Evolution, Not Revolution, Marks Progress In Targeted Oncology Therapy – AACR

The American Association for Cancer Research’s second annual Cancer Progress Report makes the case that oncology progression is more a process of refinement than breakthrough right now.

Though targeted oncology is still a booming sector, growth in the field is being driven less by revolutionary new approaches than by evolutionary or incremental improvements in targeting, sequencing and combining the new cancer drugs, according to a new report by the American Association for Cancer Research. But those gains are helping to shrink development and FDA review times in oncology.

Oncology drugs are currently experiencing a boom in approvals. In the first nine months of 2012, FDA approved 12 new molecular entities and novel biologic entities for cancer patients out of 27 total novel agents approved by CDER in that time.

The oncology class of 2012 is well-stocked with new drugs representing a significant advance in therapy: seven of the approvals – more than half – were awarded priority review status.

However, only two agents approved in the last 12 months represent “entirely new classes of drugs,” the AACR observed in its second annual Cancer Progress Report, released Sept. 12. Those agents are Genentech Inc./Curis Inc.’s Erivedge (vismodegib), the first Hedgehog pathway inhibitor, and Incyte Corp.’s Jakafi (ruxolitinib), the first inhibitor of the JAK pathway.

The preponderance of new drugs entering already established classes does not indicate that the current wave of oncology approvals are mere follow-on or me-too products. Rather, advances in medical knowledge are enabling researchers to better exploit the insights behind the first wave of molecularly targeted drug development in cancer. “Large-scale analyses of the genetic underpinnings of cancer are now guiding the development of new cancer drugs and are directing the repurposing of proven therapies to treat novel cancer types,” AACR noted.

“Despite the tremendous progress in patient care that has been achieved through the development and use of molecularly targeted drugs, at this time not all cancer patients are able to benefit to the same extent,” AACR said. “Leveraging our current knowledge has proven fruitful, both in enabling cancer researchers to address these challenges and in further advancing quality patient care.”

The group observed that the majority of the cancer therapies approved by FDA in the last 12 months are more effective and less toxic than older therapies.

Oncology is perennially one of the most active areas for new drug approvals, but even so 2011 and 2012 have been notable, not just for their numbers but because they represent advances over existing therapy. The current year-to-date total of 12, split between eight therapeutics and four complementary or supportive therapies, follows the recent high of eight NMEs and NBEs in 2011.

Oncology approvals represent over 40% of the NMEs and NBEs cleared by FDA through September, a higher proportion of novel approvals than in 2011, when a little over a quarter of approvals were for cancer agents, and 2010, a poor year for new oncologics with only two NMEs or 9.5% of novel approvals (Also see "Innovation Pays: Priority Drugs Drove Novel 2011 Approvals To New Heights" - Pink Sheet, 1 Jan, 2012.).

In 2012 and 2011 – which could mark an oncology renaissance of sorts – the preponderance of priority reviews in the NME class indicates that the new drugs are not only plentiful, but are meaningful advances in therapy. Even more striking are the number of approvals received in less than the six-month review goal for priority applications, signifying extra attention from FDA due to the perception of notably significant benefit to patients: six of the 2012 approvals and five from 2011 came in under six months. Indeed, those two years account for half of FDA’s 10 fastest oncology approvals.

Sprinters: The 10 Fastest Times From Submission To Approval For New Oncologics
Time To Approval	Drug	Year
2.4 mo.	Novartis’ Gleevec (imatinib)	2001
2.6 mo.	Sanofi’s Jevtana (cabazitaxel)	2010
3.3 mo.	Medivation/Astellas’ Xtandi	2012
3.7 mo.	Millennium’s Velcade (bortezomib)	2003
3.7 mo.	OSI’s Tarceva (erlotinib)	2004
4.3 mo.	Roche’s Zelboraf (vemurafenib)	2011
4.3 mo.	Johnson & Johnson’s Zytiga (abiraterone)	2011
4.7 mo.	Celgene’s Vidaza (azacitidine)	2004
4.7 mo.	Roche (Genentech)/Curis’ Erivedge (vismodegib)	2012
4.9 mo.	Pfizer’s Xalkori (crizotinib)	2011

