The OBR Blog

June 05, 2012 - 01:06 pm Posted in Featured comments0 Comments

One of the hottest topics at ASCO this year was the role of PD-1 in suppression of antitumor immunity. A variety of signals regulate T-cell responses and it is well established that tumor cells are able to suppress immune response via distinct immune checkpoints. Proof of concept for targeting these immune checkpoints was provided by the development and commercialization of Yervoy (ipilimumab, Bristol-Myers Squibb), a monoclonal antibody directed against CTLA4 approved for treatment of metastatic melanoma. The launch of Yervoy represented a significant breakthrough in treatment of late stage melanoma where durable responses lasting years are achieved in as many as 20-25% of patients. However, Yervoy’s efficacy comes with the price of toxicity in the form of immune-related adverse events that include skin and gastrointestinal toxicities.

PD-1 is another immune checkpoint receptor expressed on activated T-cells. Binding of PD-1 to its ligand, either PD-L1 or PD-L2, inhibits immune response and leads to T-cell anergy, exhaustions and death. Many tumors elicit immune responses and are infiltrated by activated T-cells. PD-L1, frequently expressed on the surface of tumor cells, binds PD-1 and suppresses the immune response. A number of agents that block the interaction of PD-1 with PD-L1 are now in early stages of development and some exciting clinical data from these studies were released at ASCO.

Impressive results from a large Phase I study of BMS-936558 (anti-PD-1; Bristol-Myers Squibb / Ono Pharmaceuticals), a fully human anti-PD-1 monoclonal antibody, were presented (Topalian, Abstract CRA2509). Patients (n=296) with advanced melanoma, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), colorectal cancer (CRC) or castrate-resistant prostate cancer (CRPC) with progressive disease after 1-5 systemic therapies, were treated with BMS-936558 (dose cohorts of 1, 3, and 10 mg/kg every two weeks in 8 week cycles). The MTD was not identified and expansion cohorts were enrolled at 10 mg/kg in all tumor types. Just 15 patients of 296 (5%) discontinued treatment due to BMS-936558-related adverse events (AEs). The most common AEs were fatigue, rash and diarrhea. Grade 3/4 toxicities occurred in 14% of patients and there were three deaths in patients due to pneumonitis (2 NSCLC, 1 CRC). Overall response rates (ORR) were reported in patients with melanoma (28%), NSCLC (18%) and RCC (27%) and preliminary data suggests that PD-L1 expression in pretreatment tumor biopsies correlates with clinical outcome. Registrational trials are planned in melanoma, NSCLC and RCC.

Preliminary results from the ongoing, first-in-human, Phase 1 trial of BMS-936559, an anti-PD-L1-specific monoclonal antibody were reported (Tykodi, Abstract 2510). Patients with advanced melanoma, NSCLC, RCC, CRC, ovarian, pancreatic, breast, or gastric cancers with progressive disease received BMS-936559 (every two weeks in 6 week cycles). The MTD was not identified and no correlation between AEs and drug dose was observed. Just 12 patients of 207 (6.8%) discontinued treatment due to drug-related AEs. The most common AEs included fatigue, infusion-related reaction, and diarrhea. Grade 3/4 AEs occurred in only 9% of patients and no drug-related deaths were observed. ORR were reported in patients with melanoma (17%), NSCLC (10%), RCC (12%), and ovarian cancer (6%). Durable tumor regressions and prolonged disease stabilization was reported for a proportion of patients with NSCLC, melanoma, and RCC.

These studies demonstrate the potential of targeting the PD-1/PD-L1 checkpoint as a therapeutic strategy. These molecules appear to be very well tolerated and have efficacy in many advanced tumor types. Many questions remain unanswered about this novel approach to targeting cancer including: Is efficacy limited to tumors that express PD-L1? If so, PD-1 may serve as a biomarker to select patients for anti-PD-1 therapy. How durable are responses? Can these agents be utilized in combination with other therapies to improve efficacy? How do these agents compare to CTLA4 inhibitors? This is only the beginning of the road for this class of agents, and many of these questions may be answered in the near future as additional studies are completed with these agents and those also being developed by numerous other pharmaceutical companies. ASCO 2012 was PD-1’s debutante ball, but we may be only a few years away from its coronation.

