Xalkori And The Art Of Modern Drug Development

Pfizer developed crizotinib and its companion diagnostic in just four years after identifying an aberrant ALK gene as the target, spanning a corporate restructuring, the Wyeth integration, and the departure of senior staff in the R&D organization and oncology BU. The next year or so will tell whether Xalkori was a flash in the pan, or whether it marks the long awaited turnaround for Pfizer’s oncology business and a model for nimble drug development.

• Xalkori’s accelerated approval in August 2011 in tandem with a companion diagnostic to identify NSCLC patients with an ALK genetic rearrangement is partial validation of the company’s restructuring into therapeutically aligned business units to simplify governance and decision making, and its strong push into precision medicine.
• In particular, the decision to leave discovery and preclinical outside of the BU, and to join development and commercial into an integrated construct with an oncology mandate set Pfizer’s restructuring apart from similar experiments at GSK, Sanofi and elsewhere.
• The early use, and tandem development, of a diagnostic to screen for the 5 to 7% of patients harboring the genetic abnormality was critical to the drug’s successful development and regulatory approval.
• Xalkori’s success also hinged on specific people and on a fortuitous publication in Nature that put the crizotinib program on a winning track – suggesting that state-of-the-art drug development is equal parts strategy, management, and chance, and thus may not be so easy to reproduce.

It is rare to hear of a scientific discovery turning into a marketed product in just four years. But that’s what Pfizer Inc. managed to do with Xalkori (crizotinib), its oral, small molecule inhibitor of c-Met and ALK. The ALK discovery came to light in August 2007, and was well-timed for Pfizer, which had crizotinib in development as a c-MET inhibitor – unsuccessfully. But Pfizer, a pharma giant that has seen more than its share of development failures, was able to turn the program around and obtain an unprecedented approval based on Phase I data a mere four years after identifying an ALK rearrangement as the target. It remains to be seen whether the speed and sure-footedness of that approval can be replicated, or if it was a rare case of capturing lightning in a bottle.

What is remarkable about the crizotinib development program was Pfizer’s ability to capitalize on a scientific discovery. It took a certain organizational nimbleness to take advantage of that opportunity, which was precisely what the creation of the oncology business unit was supposed to achieve. (See (Also see "Pfizer's Increasingly Specialist Focus" - In Vivo, 1 Nov, 2008.).) But Pfizer has a long way to go before being counted a major force in oncology – although crizotinib is an extraordinary accomplishment, it is only a modest first step.

Though not unheard of, instances of R&D repurposings – wherein new information surfaces that leads an early-stage R&D team to rethink a drug’s biological target and indication and place it on a different clinical path – are rare. It is more typical to hear about repurposing as lifecycle management of marketed products, or last-ditch efforts to salvage failed late-stage programs; early-stage examples are murkier and seldom reported. Kenneth Kaitin, PhD, professor and director of Tufts University’s Tufts Center for the Study of Drug Development, thinks that companies want to say, “We went in looking for that.” They’re also reluctant to repurpose to a lesser indication, he says, and to concede that they started on a bigger disease but diverted resources to the smaller one because they were surer of getting to market.

It is more typical to hear about repurposing as lifecycle management of marketed products, or last-ditch efforts to salvage failed late-stage programs; early-stage examples are murkier and seldom reported.

This may be changing, in part because companies have been criticized in the past for not taking full advantage of the science, and for being too corporate-driven. Also, the tools – organizational, knowledge management, personalized medicine technologies – are increasingly available to allow such pivoting before the compound has gone on to absorb funding and resources.

Kaitin believes that the serial restructurings that Big Pharma went through over the past decade, in which they’ve tried to create nimble, science-driven R&D organizations, is a key factor behind the willingness and the ability to repurpose. In conversations with individuals in Pfizer’s oncology business unit who are central to the crizotinib story, other enabling factors emerged: the chemistry between scientists, the rapid advance of biological science and the ability to track new information and use it, and the latitude given senior management to recognize and support innovation.