AACR, looking at the research side as opposed to the regulatory side of drug development, notes that advances in technology and biological knowledge have accelerated the time from identification of a gene alteration associated with cancer to the development and approval of a therapeutic targeting that alteration. “The initial scientific breakthrough that ultimately led to the cancer chemotherapeutic drug imatinib occurred in the 1950s, but with available technology and understanding … it took 40 years to convert that basic science discovery into a life-saving treatment,” the report states. “Today, thanks to the knowledge that research has provided about both normal and cancer cell biology, as well as advances in technology, the time from basic discovery to an effective treatment is now much shorter.”

Fast-forwarding, AACR points out that genome-wide screens first identified mutated B-Raf as a causative agent for nearly 50% of melanomas in 2002. Roche/Genentech’s BRAF inhibitor Zelboraf (vemurafenib) was approved in 2011. And GlaxoSmithKline PLC is fast on its trail, with its BRAF inhibitor tremetinib and MEK inhibitor dabrafenib under review at FDA; the combination of the mechanisms is anticipated to improve on the efficacy and safety of BRAF inhibition alone (Also see "GlaxoSmithKline Deals One-Two Punch With BRAF/MEK Pair" - Pink Sheet, 4 Jun, 2012.).

Target Discovery To Drug Approval

As technology advances, the time from identification of a druggable target to drug approval is shrinking.

American Association for Cancer Research Cancer Progress Report 2012

AACR suggests that the inherent needs of the clinical trial process may set a floor for how low the time from discovery to approval can drop – a low-water mark that could have been set by Pfizer Inc.’s Xalkori (crizotinib). Famously, only four years elapsed from the 2007 discovery of an ALK gene alteration in a small proportion of lung cancer patients to approval of Xalkori for those patients in 2011 (Also see "Synchronized Regulation: Tandem Approvals Of Xalkori, Diagnostic Required Considerable Coordination" - Pink Sheet, 1 Mar, 2012.). “The development and approval of crizotinib had many advantages (such as jumpstarting development with a potent drug that had been previously tested in early phase trials for other indications),” AACR pointed out. “Clinical development times cannot be reduced further as clinical trials are required to assess safety and efficacy steps.”

Resistance Requires A Continual Stream Of New Agents

Novartis AG’s Gleevec (imatinib), the first molecularly targeted small molecule, set a high bar for the field. “Its discovery was the result of a series of groundbreaking scientific findings,” AACR noted. First, an abnormal chromosome, known as the Philadelphia chromosome, was associated with chronic myelogenous leukemia, followed by the finding that the BCR and ABL genes fused to create the abnormal chromosome and an associated mutated protein which promoted CML development. “Because imatinib effectively blocks the activity of the BCR-ABL fusion protein, its 2001 FDA approval changed the lives of CML patients,” the AACR report recalled. “Five-year survival rates increased from just 31% to more than 90%.”

But Gleevec would not be enough. Some patients do not respond to imatinib, and others acquire resistance to the drug. “Fundamental research determined that those patients who either fail to respond or ultimately relapse have leukemias that harbor mutations in imatinib’s target, the BCR-ABL fusion protein, that prevent the drug from blocking BCR-ABL activity,” AACR said. Two second-generation drugs, Bristol-Myers Squibb Co.’s Sprycel (dasatinib) and Novartis’ Tasigna (nilotinib), built on the scientific foundation and clinical experience of imatinib to circumvent many of the mutations behind imatinib resistance.

However, both second-generation agents “fail to block one particular mutation, and that remains a significant clinical problem,” AACR observed, but the association pointed to the development of ponatinib, an investigational agent from Ariad Pharmaceuticals Inc. with activity against that Bcr-Abl T315I mutation. “Ponatinib is showing tremendous promise in Phase II clinical trials, where robust anti-leukemic activity has been reported in patients with CML that is resistant or intolerant to currently available treatments.”