By Gordon Gochenauer, Director, Commercial Development, Kantar Health

June 04, 2012 - 04:06 pm Posted in Featured comments0 Comments

Following decades of frustration and failure, recent advances for the treatment of metastatic melanoma have resulted in approvals of Yervoy (ipilimumab) in 2011 and, for patients with BRAFV600E, Zelboraf (vemurafenib) in 2012. The progress and excitement continues in the treatment of metastatic melanoma with today’s ASCO presentations of data from two Phase III trials sponsored by GSK; the BREAK3 trial of dabrafenib versus dacarbazine (Abstract LBA8500, Hauschild), and the METRIC trial of trametinib versus chemotherapy (Abstract LBA8509, Robert).

BREAK3, is a randomized, Phase III trial designed to compare safety and efficacy of GlaxoSmithKline‘s BRAF inhibitor, dabrafenib (GSK2118436) with dacarbizine (DTIC) in previously untreated patients (except IL-2, radiotherapy and surgery) with advanced (stage III or stage IV) metastatic melanoma. In BREAK3, patients were randomized (3:1) to receive either dabrafenib or DTIC and the primary endpoint was progression-free survival. Median PFS was 5.1 months for the dabrafenib arm versus 2.7 months for DTIC treated patients (p=0.0001; HR=0.30) as determined by investigator assessment. The ORR for the dabrafenib arm was 53% including CRs (3%) and PRs (50%) compared with an ORR of 19% for DTIC. Serious adverse events were observed in 23% and 22% in the respective groups including the 2% incidence of squamous cell carcinoma also observed with Zelboraf.

METRIC is a randomized Phase III trial designed to compare safety and efficacy of GSK’s MEK inhibitor, trametinib (GSK1120212) with chemotherapy (DTIC or paclitaxel) in patients with BRAFV600E/K metastatic melanoma with chemo. In METRIC, patients were randomized (2:1) to receive either trametinib or chemotherapy with the primary endpoint as PFS in BRAFV600E patients. The trametinib arm comprised 186 (86%) patients with V600E mutations and 29 (14%) patients with V600K compared to 97 (90%) patients with V600E mutations and 11 (10%) patients with V600K patients in the chemotherapy arm. The median PFS was 4.8 months versus 1.4 months in favor of trametinib therapy (HR, 95% CI = 0.44; p=0.0001). The confirmed ORR was 22% in the trametinib are versus 8% in the chemotherapy and the preliminary overall survival at 6 months was 85% versus 67%. As previously observed with trametinib, no patients developed squamous cell carcinoma as observed with BRAF inhibitors.

Additionally, extremely promising data was presented from a Phase I/II trial that examined the combination of dabrafenib plus trametinib in treatment naïve patients with metastatic melanoma (Ascierto, Abstract 8511). The rational for this combination is the proposed compensatory increase MEK signal transduction as a possible mechanism of resistance to BRAF inhibition. This study demonstrated that both drugs could be safely administered at full monotherapy dose levels. The ORR was 67% with an impressive median duration of response of 11.3 months and median PFS of 10.8 months. This combination yielded a lower incidence of BRAF-induced squamous cell carcinomas in 3% of patients. Phase III combination studies of dabrafenib and trametinib are ongoing (NCT01584648 and NCT01597908).

Based on data presented today, it is likely that dabrafenib and trametinib will receive regulatory approval though GSK has yet to file for approval. With a somewhat better safety profile than Zelboraf, it will be a worthy competitor in the market and provide a treatment alternative for patients with BRAF mutations. Preliminary data from the combination of dabrafenib and trametinib looks very impressive in terms of safety and efficacy and may ultimately prove superior the BRAF inhibitor monotherapy. Questions still remain as to sequencing of the new agents in metastatic melanoma, particularly with regard to Yervoy versus BRAF/MEK inhibition. What is clear is that GlaxoSmithKline is staking a major claim to this segment of melanoma following the success of Roche’s Zelboraf.