Oncology At Pfizer: Getting The Organization Right

Pfizer has struggled to build an oncology franchise, though not for lack of trying. According to Elsevier’s Strategic Transactions database, in the five-year span of 2007 through 2011, Pfizer concluded more than 20 deals over cancer assets, both drugs and diagnostics – including licensing, R&D collaborations, and equity investments. And that doesn’t include the oncology assets it inherited in the Wyeth acquisition. [See Deal] Nor does it include earlier acquisitions still in its portfolio such as Warner-Lambert, [See Deal] which brought the cancer pipelines of Agouron Pharmaceuticals Inc. [See Deal] and Parke-Davis, or of Pharmacia Corp., [See Deal] which brought Sugen Inc.’s fertile pipeline, including both sunitinib and crizotinib. [See Deal]

Despite this treasure chest of assets, platforms, and capabilities, and some promising starts, the company has repeatedly stumbled. In 2006 Sutent (sunitinib) received FDA approval for advanced/metastatic renal cell carcinoma and for gastrointestinal stromal tumor after disease progression on or intolerance to Novartis AG's Gleevec (imatinib). In May 2011, Sutent won approval for use in progressive, well-differentiated pancreatic neuroendocrine tumors (PNET) in patients with unresectable, locally advanced or metastatic disease. However, the PNET labeling contains a caveat that the magnitude of benefit seen in the pivotal study may have been overestimated because of the trial's early termination. (See (Also see "Sutent Cleared For Pancreatic Tumors, But With Caveat On Efficacy" - Pink Sheet, 23 May, 2011.).) This cautionary statement, combined with a lower PFS than Novartis' competing agent Afinitor (everolimus), will likely limit the drug’s commercial prospects in what is a niche indication with fewer than 1,000 new cases in the US each year.

Pfizer had plans to launch Sutent in larger indications, including hepatocellular, breast, lung, and prostate cancer, but the clinical data didn’t prove out. It had been looked to as a linchpin of Pfizer's oncology strategy, but a range of side effects and high dropout rates has prevented it from expanding into significant new markets beyond its launch indications. Deutsche Bank, in a recent research report, pegged Sutent's 2015 estimated revenue at $1.39 billion with little better than flatline growth through that period.

In 2008, Pfizer discontinued a Phase III trial of its fully human anti-CTLA-4 monoclonal antibody tremelimumab in advanced melanoma patients; the drug was eventually out-licensed to AstraZeneca PLC’s MedImmune LLC. [See Deal] In early 2010, the company released disappointing Phase III results for its fully human anti-IgG2 antibody figitumumab in NSCLC. And later that year, in what appeared to be a business decision, it terminated a deal for development of Celldex Therapeutics Inc.’s CDX-110 vaccine for neuroblastoma. [See Deal]

In 2011 the company’s oncology franchise, led by Sutent, was $1.3 billion, down from $1.4 billion 2010. The loss of exclusivity in 2011 of the aromatase inhibitor Aromasin (exemestane) probably accounted for the slide.

But the company has seen more recent success. Pfizer followed up on Xalkori with the approval of Inlyta (axitinib) for metastatic renal cell carcinoma and the filing of bosutinib for chronic myeloid leukemia, and has several other Phase III agents in large and small indications.

Exhibit 1

Pfizer's Oncology Pipeline

Pfizer

The establishment of an oncology business unit (BU) in March 2008 presaged a corporate-wide restructuring eight months later into autonomous, financially responsible business units. (See (Also see "With A Novel Pipeline, Pfizer Tries A New Oncology Business Unit Too" - Pink Sheet, 23 Jun, 2008.).) The move was part of Pfizer’s drive to focus and improve its performance, which started a year earlier with an R&D review that pared its pipeline down to a handful of disease areas where it felt it could compete. (See (Also see "Pfizer Restructures for a More Flexible Future" - In Vivo, 1 Oct, 2008.).)

“Pfizer made a very conscious decision to innovate the organizational construct to enable a more focused and clearer customer orientation,” Andy Schmeltz, president of the US oncology BU, said. “We were getting so large, and the needs were so diverse, to be successful in our chosen areas we needed to have focus.” Martin Mackay, Pfizer’s former head of global R&D, championed the organization-wide restructuring that occurred under Jeff Kindler’s tenure as CEO.

