Postcards from the Edge - ASCO 2008: HER2+ Disease

There were over a hundred studies reported at ASCO 2008 on HER2-positive breast cancer, reflecting the importance of continued and aggressive research into HER2 disease. Various themes can be discerned:

1. cardiotoxicity of anti-HER2 therapies;
2. rising importance of the lapatinib (Tykerb);
3. issue of TBP - trastuzumab beyond progression;
4. issue of the brain as sanctuary for HER2 CNS metastasis;
5. role of new biological therapies in HER2 disease

among several others. In this issue, I take up what I interpret as the most critical ASCO 2008 HER2 studies. I have striven throughout to go beyond the narrow abstracts and to put the findings into the broadest context of our latest understanding of the best evidence to date about HER2-positive breast cancer.

Anti-HER2 Therapy Toxicities: Trastuzumab + Lapatinib
Chau Dang and colleagues at Memorial Sloan Kettering Cancer Center (MSKCC)¹ presented preliminary feasibility and cardiac safety findings from their pilot study of adjuvant DD-AC (4 cycles of dose-dense AC) followed by 12 weekly cycles of PTL (paclitaxel (Taxol) with trastuzumab (Herceptin) and lapatinib (Tykerb), administered for one year, in HER2+ BC. Trastuzumab and lapatinib (PTL) were initiated in combination with paclitaxel and administered for a total duration of 1 year (dosing: Trastuzumab (Herceptin) as a loading dose of 4 mg/kg IV, then 2 mg/kg each week during paclitaxel (Taxol) administration, and then 6 mg/kg every 3 weeks thereafter, with lapatinib (Tykerb) orally administered at 1000 mg daily). No cardiac safety issues have been identified to date, however diarrhea was the major toxicity observed with concurrent PTL paclitaxel/trastuzumab/lapatinib administration), and after a median 6-month follow-up period it was found impossible to administer of all 3 agents at the recommended doses (paclitaxel 80 mg/m2, trastuzumab 2 mg/kg, lapatinib 1000 mg daily) because of associated GI toxicity making the regimen infeasible, the study was closed early. In response to this toxicity data, the dosing schema of the comparable regimens in the ongoing international ALTTO trial (evaluating adjuvant chemotherapy with lapatinib alone vs trastuzumab alone vs the combination) is being modified in design appropriately.

HERTAX: Concurrent v Sequential Trastuzumab/Chemotherapy
The HERTAX trial² compared the initial use of chemotherapy (docetaxel (Taxotere) plus trastuzumab (Herceptin) to sequential trastuzumab followed by chemotherapy treatment at time of progression in patients with HER2+ MBC (metastatic breast cancer) receiving first-line chemotherapy. The power of the trial was limited by its small size (99 patients) and results were mixed: concurrent therapy yielded a higher response rate (73%) and longer (9.4 months) initial time to progression (TTP)than sequential therapy (50% RR and 3.9 months TTP), but ultimately TTP with sequential monotherapy or combination therapy was equivalent. A strong trend toward a survival advantage was suggested with the initial concurrent regimen, but none of these findings achieved statistical significance owing to the small study size. Nonetheless, my interpretation is that the HERTAX trial suggests that the strategy of initial concurrent chemotherapy plus trastuzumab may be associated with better long-term tumor control, as compared to sequential trastuzumab followed by chemotherapy, in patients with HER2+ advanced BC.

TBP (Trastuzumab Beyond Progression):
Lapatinib + Trastuzumab
Lapatinib (Tykerb) is small molecule dual-kinase inhibitor of HER2 and EGFR (epidermal growth factor receptor), approved for use in trastuzumab (Herceptin)-treated, advanced HER2+ BC for those HER2-positive patients progressing after trastuzumab, based on the findings of RCTs which found that in combination with capecitabine (Xeloda) it improved response rate and TTP (time to progression) compared with capecitabine (Xeloda) alone. But it should be noted that In the lapatinib (Tykerb) registration study, patients were required to discontinue trastuzumab treatment before starting on lapatinib, yet preclinical models have suggested that combined trastuzumab + lapatinib treatment might be superior to single agent therapy, and it was precisely this hypothesis that was tested in the open-label randomized phase III trial presented by Dr. Joyce O'Shaugnessy with US Oncology³ in heavily pretreated HER2+ patients (previously treated with anthracyclines and taxanes, averaging 5 or 6 prior chemotherapy regimens and 3 prior trastuzumab-based regimens) who had experienced overt tumor progression while on trastuzumab. The study found that despite the extensive prior therapy, the trastuzumab (intravenous at 4 mg/kg as the loading dose followed by 2 mg/kg weekly) + lapatinib (1000 mg) combination appeared to be superior to lapatinib (1500 mg) monotherapy; indeed, despite using the lower dose of lapatinib, the combination treatment yielded both improved TTP and modest advances in response rate and clinical benefit rate, with no excess toxicity findings on the combination regimen.

