Therapy focus – Roche looks ready to rule another cancer niche

Analysis

With Aphinity data in the bag for Perjeta, another trial promises to change the game for a different Roche cancer asset – the Alk inhibitor Alecensa. The Alex study could confirm that the lung cancer drug is best in class.

Novartis set the bar late last year with its contender Zykadia, which generated a very impressive eight-month survival benefit in first-line patients. Ariad’s brigatinib, meanwhile, has emerged as a late runner. First-in-class Xalkori from Pfizer looks unlikely to hold off these challenges for long, and it appears that this small segment of the lung cancer market is about to get very crowded (see tables below).

All of these agents target Alk-driven non-small cell lung cancers, a previously intractable tumour type that was transformed with the arrival of Xalkori in 2011 (Asco – Pfizer basks in glow of crizotinib applause, June 8, 2010). The patient population is small, amounting to only 3-5% of NSCLC or around 10,000 cases in the US each year, but the cancer is aggressive and frequently unresponsive to chemotherapy.

As such, Xalkori was practice-changing, but most patients still progress within one year as the cancer acquires resistance to the kinase inhibitor. Brain metastases also remain a major problem, as Xalkori cannot travel into the central nervous system. The follow-on agents can, however, and their efficacy against intra-cranial lesions is being closely watched.

Stacking up the Alk inhibitors
Second-line setting (post Xalkori) First-line setting (phase III data only)
Product ORR  PFS (mths) CNS response rate ORR  PFS (mths vs control) CNS response rate
Xalkori - - - 74% vs 45%* 10.9 vs 7.0* -
Alecensa 38%-48% 8.2 61% 85% vs 70%** not reached vs 10.2^ -
Zykadia 55% 5.4-7.6 33% 73% vs 27%* 16.6 vs 8.1* 73%
Brigatinib 48% - 55% 9.2-15.6 46-67% - - ?
Source: Press releases, drug labels, abstracts; *vs chemo; **vs Xalkori    

Novartis’s Zykadia followed Xalkori onto the market in 2014, and is conditionally approved in Xalkori failures. Its successful confirmatory first-line study, Ascend-4, was toplined last December, although it notably pitted the kinase inhibitor against chemotherapy, which is surely no longer standard of care in markets willing to pay for Xalkori.

Still, the doubling of progression-free survival versus chemotherapy is impressive, and even more so in patients without brain metastases at diagnosis. In these patients median PFS reached 26.3 months, versus 8.3 months for those on chemo. The drug has breakthrough designation for patients with brain mets; in this subgroup with a poor prognosis PFS reached 10.7 months versus 6.7 months. Full US approval – in first and second line – is expected in the coming months.

Roche is not far behind with Alecensa, which reached the market in a second-line setting in late 2015. Its confirmatory first-line trial, Alex, is due to yield results in the coming weeks and pivotal data from partner Chugai bode well. The FDA awarded the drug a second breakthrough designation on the back of Chugai’s study.

When data from this trial, J-Alex, reported last year median PFS had not been reached, but PFS exceeded 20 months, versus 10.2 months for control patients, who were given Xalkori. This equated to a 66% reduction in the risk of death compared with Pfizer's drug.

Hopes are thus high for Alex, which also uses Xalkori as control. J-Alex did not stratify patients at baseline for pre-existing brain lesions, but a strong CNS response rate in Alecensa’s second-line study, which is already highlighted on the drug’s US label, also raises hopes in these harder-to-hit metastases.

Safety will also be factor, of course, and here Alecensa also appears to have the edge, with the profile of Novartis’s Zykadia looking more like Xalkori, with very high rates of diarrhoea, nausea and vomiting. 

The sellside view of the Alk space
Annual sales ($m)
Product Company 2016 2018 2020 2022 Kinase target
Xalkori Pfizer 561 646 694 722 Alk,c-Met & Ros1
Alecensa Roche 76 361 557 670 Alk
Alecensa Chugai 110 168 169 169 Alk
Zykadia Novartis 91 174 263 306 Alk
Brigatinib* Takeda (Ariad) - 69 180 323 Alk & EGFR
Source:  EvaluatePharma; *forecasts made by analysts previously covering Ariad

Alecensa has already enjoyed a very strong launch, and is forecast to overtake Zykadia swiftly. Consensus seems to suggest that Xalkori will continue to enjoy first mover advantage, although these estimates will surely look optimistic if Alex results knock Alecensa out the park. The Pfizer drug does have the distinction of also being approved in Ros-1-positive tumours, an even smaller subset of NSCLC patients, accounting for about 1% of new cases each year.

However, while Alecensa is emerging as the horse to back in this race brigatinib should not be overlooked. Developed by Ariad and now owned by Takeda, this project has generated very compelling second-line data – though, as with the other projects in this setting, the trials were uncontrolled.

The FDA will rule on brigatinib’s use in Xalkori failures by the end of April; the drug also has breakthrough therapy designation in this setting.

It was clearly one of the main drivers of Takeda’s move on Ariad, though arguably it must show that it can compete with Alecensa to justify the $5.2bn price tag. This will remain unknown until results from its first-line trial, Alta-1L, emerge, probably towards the end of 2018.

By that time brigatinib will be entering a crowded and competitive market, and it seems likely that a more relevant population to study will be Alecensa failures. A study in that population is expected to start this year.

Progress in the treatment of Alk-positive lung cancer has been remarkably swift – Alk was identified as a genetic driver in lung cancer in 2007, and a mere five years later Xalkori was launched. Another five years on and three more products are on or near the market.

While targeting this genetic driver has transformed treatment for these patients it is by no means a cure. But with advances in immuno-oncology, perhaps even greater survival benefits are on the horizon.

Trial information 
Zykadia
Ascend-1 NCT01283516
Ascend-3 NCT01685138
Ascend-2 NCT01685060
Ascend-4 NCT01828099
Alecensa
Alex NCT02075840
J-Alex JapicCTI-132316
Brigatinib
Alta NCT02094573
ALTA-1L NCT02737501

To contact the writer of this story email Amy Brown in London at AmyB@epvantage.com or follow @ByAmyBrown on Twitter

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