The solution was to break down organizational boundaries through focusing dedicated resources in the BUs. In oncology, which was established ahead of the other BUs, the aim was to bring together global oncology functions spanning clinical development, medical, and the commercial organization. “A by-product of that,” adds Schmeltz, “is the ability to simplify governance and decision making. No longer do all these leaders need to think about trade-offs for oncology decisions versus decisions affecting the rest of the portfolio, all the other disease areas and opportunities. The mandate was simply in oncology.”

In the case of crizotinib, prior to the establishment of an oncology BU the standard approach would have been to stop the Phase I trial once the research team identified the ALK fusion gene (EML4-ALK) as the target and NSCLC as the population, and start a Phase II trial. “Activate it, accrue the patients, and see how they do,” says Mace Rothenberg, MD, SVP of clinical development and medical affairs for the oncology BU. “That process would have probably taken nine months to activate and another year or two to get done. Instead, the team was able to say ‘We found a signal here, let’s change course.’” Rather than closing down that expansion cohort of 10 patients, the BU structure allowed the team to quickly expand it, to add more patients. “One cohort would be patients with the c-Met amplified tumors, because we were still thinking that that was a good target; and the other group would be the ALK fusion gene-carrying patients with NSCLC.”

It is the move into Phase I that triggers the involvement of the BU, Schmeltz said. “When the drug moves into first-in-human, that’s when the business unit takes over accountability for moving things forward.” At the time the Nature article revealed the role of the ALK translocation in NSCLC, crizotinib was in an exploratory Phase I trial. In the pre-BU construct, there was a research and an early development organization that would carry the compound through Phase II. “The discovery of the role of the ALK translocation in lung cancer came at a very pivotal moment. You’ve got an engaged group of people that were able to go through and talk about making some simple, straightforward changes to the entry criteria of this Phase I trial. Because doing so could really unlock a path that could have significant implications.”

Not to say the older construct wouldn’t have enabled that. But in the pre-BU days, people in the management chain would have accountability across disease areas. As Schmeltz puts it: “The internal structure was not set up to enable speed-to-market in any one category. There simply wasn’t the focus, the ability to trade off resources within the BU. You’re not being called into meetings in infectious disease or in cardiovascular. There’s no head of statistics, in terms of governance, that’s thinking you’ve got four other projects in other areas that are reading out. The BU aligns all the folks involved.”

The Early History Of Crizotinib (PF-02341066): Something’s Happening Here

James Christensen is senior director of precision medicine at Pfizer Global R&D’s La Jolla laboratory. His group, which proposes clinically testable hypotheses for drugs in Pfizer’s cancer portfolio, is basically a translational research group. The crizotinib story actually begins at Redwood City, CA-based Sugen, a biotech specializing in kinase biology that was acquired by Pharmacia in 1999. Pfizer acquired Pharmacia in 2002 and in the following year disbanded the Sugen team. (Sutent also originated in Sugen’s labs.) According to Christensen, a former Sugen employee, crizotinib began as a c-Met inhibitor program in the early 2000s. C-Met, a receptor-targeting kinase that may have a role in angiogenesis, is amplified in about 10 to 20% of gastric tumors. “There would be a certain type of development path you would probably take a c-Met inhibitor down, based on the biological information available on the target,” Christensen noted.

When Pfizer consolidated its operations after the Pharmacia acquisition, a number of Sugen scientists ended up at the 34-acre La Jolla campus and continued working on the c-Met program. Christensen was one of them.

Although he sits in research, Christensen likes to play in Phase I. “I’m a unique case of a researcher that tried to become really involved in clinical trial design. I’m intrigued by clinical oncology and wanted to stay as closely involved as possible.” It’s striking how closely Christensen seems to have worked with the clinical lead for the crizotinib ALK program, Keith Wilner, PhD. “I think we had a nice team between the basic researchers like me and the clinical research scientists.” Having that sort of dedication and close and continual interaction between the Pfizer La Jolla staff certainly played a role in the crizotinib success.

