May 2014 Edition Vol.11, Issue 5

What’s in Store at ASCO 2014? Kantar Health Offers a Preview

What’s in Store at ASCO 2014? Kantar Health Offers a Preview (continued)

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ALTTO: The last hope for adjuvant Tykerb?

GlaxoSmithKline has been diligently working towards getting Tykerb® (Tyverb® in Europe, lapatinib) established in the adjuvant HER2-positive breast cancer setting. Toward that goal, Tykerb has been evaluated either against Herceptin® (trastuzumab, Genentech/Roche/Chugai) or in combination with Herceptin and chemotherapy in an adjuvant trial (ALTTO) and three neoadjuvant trials (NeoALTTO; NSABP B-41; CALGB 40601). In the NSABP B-41 and CALGB 40601 studies, Tykerb was unable to show statistical significance in improving the pathologic complete response (pCR) rate. A statistically significant pCR benefit for the combination of Tykerb, Herceptin and chemotherapy was observed in the NeoALTTO trial.[1] Given the lack of consistent data, the last hope to promote Tykerb for early-stage breast cancer will be the results of ALTTO, which will be presented in a plenary session at this year’s ASCO.

The ALTTO trial randomized more than 8,000 patients to one of four arms: Tykerb, Herceptin, Tykerb plus Herceptin, or Tykerb following Herceptin. All treatments followed anthracycline-based chemotherapy, and as a further evaluation patients could be treated concurrently with paclitaxel or docetaxel plus carboplatin. The comparison between the two single-agent arms was designed to evaluate non-inferiority between the arms, while all other comparisons were designed to evaluate whether either combination was superior to Herceptin alone. In September 2011, GlaxoSmithKline closed accrual on the Tykerb (with or without chemotherapy) arm as it was determined the arm would not show non-inferiority to Herceptin. The primary endpoint for these comparisons is disease-free survival.

Tykerb’s past struggles in the neoadjuvant setting foreshadow difficulty in the adjuvant ALTTO trial. However, the other difficulty is that breast cancer therapies have rapidly evolved since the May 2007 initiation of ALTTO. The combination of Perjeta® (pertuzumab, Genentech/Roche/Chugai) with Herceptin and docetaxel has proved beneficial relative to Herceptin plus docetaxel as a front-line metastatic therapy in HER2-positive patients, and the combination is currently being evaluated in the APHINITY trial, which should report in 2016. Therefore, not only does Tykerb need to show a statistically significant advantage either in combination with Herceptin or following Herceptin, but it will need to show a clinically relevant benefit or it will be turned aside by physicians once APHINITY data are available.

The other issue with Tykerb is toxicity, which will need to be closely monitored when the results of ALTTO are presented. Unlike Herceptin, which is an anti-HER2 monoclonal antibody, Tykerb is a dual HER2/EGFR tyrosine kinase inhibitor. Similar to other EGFR TKIs, Tykerb administration was associated with increased incidence of grade 3-4 diarrhea. Although these toxicities can be managed generally well in metastatic patients, will the increased duration of therapy associated with adjuvant treatment also hinder Tykerb’s prospects?

In spite of all the history, there is still hope for Tykerb. We will know the outcome for its prospects in the adjuvant treatment during the ASCO plenary session.

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Panobinostat plus VelDex in Relapsed/Refractory Multiple Myeloma

Panobinostat (LBH589; Novartis) is a multitargeted pan-deacetylase inhibitor in development for multiple myeloma. Originally planned to be tested as a monotherapy, Novartis ultimately chose to position the agent in combination with VelDex in relapsed or refractory myeloma. The vehicle for this development is the randomized Phase III PANORAMA-1 trial, which is comparing panobinostat plus VelDex versus placebo plus VelDex in more than 750 previously treated multiple myeloma patients.

In December 2013, Novartis announced via press release that PANORAMA-1 met its primary endpoint of significantly improving PFS. The data supporting this press release will be presented at ASCO on Monday, June 2, 2014, and it will be important to learn the extent of the efficacy benefit. If approved, panobinostat will be thrown into a highly competitive segment, as both the proteasome inhibitor Kyprolis® (carfilzomib, Amgen) and the immunomodulatory agent Pomalyst® (pomalidomide, Celgene) have been already approved by the FDA for use in these patients. A perceived lesser benefit relative to other agents typically pushes agents to later lines of therapy, but in the case of panobinostat the trial design (combining with VelDex) perceived lesser benefit might mean that panobinostat is just used very sparingly instead.

