Friday Five – The week in review: ASCO special

Zytiga finds a second wind – KOL predicts a problem for Pfizer's Xtandi

New Phase III data presented at the ASCO annual meeting showed that Zytiga plus prednisone, in combination with androgen deprivation therapy (ADT), demonstrated a significant improvement in overall survival (OS) and significantly prolonged radiographic progression-free survival (rPFS) in patients with high-risk metastatic hormone-naïve prostate cancer (mHNPC) versus placebo plus ADT. Karim Fizazi, principal investigator of the LATITUDE trial, which was presented at ASCO, remarked "this is important new information, as not all patients respond well to the current standard of care."

The findings, also published in the NEJM, showed that Zytiga was associated with a 38-percent reduced risk of death versus placebo. Johnson & Johnson noted that median OS for the Zytiga group was not reached, but that it was 34.7 months in the placebo arm. Further, Zytiga cut the risk of progression or death by 53 percent versus placebo, with the groups achieving median rPFS of 33 months and 14.8 months, respectively.

KOL Views Results: LATITUDE is a big problem for Xtandi but clock is ticking for J&J to capitalise, according to leading urologist

"This is a big deal," one key opinion leader (KOL) told FirstWord this week, adding "I would not call the results terribly surprising, but the magnitude of effect may come as a bit of a surprise to some people."

ASCO updates prove largely inconsequential to current IO race, but show momentum is on Merck & Co.'s side

Data presented at ASCO this week did little to challenge the current status quo in terms of competitive positioning among the leading players in immuno-oncology.

Investors in Bristol-Myers Squibb remain cautious ahead of data from the pivotal Checkmate-227 trial readout, which is expected early next year and will determine whether the company's Opdivo/Yervoy combination has a role to play in first-line non-small-cell lung cancer (NSCLC). For some, additional concerns were raised after presentation of two-year follow-up data from a smaller, non-randomised Phase I trial looking at this same combination; in all comer patients, the Opdivo/Yervoy combination was only shown to deliver a modest benefit versus Opdivo monotherapy (but with greater toxicity and what would be considerable extra cost in a commercial setting).

ViewPoints: Bristol-Myers Squibb finds itself caught in Merck & Co.'s pincer movement

Merck & Co. was therefore able to retain momentum as the most upwardly-mobile player in immuno-oncology without the need for any ASCO fireworks. The company continues to exert pressure on its chief rival along two flanks; by strengthening its first-mover advantage in treatment-naïve NSCLC patients and by maintaining its lead as the most advanced Big Pharma player in IDO inhibition.

ViewPoints: ASCO delivers mixed messages for IDO inhibitors

IDO inhibitors – led by Incyte's epacadostat, for which positive combination data with Keytruda was presented at ASCO – may represent the next key opportunity to expand use of PD-(L)1 inhibitors into a larger number of patients. Roche remains unconvinced, announcing on Thursday it has handed back rights to NewLink's experimental IDO inhibitor GDC-0919.

Investors may need to look beyond Roche's APHINITY disappointment

Roche investors will perceive the company's experience at ASCO this year as one they would rather forget; the company's share price has declined more than 6 percent over the past week. In reality it was a case of the good, the bad and (arguably) the misunderstood for Roche in Chicago.

Data from the ALEX trial, studying Alecensa versus Pfizer's Xalkori as first-line therapy in ALK-positive NSCLC was one of the meeting's highlights, albeit if this result was largely expected and, from a commercial perspective, will have a more limited impact given the small proportion of lung cancer patients whose tumours carry an ALK mutation. That said, Alecensa more than doubled the progression-free survival benefit seen with Xalkori – the current standard of care – while delivering a significant reduction in brain metastases and superior toxicity profile. Rapid installation as the new gold standard in first-line therapy appears to beckon – ViewPoints: ASCO – Roche's ALEX study lives up to high expectations

Less impressive were data from the much anticipated APHINITY trial, assessing the combination of Herceptin plus Perjeta versus Herceptin alone in adjuvant HER2-positive breast cancer. While the addition of Perjeta was shown to confer an additional survival benefit, it remains unclear whether this will convert into significant real-world use of Perjeta in the adjuvant setting, with results also showing that only higher-risk patients lived longer with the combination – ViewPoints: Roche's APHINITY data appears to fall below oncologist expectations

Speaking at a Roche event during ASCO, breast cancer specialist Jose Baselga, from the Memorial Sloane Kettering Cancer Centre, argued the message from APHINITY had been lost during initial assessment of the data. Not only is a 19-percent reduction in risk of death very meaningful, said Baselga (a majority of oncologists we snap-polled earlier this year did not agree), but the data are "far from mature," and should improve over the next decade, he added.

An editorial in the NEJM was notably less enthusiastic and suggested the data were particularly disappointing in the context of how Perjeta has driven paradigm-shifts for the treatment of neo-adjuvant and metastatic HER2-positive breast cancer. Results of APHINITY also provide more evidence of just how revolutionary Herceptin has proven to be in this disease area; little consolation for investors licking their ASCO wounds, but a legacy worth celebrating (in tandem with the ALEX data) given the increased competition that Roche faces in the oncology market.