Christensen says that around 2005 or 2006, his team identified that the molecule had alternative kinase targets in addition to Met, and that one of those was anaplastic lymphoma kinase, or ALK. They knew that ALK was altered in a rare type of lymphoma called anaplastic large-cell lymphoma. “There weren’t major opportunities to test crizotinib in the lymphoma population, but we became interested in it and actually wrote it into our Phase I trial protocol early on. So we knew this was an ALK inhibitor, but we weren’t sure what the application would be.” Christensen and his team did a lot of work in cancer cell lines in preclinical models. Certain cell lines and models responded well to crizotinib, but the responses were rare, so the thinking was that the drug would probably only work in tiny, niche populations.

Rothenberg says that, in the 2006-2007 time frame, ALK was thought to be an off-target effect. “It was not a commercially attractive target. A rare lymphoma, some sarcomas – one called inflammatory myofibroblastic tumor (IMT) – and also neuroblastomas, a rare, pediatric brain tumor. In fact, we were developing a back-up to crizotinib that was a pure c-Met inhibitor.”

One of the interesting things to come out of Christensen’s screens was that a couple of lung cancer cell lines had an EML4-ALK translocation, but the relevance of the translocation was unknown to the Pfizer team. A genetic translocation is the movement of a gene fragment from one chromosomal location to another, with the resulting disruption of gene expression or creation of a fusion gene such as EML4-ALK that induces cancer.

By the summer of 2007, crizotinib was in an exploratory Phase I trial, looking at all tumor types, especially gastric tumors, trying to determine the maximum tolerated dose. Keith Wilner, a senior director in the oncology BU and clinical lead for the ALK program, said that a study site had recently opened in Korea screening for c-Met amplification, “but the first 100 patients they screened they found zero. So we were thinking the percentage is probably quite a bit lower than the 10 to 20% we were led to believe.”

The timing of the publication on the role of the ALK translocation in NSCLC, in the journal Nature, in August 2007 was fortuitous – because six years after the discovery of crizotinib, the c-Met theory was beginning to run out of steam. The team knew a little bit about ALK – and had told senior management that they’d be modifying the enriched population by looking at ALK fusions – but mostly in terms of anaplastic large-cell lymphoma, not NSCLC.

Christensen read the article, by a group of Japanese researchers led by Dr. Hiroyuki Mano of Jichi Medical University, describing the role of the ALK translocation in NSCLC, and sent it over to Wilner. In fact, the Pfizer team got a contact with Dr. Mano and consulted with him on the diagnostic strategy for going after that patient population. “We modified the protocol in October,” Wilner says, “to allow patients that had the ALK translocation to enroll in the trial. Our investigative site at [Massachusetts General Hospital] had also seen the article, and they had developed a test to identify ALK positivity using the Vysis FISH probes on the market from Abbott Laboratories Inc. Our very first ALK+ patient enrolled in the trial – we always think of this date because it’s so unusual – on December 26, 2007.”

The publication of the Nature article and the extraordinary response seen in the first patient – that was the pivot.

That patient had an extraordinary response to the drug, although the patient also had some liver function abnormality that limited dosing. The patient was on oxygen and wasn’t really ambulatory, in fact was very close to hospice. “But that was the first signal that something was happening here,” says Wilner.

How PF-02341066 Found A New Groove

The publication of the Nature article and the extraordinary response seen in the first patient – that was the pivot. Things started moving ahead rapidly from this point. “We modified the protocol to allow patients if they had any type of molecular marker, c-Met or ALK,” says Wilner. “And in that case, we were able to enroll an additional three patients who were ALK positive – two were NSCLC and one was IMT. With the two NSCLC patients, we saw a very nice response.” In fact, according to Rothenberg, there was a dramatic response in all three patients with translocation-activated ALK. All three of the first ALK+ patients were good to move ahead – something “very, very unusual in a Phase I trial,” Wilner notes. The IMT patient is actually still currently on trial, and is just going to start cycle 50. In the next few weeks, he’ll be switched from the trial to commercial supply.