FDA oncology chief Richard Pazdur apparently concurs in AACR’s assessment of ponatinib’s promise, calling the drug “impressive” and backed by “relatively exquisite” science at a recent drug/diagnostic co-development conference (Also see "Pazdur’s Tale Of Two Targeted Therapies" - Pink Sheet, 24 Sep, 2012.). The ponatinib NDA for patients with resistant or intolerant CML or Philadelphia chromosome-positive acute lymphoblastic leukemia is pending at FDA; the user fee goal could be as early as January if FDA grants the sponsor’s priority review request.

HER2 Evolution

The AACR report also highlights the evolving understanding of treatment of HER2-positive breast cancer as another pivotal saga in the annals of targeted oncology. “Decades of fundamental research led to the clinical development and FDA approval of the therapeutic antibody trastuzumab (Herceptin), which exerts its anticancer effects after attaching to HER2 on the surface of the breast cancer cells,” AACR recalled. “It revolutionized treatment for women with HER2-positive breast cancer, prolonging survival in those with metastatic disease by 24% and reducing the risk of recurrence after surgery in those with early-stage disease by up to 24%.”

But again, some patients with advanced HER2-positive breast cancer fail to respond, AACR continued, “and in most of those who do respond initially, the disease ultimately progresses.”

A second HER2-targeted therapy, GlaxoSmithKline’s Tykerb (lapatinib), was approved in 2007. Tykerb “provides some benefit” in patients who fail to respond, or respond temporarily, to Genentech’s Herceptin, AACR said, but the need for new therapies for these patients remained.

“Rigourous scientific assessment of the reasons why trastuzumab fails to eliminate all HER2-positive breast cancer cells in most patients led to the development of pertuzumab (Perjeta),” AACR declared. The new Genentech biologic was approved for metastatic HER2-positive breast cancer in June 2012 in combination with the company’s older MAb “because together, they are thought to provide a far more comprehensive blockade of HER2 function, and thus greater anticancer activity than either does alone.” The report notes that “in patients with advanced HER2-positive breast cancer, this dual targeting of a single molecule (HER2) significantly prolongs the time to disease progression by almost 50%.”

The report expressed cautious enthusiasm over the early clinical trial results of Genentech’s investigational trastuzumab emtansine, or T-DM1, an antibody-drug conjugate that attaches the cytotoxic chemotherapeutic DM1 to trastuzumab; the antibody delivers the drug directly to HER2-expressing cancer cells, reducing the chemotherapy’s side effects compared to systemic administration. AACR calls T-DM1 “an exciting new approach” with early results suggesting a significant reduction in risk of progression or death in women with metastatic HER2-positive breast cancer, but cautions that “additional time to follow patients on these trials is necessary to make a definitive conclusion as to the efficacy of this approach.”

In the market, excitement over T-DM1 continued to build when Genentech concurrently published and presented full results of the Phase III EMILIA trial on Oct. 1, including a 5.8 month survival benefit over the standard of care in mostly second-line advanced breast cancer and a comparatively manageable side effect profile (Also see "Survival Benefit Plus Safety Profile Cements T-DM1 As Successor To Herceptin" - Pink Sheet, 1 Oct, 2012.). Genentech had already submitted the T-DM1 BLA and could see a user fee goal in February 2013 if it receives priority review and FDA uses the full review period.

New Routes In Known Pathways

In prostate cancer, androgen deprivation has long been a mainstay of advanced prostate cancer treatment, but “unfortunately, in most cases, the prostate cancers eventually stop responding,” leading to castration-resistant disease “which has a very poor prognosis and urgently requires new treatment options,” AACR said.

The significant advance in CRPC treatment represented by the approval of Johnson & Johnson’s Zytiga (abiraterone) in April 2011 and Medivation Inc./Astellas Pharma Inc.’s Extandi (enzalutamide) on Aug. 31, 2012, grew out of improved understanding of the same aspects of androgen biology that had driven earlier generations of hormonal prostate cancer therapy. Both Zytiga and Extandi rank among FDA’s fastest NME approvals, a sign of how FDA valued the potential benefit for an unmet need.