One thing in favor of panobinostat relative to its potential competition in this setting is that it has a different mechanism of action than its competition. However, this also implies a different toxicity profile, so toxicity in PANORAMA-1 will be closely monitored. Will the toxicities noted in Phase II trials (thrombocytopenia, neutropenia, anemia, asthenia and respiratory tract infections) be viewed favorably relative to the toxicity profiles of the approved agents?

Prior to Novartis’ press release, the enthusiasm level for this agent was slightly lower compared to the recently approved Kyprolis and Pomalyst. However, Novartis got our attention with the news of statistically significant data in spite of the lack of quantitation associated with that press release. The data at ASCO will now have the chance to get us further excited.

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Lambrolizumab in relapsed/refractory advanced melanoma

The past several years have seen an explosion of new agents for the treatment of advanced melanoma: Yervoy® (ipilimumab, Bristol-Myers Squibb), Zelboraf® (vemurafenib, Genentech/Roche/Daiichi Sankyo), Tafinlar® (dabrafenib, GlaxoSmithSkline) and Mekinist® (trametinib, GlaxoSmithSkline). Moreover, other agents are waiting in the wings, as past ASCO meetings have highlighted the promise of Bristol-Myers Squibb’s anti-PD-1 monoclonal antibody nivolumab. However, at ASCO 2014 another anti-PD-1 monoclonal antibody will take center stage.

Lambrolizumab (MK3475, Merck) is a humanized monoclonal IgG4 antibody against PD-1. In a Phase I trial the response rate in advanced melanoma patients, who may or may not have been treated with prior Yervoy, treated with the highest dose level of lambrolizumab (10 mg/kg) was 52%, including a 10% complete response rate.[2] Although cross-study comparisons should be viewed carefully, such a comparison with the fully human monoclonal antibody nivolumab suggest that the antibodies could have similar activities in melanoma patients, as a Phase I trial for nivolumab indicated that the best response rate for nivolumab monotherapy (at the 3 mg/kg dose) was 41%.[3]

As Bristol-Myers Squibb initiated Phase III trials for nivolumab in December 2012 (for relapsed melanoma) and January 2013 (for first-line melanoma), it appeared that this agent would be the first to market. However, Merck announced in January that they started to file a rolling submission for lambrolizumab based on the results of a Phase II trial, which will be presented at this ASCO meeting, and they expect to complete this application in the first half of 2014. This Phase II trial compares lambrolizumab to standard cytotoxic chemotherapy in approximately 500 patients who have progressed after prior therapy, although it appears that data from only 411 patients will be presented at the ASCO 2014 presentation.

Given the high level of competition as mentioned above, it will be important to compare the efficacies and toxicity profiles. The co-primary endpoints for the lambrolizumab Phase II trial are PFS and OS, and given the past data (plus the poor activity of cytotoxic chemotherapy in these patients), Kantar Health feels that lambrolizumab will show a benefit compared to the control arm and therefore should be strong enough to support Merck’s rolling submission. The toxicity profiles, based on data from the Phase I trials, also appear similar, with both agents having similar levels of grade 1-2 pneumonitis (about 4% for each).

Although Merck’s submission might allow lambrolizumab to beat nivolumab – one of lambrolizumab’s more direct competitors given their similar mechanisms of action – to market in relapsed or refractory patients, nivolumab still might ultimately prevail. Nivolumab is being examined in two Phase III trials in newly diagnosed melanoma patients (as monotherapy or in combination with Yervoy). If one or both of these trials are successful, nivolumab could enjoy strong utilization in this setting – and as a consequence, keep lambrolizumab confined to later lines of therapy.

The primary question for lambrolizumab in this phase II trial, therefore, will be efficacy as this will be a guide in assessing lambrolizumab’s further prospects in other melanoma settings. Will it be strong enough to offer hope against front-line Yervoy and, in the future, nivolumab?

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[1] Blackwell, J Clin Oncol, 28: 1124-1130, 2010.

[2] Ribas, Abstract 9009, ASCO 2013

[3] Sznoll, Abstract CRA9006, ASCO 2013

 

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