The excitement around the project led to creative thinking, which improved the possibilities for success. In the dose-escalation trial, where there are a limited number of slots for new patients and more cannot be enrolled until the next dose level opens, Wilner’s team went to the governance committee (a group of senior management in business and R&D that approves oncology development decisions) and requested a protocol modification. They asked that patients with a c-Met or ALK molecular marker be allowed in the trial at a lower dose level that was already shown to be safe. “We amended the protocol to allow an ALK cohort. We amended the protocol to allow patients to enroll at a lower dose level that was shown to be safe, so as we identified those patients there would always be a slot available for them. Those are all new things that we did that we hadn’t done previously.”

Pharma companies generally try to streamline protocols, reducing the number of protocol amendments in particular, to better ensure successful protocol execution. It’s noteworthy that the oncology governance committee approved the changes that the crizotinib ALK team was proposing. Senior management in the oncology BU got it – they saw the potential value to be unlocked by testing the drug in ALK+ NSCLC patients – and having that buy-in gave the team the freedom to conduct a revolutionary development program.

Wilner says that as long as they had approval from governance, “no one ever questioned anything, so I didn’t have to keep going to governance every time to make a decision. We were able to make decisions within the team and move forward. That allowed us to be nimble because we didn’t have to wait for anything.” Prior to the oncology BU structure, they would have had to go before general governance. “If we didn’t have the business units as created, these decisions would have gotten mixed in with all other drug-related decisions across all therapeutic areas. So the timing for this compound worked very well in terms of the changes in the organization and when this compound started moving forward.”

Rothenberg arrived at Pfizer from the Vanderbilt Ingram Cancer Center in December 2008, not long after the introduction of the business unit structure and a month before Pfizer’s acquisition of Wyeth. He’d been brought in by Garry Nicholson, president and general manager of the oncology business unit, who had joined the company earlier in 2008 – so there was plenty of fresh perspective at the business unit and energy from the new organizational approach.

Rothenberg’s first order of business was to act on the extraordinary results that were emerging from the crizotinib Phase I trial, for which the team had started adding sites and lung experts. “We were very excited, but we had only 20-25 patients at this time, and follow up on these patients was limited.” So as a next step, they met with FDA, in April 2009, to share the information. Rothenberg felt it was important to engage with the agency for two main reasons: given the strong signal they were seeing, he wanted to discuss the possibility of an accelerated approval strategy. But even more importantly, he wanted to talk about how Pfizer might develop a diagnostic to identify ALK+ NSCLC patients, because it was clear that the only way to identify patients who would benefit from the drug would be through molecular testing, but there was no approved test for the ALK fusion gene.

Rothenberg’s first order of business was to act on the extraordinary results that were emerging from the crizotinib Phase I trial, for which the team had started adding sites and lung experts.

The diagnostic was critical. A 2009 article in the Journal of Clinical Oncology was the first substantive description of the demographics for ALK+ NSCLC. For instance, most patients were non-smokers, the average age was 50 years old, and a majority of cases were adenocarcinoma. This article, according to Wilner, enabled the team to focus the screening for the ongoing trial, increasing their hit rate from about 3 to 5%, to 10 to 20%.

“The diagnostic they were using,” says Rothenberg “was basically the probes from Abbott Molecular Diagnostics. Now that’s fine for research purposes, but not for regulatory purposes.” The regulatory requirements for registering a new diagnostic are set by another part of FDA, the Center for Devices and Radiological Health (CDRH). “This was the first time that we were challenged to develop an FDA-approved diagnostic in tandem with a therapeutic. These two things had not been done in tandem before.” Pfizer met again with FDA in April 2010, asking that members of CDRH join in. “To give you an idea of what the environment was like then,” Rothenberg said, “we came in, we introduced ourselves. First we introduced ourselves to FDA’s oncology and diagnostics groups, and then they began introducing themselves to one another!”

As expected, FDA said it needed to see more data. But the agency indicated its willingness to accept the single-arm data that had been generated from the expansion cohort – an unprecedented move. However, reviewers also said they wanted a separate Phase II single-arm study that used a FISH probe from Abbott that was going to be subject to FDA’s diagnostic test approval requirements. Basically, the agency said that if the ongoing Phase I data, with the addition of more patients screened using a research probe, held up, and if the Phase II trial using the regulatory probe went forward, they could consider accelerated approval. That cooperation from the agency drastically cut the time needed for development.