By Gordon Gochenauer, Director, Commercial Development, Kantar Health

June 04, 2012 - 04:06 pm Posted in Featured comments0 Comments

Cabozantinib (XL184, Exelixis) is an inhibitor of multiple receptor tyrosine kinases (RTKs), including RET, c-MET and VEGFR2. Mutations in the RET proto-oncogene play an important role in the development of medullary thyroid cancer (MTC), and cabozantinib has shown activity against the common mutant forms of RET and MET. In June 2008, Exelixis initiated a pivotal Phase III EXAM study to confirm the activity of cabozantinib observed in an earlier Phase I trial. The EXAM study evaluated cabozantinib monotherapy versus placebo in patients with unresectable, locally advanced or metastatic MTC with documented RECIST progression within 14 months of screening as determined by an independent radiology committee (IRC). In October 2011, the company announced via a press release that the drug improved progression-free survival (PFS) in the EXAM trial. Based on the positive data, a New Drug Application (NDA) was submitted to the U.S. regulatory agency in May 2012. The full data from the EXAM trial were presented this morning at the Targeting Therapeutics for Thyroid Cancers oral session (Abstract 5508).

Baseline patient characteristics showed that prior systemic therapy was administered in 37% of enrolled patients on the cabozantinib arm (20% of whom had received a TKI, and 46% were positive for RET mutation) and 42% patients on the placebo arm (of whom 22% had received a TKI, and 52% were positive for RET mutation). Cabozantinib improved PFS from 4.0 months for placebo to 11.2 months (HR 0.28, p < 0.0001), 1-year PFS from 7.2% to 47.3%, and objective response rate (ORR) from 0% to 28% (p<0.0001), respectively. Median duration of response was 14.6 months. Patients previously treated with other targeted agents such as Caprelsa® (vandetanib, AstraZeneca), a RET / VEGFR2 / EGFR TKI also indicated for MTC, also benefited. Interim overall survival data was not mature at the time of presentation, and final analysis will be conducted after 217 events. However, no difference in overall survival was observed at the time of interim analysis conducted in June 2011. A biomarker analysis showed a correlation between changes in serum calcitonin (and CEA) and target lesions.

In terms of safety, common Grade 3 toxicities in the cabozantinib versus placebo arm included diarrhea (16% vs 2%), hand foot skin reaction (13% vs 0%) and fatigue (9% vs 3%). Death for reasons other than progressive disease occurred in 5.6% patients on the cabozantinib arm (of which 1.9% were from causes typically associated with VEGF inhibition versus 2.8% in the placebo arm. No data was reported on the percentage of patients who required dose reductions.

With the positive data, cabozantinib will clearly represent a new treatment option for MTC patients when it gets approved. But how will it be used by physicians? Will it compete with Caprelsa which earned its MTC regulatory approval in the U.S. in 2011 based on the results of ZETA Phase III trial, or will it be used after patients progress on Caprelsa?

In the ZETA trial, Caprelsa improved PFS from 19.3 months for the placebo arm to 30.5 months. The difficulty in making the comparison of cabozantinib versus Caprelsa is that the control arms performed so differently (4.0 months in the EXAM trial compared to 19 months in the ZETA trial). Clearly, the patient characteristics were very different. Unlike Caprelsa, the EXAM trial enrolled patients with documented worsening of disease at screening compared with a previous CT scan or MRI done within 14 months of screening. The presence of progressive disease would explain why the PFS was so short for these patients. This patient population was not previously evaluated in a Phase III trial, and it is unclear whether the strategy of Exelixis was to get an approval in a patient population with a high unmet need or to create a new patient segment that would help them differentiate from Caprelsa competitor. Given such specific inclusion criteria of progressive disease, it will be interesting to see whether physicians will choose to utilize cabozantinib before Caprelsa or after patients progress on Caprelsa. Even if relegated to post-Caprelsa setting, the good news for cabozantinib is that it showed activity in patients previously treated with a TKI (which included sunitinib or Caprelsa), although the magnitude of the benefit is currently unknown as no data was presented specifically for the Caprelsa-treated patient population.