“While the most frequently used androgen-deprivation therapies reduce androgen levels, they do not eliminate these hormones completely,” AACR explained. “Basic research led to better understanding of how the body manufactures and responds to androgens, which revealed a way to more completely block androgen production. This, in turn, led to the development of a groundbreaking new anti-androgen therapy, abiraterone.” Extandi has a different approach. Enzalutamide “attaches to androgen receptors and blocks their attachment to androgens,” AACR noted. “It is more effective than current drugs and has fewer side effects.”

The recent European Society of Medical Oncology meeting featured a range of second-generation targeted therapies for non-small cell lung cancer. A number of ALK inhibitors are following in the wake of Pfizer’s Xalkori (crizotinib) approval for ALK-positive non-small cell lung cancer, promising greater potency and broader efficacy (Also see "New Drugs Build On Personalized Medicine Momentum In Lung Cancer" - Pink Sheet, 8 Oct, 2012.).

Addressing The Variability Of Patient Response

“Variability in patient responses to new targeted drugs is a major challenge in cancer treatment,” the association said. “While some patients’ tumors will respond, some will not respond at all, and still others will initially respond and stabilize or begin to grow again.”

“We need to understand what causes the variability and use this information to overcome these causes” of variable response. “This is an active area of research and it is beginning to bear fruit,” AACR said. “In many cases, diligent analysis of the drug and its molecular target is critical, and it is enabling the design of more efficacious drugs that target the same molecule as the original therapies.”

FDA has approved seven drugs in the last 10 years that similarly impede the growth and stability of emerging blood and lymphatic vessel networks, the report states. Bayer HealthCare LLC’s kinase inhibitor Stivarga (regorafenib) brought the number of vascular endothelial growth factor targeting agents to eight with its Sept. 27 approval for metastatic colorectal cancer patients who have already received a range of chemotherapy and targeted therapies. The AACR report pointed to regorafenib’s targeting of the TIE2 receptor in addition to VEGF receptors, saying “this agent has the potential to increase its effectiveness … since TIE2 is also believed to play an important role in blood and lymphatic vessel stability and growth.”

Even with a range of marketed VEGF receptor-blocking antiangiogenesis drugs, the “ability to suspend new vessel growth differs, due in part to varying efficacy in VEGF blockade as well as their effects on several related molecules,” AACR said. “Drugs with greater potency and specificity for the VEGF receptors are being developed.”

Two VEGF-targeting candidates are currently pending before FDA. First up is Exelixis Inc.’s cabozantanib, which targets VEGF receptor 2, as well as the kinases MET and RET; the NDA has priority review for advanced medullary thyroid cancer with a user fee goal of Nov. 29.

Astellas and Aveo Pharmaceuticals Inc. are positioning tivozanib, an inhibitor of all three VEGF receptors, to take on Onyx Pharmaceuticals Inc./Bayer’s Nexavar (sorafenib) in first-line treatment of metastatic renal cell carcinoma, a disease that has been fertile ground for kinase inhibitors. The NDA is based on the Phase III TIVO-1 trial, a superiority trial comparing the two tyrosine kinase inhibitors; looking forward, the company has started enrollment in a patient preference study, TAURUS, a Phase II crossover trial that compares tivozanib and sorafenib. After announcing the NDA submission Oct. 1, the sponsors presented TIVO-1 data highlighting tivozanib’s reduced rate of side effects and dose modifications compared to the Bayer drug at a European oncology meeting.

The Future Is Large: The Cost And Promise Of Wholesale Genomic Analysis

As there’s more understanding of the genetic complexity of various cancers and the potential involvement of multiple pathways, AACR sees the need to move from individualized companion diagnostic testing to a broader assessment that captures more information and puts it into more context.

“It is now clear that tests that look for the presence or absence of a single molecular defect are insufficient to definitively predict a patient’s response to a drug,” the report says. AACR foresees the emergence of panels of biomarker signatures, made possible by advances in genome sequencing technology. Biomarker panels based on wholesale genomic analysis are “an area of intense research investigation, as these panels hold the promise of dramatically increasing the precision of cancer medicine,” AACR stated.