This was occurring at a time when FDA was beginning to tighten up its requirements for accelerated approval. Rothenberg says that, in addition to the pivotal trials for accelerated approval, FDA asked Pfizer to define at least two randomized Phase III trials to confirm that the response rate held up. They agreed on a second-line trial in which single agent crizotinib was compared to either Alimta (pemetrexed) or Taxotere (docetaxel), both standards of care in NSCLC, and another trial looking at single agent crizotinib versus combination chemotherapy in a front-line setting. Both Phase III trials began in 2009; the event-driven trials are still accruing. But starting the trials early, and coordinating on the design with FDA, appeased the oncology office enough to grant accelerated approval for Xalkori on August 26, just 4.9 months after submission, beating the priority review date by one month. The companion FISH diagnostic was cleared the same day. Approval of both is pending in the EU.

Is The Xalkori Development Story Replicable?

Schmeltz suggests that Xalkori was a “proof point” validating the move to the BU structure. Maybe. Upcoming cancer approvals (bosutinib, dacomitinib, inotuzumab ozogamicin) – all in Pfizer’s focal therapeutic areas of renal cell carcinoma, lung cancer, and hematological cancers – will show that crizotinib wasn’t a one-off, and that Pfizer may have turned a corner with its oncology business. Of course, crizotinib in NSCLC will likely be a modest product. Its sales in Q4 2011, its first full quarter, were $12 million. Most analysts forecast its revenues between $500 million and $1 billion by 2015. However, analysts may not yet have modeled the addition of an immunohistochemistry diagnostic, which will broaden the ability to screen patients, particularly in emerging markets, nor the revenue contribution post 2015 of various indications for crizotinib now in Phase I. (See (Also see "Pfizer Turns To Ventana To Expand Companion Dx Options For Xalkori" - Pink Sheet, 18 Jan, 2012.).) Also, Pfizer continues to explore the drug’s other targets – c-MET and ROS-1 – in undisclosed indications. But the drug’s significance is as an early indicator of the potential of the company’s precision medicine initiative and its oncology BU construct – not as a cornerstone of the oncology portfolio.

And for Pfizer to prove itself in oncology, it will need more significant accomplishments. The January 27 approval of Inlyta for patients with advanced kidney cancer, who have failed one prior therapy including Pfizer’s own Sutent, appears to be a sign that Pfizer oncology’s pipeline continues to deliver. Approved five months after Xalkori, Inlyta enters a crowded field but brings a unique safety profile that assures it a place in the second-line setting. (See (Also see "Inlyta Approval Expands Pfizer Kidney Cancer Options, But With Unique Safety Profile" - Pink Sheet, 27 Jan, 2012.).) The same day as the Inlyta approval, Pfizer announced FDA had accepted for review its NDA for its dual Src/Abl kinase bosutinib for previously treated patients with chronic myeloid leukemia. How these drugs, including Xalkori, fare with payors, perform in the market, and expand into other indications over the next 12-18 months will be the real test of the oncology BU’s success.

The drug’s significance is as an early indicator of the potential of the company’s precision medicine initiative and its oncology BU construct – not as a cornerstone of the oncology portfolio.

To be sure, in the case of crizotinib the move to an oncology BU, which empowered BU heads to run their own P&Ls, conferred the right degree of focus and accountability. Of course Pfizer isn’t the only Big Pharma to attempt to duplicate the science-driven focus and flexibility of biotech companies. GlaxoSmithKline PLC pioneered the idea with its Centres of Excellence for Drug Discovery in 2000 and has been refining it ever since. Having broken down the CEDDs into even smaller Drug Performance Units (DPUs), GSK is now moving in a direction similar to Pfizer and creating disease-specific, integrated BUs bringing together DPUs and latter stage Medicines Development Centers. (See (Also see "Putting The Pieces Together Again: GSK Creates End-To-End Business Units " - In Vivo, 1 Jan, 2011.).) But where Pfizer leaves discovery and preclinical out of the BU construct – the better to shield scientists from commercial pressures – and joins clinical development to the commercial organization, GSK preserves the fault line between R&D and commercial.