Loxo laps up the plaudits  

Right time, right place and, most importantly, the right data – Loxo Oncology was a clear winner at this year's ASCO meeting, with the company's shares up 53 percent since last Friday.

Interim data from three ongoing studies of the experimental oral drug larotrectinib, also known as LOXO-101, in patients whose tumours harbour tropomyosin receptor kinase (TRK) fusions demonstrated a 76 percent confirmed objective response rate (ORR) in both paediatric and adult patients (a first in cancer drug development) across 17 tumour types.

 "Larotrectinib delivers consistent and durable responses in TRK fusion patients across all ages, regardless of tumour context, and does so with few side effects," remarked David Hyman, global principal investigator of the Phase II NAVIGATE trial. Hyman added "the larotrectinib TRK fusion story fulfils the promise of precision medicine, where tumour genetics rather than tumour site of origin define the treatment approach."

ViewPoints: Loxo Oncology builds case for being next in line for a genetically defined cancer approval

Loxo plans to submit a marketing application to the FDA based on these data in late 2017 or early 2018, with primary analysis for the filing reliant upon central, independent radiology review, which will be performed later this year.

Larotrectinib could be well placed to be swept along by a tailwind from recent FDA approval of Merck's Keytruda for the treatment of any metastatic microsatellite instability-high or mismatch repair deficient solid tumours, marking the first time the agency cleared a cancer drug based on the presence of a specific biomarker as opposed to its location in the body.

Loxo's biggest challenge will likely be promoting the adoption of genetic testing to identify TRK fusions, which the company says are present in between 1,500 and 5,000 newly-diagnosed US cancer patients each year. Speaking about Merck's recent approval, one key opinion leader told FirstWord that a legitimate concern will be "testing fatigue."

CAR-T competition set to intensify

CAR-T players continue to jockey for position with the race to bring the first of these cell-based therapies appearing to near a conclusion.

ASCO saw Juno Therapeutics revive its own CAR-T offering with promising data for JCAR017 in relapsed and refractory B-cell non-Hodgkin's lymphoma (NHL), albeit if safety concerns remain a focus.

Juno's data look broadly comparable to Kite Pharma's KTE-C19 (from the Zuma-3 trial), as does Novartis' new data for CTL019 (from the JULIET trial), which was released in an abstract on Wednesday ahead of presentation at the International Conference on Malignant Lymphoma (ICML) meeting later this month. Results set a potential three-way CAR-T battle in diffuse large B-cell lymphomas (DLBCL), where Kite is poised to be the front-runner with potential approval of KTE-C19 in this setting earmarked for late 2017. Focus will shift increasingly to the potential differentiation of these therapies in a commercial setting, while the FDA has also announced that an advisory committee will convene next month to assess Novartis' application for CTL019 as a treatment for paediatric acute lymphocytic leukaemia. This will provide a first public opportunity to gauge the agency's views towards CAR-T therapies.

ViewPoints: CAR-T musings – Kite doesn't disappoint while Juno tacks on another patient death

ASCO also afforded both bluebird bio and the lesser known (China-based) Nanjing Legend Biotech to showcase impressive new data for their respective CAR-T therapies in multiple myeloma.  

Bluebird may feel it has momentum and the necessary commercial firepower on its side, with its anti-BCMA CAR-T therapy bb2121 partnered with Celgene. Having attracted significant attention late last year when presenting preliminary data showing bb2121 to be highly effective in a heavily pre-treated myeloma population, updated data at ASCO showed 16 of 18 patients achieved a response . Importantly, patients have now been followed for up to 12 months, significantly increasing confidence that the responses will prove durable now that they have passed the six-month time period that clinicians generally consider to be clinically relevant, according to Cowen analyst Eric Schmidt.

ViewPoints: Updated bb2121 data impress but bluebird is suddenly hearing footsteps

Investors were clearly impressed by what they saw, as shares of bluebird jumped almost 9 percent on June 5, pushing the company's market cap north of $4 billion. Reaction may be tempered, however, by late-breaking results from a competing anti-BCMA CAR-T therapy, known as LCAR-B38M, being developed – stealthily, until this week anyway – by a relative newcomer in Nanjing Legend Biotech.

Specifically, the Phase I/II readout showed that LCAR-B38M generated responses in all 35 patients (100 percent) receiving treatment, 33 of whom (94 percent) were in remission within two months. The dataset also offered initial signs of durability from the responses, as 14 of the 19 patients (74 percent) who have been followed for at least four months after treatment achieved a stringent complete response, which studies indicate is associated with better survival. What's more, all five patients for whom 12 months of follow-up is available maintained stringent complete responses.

Drawing conclusions about how bb2121 and LCAR-B38M stack up based on cross-study comparisons is particularly problematic in this case given the relatively small number of patients involved. For example, there is some suggestion that patients enrolled in Nanjing Legend's trial were perhaps less sick and had failed less prior lines of therapy than those recruited by bluebird.

See also ViewPoints: Novartis delivers promising early data as the age of CAR-T combos beckons

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