Tolerability will also likely come into play when choosing between Caprelsa and cabozantinib, although the toxicity profiles appear fairly similar. Regardless of how physicians will choose to adopt and utilize these two agents in MTC, cabozantinib did demonstrate efficacy in a patient population with rapidly progressing disease and limited treatment options, and will undoubtedly enjoy adoption into clinical practice.

By Gordon Gochenauer, Director, Commercial Development, Kantar Health

June 04, 2012 - 04:06 pm Posted in Featured comments0 Comments

Treatment of advanced non-small cell lung cancer (NSCLC) has become increasingly driven by tumor characteristics, with choice of systemic therapy now largely decided based on tumor histology, EGFR mutation status, and ALK translocation status, with several other drugs in new biomarker populations also under late-stage clinical development. In patients with EGFR mutations (18% of adenocarcinoma patients in the U.S.), 47% of patients are treated with the EGFR inhibitor Tarceva [erlotinib; OSI/Astellas/Roche] in first-line1. Boehringer Ingelheim is planning to launch afatinib, its irreversible dual EGFR/HER2 inhibitor, into this setting. If successful, it will be battling for patient share with Tarceva in the United States and both Tarceva (15% utilization)1 and Iressa [gefitinib; Astra Zeneca] (43% utilization)1 in Europe.

The LUX-Lung-3 trial randomized 345 patients (2:1) to single agent afatinib versus Alimta [pemetrexed; Eli Lilly] plus cisplatin as first-line therapy in patients with EGFR activating mutations. The study reached its primary endpoint of improved progression free survival (PFS), with mPFS of 11.1 months vs. 6.9 months (HR=0.58, p=0.0004). In common mutation patients (del19/L858R), the mPFS was even better (13.6 mos vs. 6.9 mos, HR=0.47, p<0.0001). A careful analysis of the subgroup analysis reveals that this improved mPFS is driven by the 170 Del19 patients (HR=0.28). It is also important to note that this is the first trial to use Alimta/cisplatin as a comparator arm and because Alimta/cisplatin is a very active regimen in non-squamous patients, it was more difficult for afatinib to demonstrate superiority, yet it managed to do so, albeit at the cost of a higher Hazard Ratio. The most common adverse events were diarrhea and rash. Grade 3-5 adverse events occurred in 49% of patients, including 4 deaths.

LUX-LUNG-3 has ushered afatinib into first-line EGFR mutant NCSLC alongside Tarceva and Iressa. In the pivotal EURTAC trial, Tarceva produced a 9.7 month mPFS with a (HR=0.37, p<0.0001) in the ITT population and 10.4 month mPFS (HR=0.47) in 19del/L858R mutant patients. Iressa demonstrated similar results in this 19del/L858R population with the WJTOG, IPASS, and NEJ002 trials (9.2, 9.5, 10.8 month mPFS; HR 0.49, 0.48, 0.30, respectively). Afatinib performed slightly better than its competitors, which is encouraging. However, does potential increased efficacy outweigh additional toxicity? On comparing toxicity between the LUX-LUNG-3 (afatinib), EURTAC (Tarceva), and NEJ002 trials (Iressa), what stands out is not the difference in grade 3-5 events (49% vs 45% vs 41%) nor the overall rates of rash (89% vs 80% vs 71%), but the difference in rates of diarrhea (95% vs 57% vs 35%). Grade 3 and higher rash and diarrhea are also highest with afatinib (16.2% and 14.4% respectively) and lowest with Iressa (5% and 1%, respectively), which provides some explanation for the preference of European and Asian physicians for Iressa over Tarceva.

Despite the high utilization of Tarceva in the United States, it currently is not FDA approved in the first-line setting. This lack of approval created an opportunity for afatinib to enter this market without directly challenging the market leader in a head-to-head clinical trial. The LUX-LUNG-3 results might push Roche into finally filing for Tarceva approval in the US. Additionally, investigators are already calling for a head-to-head trial and LUX-LUNG-7 (NCT01466660) will compare afatinib to Iressa in 264 del19/L8585R mutant patients in an attempt to answer the question of which agent is superior.

1 CancerMPact, Treatment Architecture, United States, 2011

By Gordon Gochenauer, Director, Commercial Development, Kantar Health

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