from investors for the data set; why the Tecentriq control arm might have underperformed, and why benefit for the TIGIT/PD-1 combo was reserved almost entirely for patients with high PD-L1 expression. Mellman speculated that a larger study- like its Phase III SKYSCRAPER programme- could show a less binary benefit than was seen in CITYSCAPE.

The same explanation also applied to relatively low response rates for the study's Tecentriq arm, which lowered the bar for success in the Tecentriq/tiragolumab combo. According to management,"it’s a small study, although randomised, and differences in numbers in one side versus another can account for differences in the response rate."

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Allogene's allogeneic offerings meet first autologous benchmark

Response rates reported by Allogene for its allogeneic, CD19-targeting CAR-T therapy suggest that the company is on its way to matching the performance of autologous counterparts- and without the graft versus host disease that is a key risk factor of the modality. Further, the company reported 'manageable' cases of cytokine release syndrome, meaning that its safety profile is also on par with its more established competitors.

The lynchpin for the performance of ALLO-501 seems to rely on Allogene's specific lymphodepletion regimen, which uses a CD52-depleting antibody to remove more host immune cells and enable more robust expansion of ALLO-501. That distinction could prove to be a key differentiator for the cell therapy, as Allogene is currently the only company targeting CD52.

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