Another model that the company looked at was Novartis, which created five divisions including an end-to-end oncology business unit in 2000.

It appears that Pfizer may be on to something. More than in any prior R&D reorganization, Pfizer’s experience with Xalkori suggests that Big Pharma can plausibly reinvent its enterprise to innovate with the speed, focus, and agility of a biotech. When the right organizational structure is joined with Big Pharma’s scale across its value chain – the results can be impressive.

But the success of Xalkori owes to more than Pfizer’s restructuring. The enabling factors consist of both hard (controllable) and soft (uncontrollable) elements. Controllable elements include the oncology BU structure, the deliberate independence of the research organization, and the corporate commitment in early 2010 to precision medicine; uncontrollable elements include the chance publication of the Nature article around the time when crizotinib ran the risk of being shelved, and the idiosyncratic interaction between the translational staff and clinical research staff at the La Jolla site. And then, of course, there’s the efficacy of the molecule itself.

External to the company, the information ecosystem, especially the ongoing health of the peer-reviewed journal system and what academic publishers call “data liquidity” is critical to the success of Xalkori and other targeted agents. And Mace Rothenberg points to the importance of the “symbiotic relationship” between academia and industry, with academic researchers unraveling the complex biology of cancer, clinical investigators around the world throwing a light on areas of unmet medical need, and industry translating the observations made in the lab and clinic into marketed medicines. (See (Also see "Back To School: Big Pharmas Test New Models For Tapping Academia " - In Vivo, 1 Feb, 2011.).)

Bernard Munos, a former Lilly executive, takes the view that Big Pharma is under increasing financial pressure to turn their drugs into targeted therapies. “I expect increasing reluctance to proceed with clinical development programs that are not targeted. It will undoubtedly put pressure on the company’s ponderous decision-making processes, but this may not be all bad.” This is what appears to have happened at Pfizer: they placed a bet on oncology, they aligned development and commercial decision making within a vertical BU, and they mobilized the enterprise around the concept of precision medicine. Rothenberg says that Pfizer is committed to giving drugs that are paired with a companion diagnostic the highest priority for development.

Is the Xalkori development story replicable? At the end of the day, Xalkori’s success owed to good management decisions, the right people working within the right structure, a potent and versatile molecule, and a dash of luck. Basically, the template worked; now it remains to pressure test it with other projects. For dacomitinib – an oral, irreversible pan-HER (1,2,4) inhibitor that is currently in Phase III for NSCLC patients with KRAS wild-type tumors – Pfizer has partnered with Qiagen NV [See Deal] for a diagnostic to screen responders in clinical trials and to develop a companion diagnostic to launch in tandem with the drug. Of the 1.5 million new cases of NSCLC reported globally each year, between 10 to 20% present with KRAS mutations and will probably develop resistance to EGFR inhibitors like Roche’s Tarceva (erolotinib). That’s a significant commercial opportunity, and a product that fits well with Pfizer’s precision medicine paradigm, although the company will also look at all NSCLC in addition to the subset of KRAS wild-type lung cancers. The clean approval and successful launch of dacomitinib will go a long way to convincing observers that Pfizer has indeed figured out something about developing targeted therapeutics. (Editor’s note: our description of the dacomitinib program was corrected post-publication.)

However, it will take more than Xalkori, Inlyta, bosutinib, and dacomitinib to vault Pfizer into the top ranks of cancer companies. Roche, whose 2011 cancer franchise was worth approximately $21 billion and Novartis, whose 2011 oncology sales were around $10 billion, are far out of reach. But Pfizer could have a shot in the next five years at breaking into the 3rd tier of companies (e.g, Eli Lilly & Co., AstraZeneca, Celgene Corp.) with oncology sales between $3 billion and $5 billion. Pfizer is starting from a low base. Xalkori shows that it’s got the machinery in place, and that it can execute. If it can template that development process – allowing of course for the unique attributes of each product and its market – and consistently turn out successful launches that can be expanded into other settings and indications, then after a long stretch of dry years Pfizer could become a significant presence in cancer.

Editor’s Note: This story was updated post-publication.