“Not all patients with a given genetic defect will benefit from a drug targeting that alteration,” AACR said. “For example, while genetic alterations that result in cancers driven by a specific cell surface protein called EGFR are found in 10% of non-small-cell lung cancers and in almost 50% of glioblastomas … drugs that precisely target EGFR provide benefit only to the non-small-cell lung patients.”

However, large-scale genomic analyses will remain limited primarily to research settings unless the cost picture changes. “The cost of deciphering a person’s genetic code and that of their particular cancer must drop even further than it has in the past decade,” AACR cautioned. “The cost is estimated to have fallen about 100-fold since 2002,” the organization noted, but is still “too high for routine clinical use.”

“Additionally, new storage infrastructure, bioinformatics systems and telecommunications networks will be required to manage the massive amounts of information generated by the large-scale analyses,” AACR said.

Novel Oncology Products Approved In 2012
Product (Review Designation)	Class & Indication	Approval Date (Time To Approval)
Therapeutic Oncology Agents
Bayer HealthCare’s Stivarga (regorafenib) (P)	Kinase inhibitor for patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy	9/27/2012 (5 mo.)
Pfizer’s Bosulif (bosutinib) (S)	Kinase inhibitor for adult patients with chronic, accelerated, or blast phase Philadelphia chromosome-positive chronic myelogenous leukemia with resistance or intolerance to prior therapy	9/4/2012 (9.5 mo.)
Medivation/Astellas’ Xtandi (enzalutamide) (P)	Androgen receptor inhibitor for patients with metastatic castration-resistant prostate cancer who have previously received docetaxel	8/31/2012 (3.3 mo.)
Sanofi’s Zaltrap (ziv-aflibercept) (P)	Recombinant fusion protein containing vascular endothelial growth factor-binding portions from VEGF receptors 1 and 2 for patients with metastatic colorectal cancer that is resistant to or has progressed following an oxaliplatin-containing regimen	8/3/2012 (6 mo.)
Onyx Pharmaceuticals’ Kyprolis (carfilzomib) (S, AA)	Proteasome inhibitor for patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression within 60 days of completion of the last therapy	7/20/2012 (9.75 mo.)
Genentech’s Perjeta (pertuzumab) (P)	Monoclonal antibody targeting epidermal growth factor receptor 2 (HER2/neu) for use in combination with docetaxel and trastuzumab (Genentech’s Herceptin) for first-line treatment of patients with HER2-positive metastatic breast cancer	6/8/2012 (6 mo.)
Genentech/Curis’ Erivedge (vismodegib) (P)	Hedgehog pathway inhibitor for metastatic basal cell carcinoma or locally advanced basal cell carcinoma that has recurred following surgery or in patients who are not candidates for surgery, and are not candidates for radiation	1/30/2012 (4.7 mo)
Pfizer’s Inlyta (axitinib) (S)	Kinase inhibitor for advanced renal cell carcinoma after the failure of one prior systemic therapy	1/27/2012 (9.5 mo.)
Complementary Oncology Products: Imaging, Supportive Care & Precancerous Conditions
Mayo Clinic PET Radiochemistry Facility’s Choline C 11 (P)	Radioactive diagnostic agent for positron emission tomography imaging of patients with suspected prostate cancer recurrence and non-informative imaging using other modalities to help identify sites of prostate cancer recurrence for subsequent histologic confirmation	9/12/2012 (9 mo.)
Sicor Biotech’s Tbo-filgrastim (S)	Leukocyte growth factor to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anticancer drugs associated with clinically significant febrile neutropenia	8/29/2012 (21 mo.)
Leo Pharma’s Picato (ingenol) (S)	Inducer of cell death for topical treatment of actinic keratoses	1/23/2012 (10 mo.)
BTG’s Voraxaze (glucarpidase) (P)	Carboxypeptidase enzyme for the treatment of toxic plasma methotrexate concentrations in patients with delayed methotrexate clearance due to impaired renal function	1/17/2012 (6 mo.)
P: Priority Review; S: Standard Review; AA: Accelerated Approval Source: FDA, Pharmaceutical Approvals Monthly