Breast Cancer Watch Commentary: Clinical Lessons
I interpret the clinical lessons from this as that:

1. trastuzumab (Herceptin) can potentiate lapatinib activity (where otherwise lapatinib antitumor activity was low as monotherapy, although not zero somewhat surprisingly),

2. ongoing trastuzumab therapy beyond overt progression can deliver clinically important benefits

· improved (27%) median PFS and increased percentage (28%) of patients progression-free at six months,

· with a doubling (24/7%) of the clinical benefit rate, and

· and with a trend toward superior median OS (45%) for the combination, which showed enhanced activity beyond what might otherwise be achieved with salvage anti-HER2 therapy)

even after progression on previous taxane, anthracycline, and trastuzumab therapy, and

3. with the only significant increase in toxicity to be expected being diarrhea;

4. we have proof of principle that simultaneous dual signal targeting of the HER2 receptor at the extracullar and the intracellular level is of clinical benefit, what I have called elsewhere dual-HER2 blockade, and that this dual-HER2 blockade establishes clinical synergy between these two anti-HER2 agents (lapatinib and trastuzumab);

5. it would appear that continuing trastuzumab and adding lapatinib to it in the resistance setting is a more optimal strategy than discontinuing trastuzumab and substituting lapatinib for it;

6. I should note that many oncologists like Charles Vogel at Aptium Oncology and Dennis Slamon at UCLA, among others, use a time-based heuristic of when to follow trastuzumab with lapatinib, namely that if a relapse occurs within one year of trastuzumab initialization, then they would use lapatinib;

7. these results are quite impressive for such a heavily pretreated, highly refractory, cohort - 28% of the lapatinib arm and 34% of the lapatinib + trastuzumab arm had 6 or more previous chemotherapy regimens at baseline - and it may in turn suggest that relativity rather than the absoluteness of trastuzumab resistance.

Breast Cancer Watch Commentary: Open Questions
It strikes me that regardless of these impressive results, three open questions remain. The first is selectivity: as I noted above, this cohort had, and survived, a median of 5 to 6 prior oncotherapies coming into the study, and without the development of progressive brain metastases, and this suggests that these patients therefore were likely significantly trastuzumab-sensitive or had relatively indolent HER2 disease, so that selection bias cannot be wholly excluded.

The second open question is far more significant still, that of dueling regimens for trastuzamab progression: this trial suggests the efficacy and viability of the combination of lapatinib + trastuzumab, but an alternative is lapatinib + capecitabine as per the trial of Geyer et al.⁴ which found that lapatinib + capecitabine was superior to capecitabine alone in women with HER2+ advanced breast cancer that has progressed after anthracycline, taxane, and trastuzumab therapy. Granting that the Geyer and the O'Shaugnessy ASCO 2008 studies involve different patient populations, nonetheless the Geyer data find for an overall response rate (ORR) of 22% and a clinical response rate of 27%, from lapatinib + capecitabine, which are appreciably higher than the ORR = 10% and clinical response rare = 24% found in the O'Shaugnessy ASCO 2008 trial of lapatinib + trastuzumab. Therefore this would suggest that for progressive HER2+ disease on trastuzumab, the lapatinib + capecitabine regimen would be relatively more favorable than lapatinib + trastuzumab.

The third and final open question is that of optimal regimen for progression to brain metastasis: as we have documented⁵, both lapatinib and capecitabine appear capable of crossing the blood-brain barrier (BBB) and the cerebrospinal fluid (CSF) barrier and hence may exhibit appreciable activity in breast cancer brain metastasis, although it should be noted that we currently have no direct comparative data of their relative benefits. However, that said, in the case of trastuzumab which is a large MoAb (monoclonal antibody) that theoretically should not traverse the BBB, it may nonetheless be that the development of a large metastatic tumor may disrupt the BBB, suggesting anecdotally that CNS tumor shrinkage with trastuzamab may still be viable. In addition, Charles Geyer has recently commented on and clarified the findings of his own study⁴: although 13 patients on capecitabine-alone developed CNS disease, only 4 on the capecitabine + lapatinib combination did so. Furthermore, I add here my own observation that on a trastuzumab + lapatinib combination as deployed in the O'Shaugnessy ASCO 2008, lapatinib dosing is required to be reduced for tolerability with trastuzumab to 1000 mg, raising the question of whether anti-CNS tumor efficacy is still maintained, a question that does not apply to the capecitabine + lapatinib regimen from the Geyer trial.

Finally, I join a small but growing chorus of researchers and clinicians in advising the utmost close surveillance and radiological monitoring, possibly including serial brain MRI, of HER2-positive patients; see for example, the conclusions of the Cross Cancer Institute team⁶ (" … these findings could prompt the consideration of brain prophylaxis strategies and/or serial radiologic screening to detect asymptomatic BM") and those of the Danish team of Charlotte Kristiansen and colleagues⁷ ("Since half of HER2 over-expressing patients developed brain-metastases close surveillance for brain metastases (clinical and/or imaging) is necessary even during effective systemic treatment. Future investigation into prophylactic cranial irradiation strategies in high-risk patients is warranted").

TBP (Trastuzumab Beyond Progression):
Trastuzumab + Capecitabine

A key clinical question is whether there is a benefit to continuing trastuzumab past first-line progression - called TBP, that is, trastuzumab beyond progression - and the Breast International Group/German Breast Group (BIG/GBG) TBP study⁸ reported at ASCO 2008 by Gunter von Minckwitz, addresses this directly by comparing capecitabine (Xeloda) alone with capecitabine plus trastuzumab in HER+ patients in patients with metastatic or locally advanced breast cancer progressing on (during or after) trastuzumab (2500 mg/m2 on Days 1-14 of a 21-day cycle with or without trastuzumab 6 mg/kg every 3 weeks). Although the trial closed early because of poor accrual was underpowered, the TGP trial investigators were still able to compare the two alternative regimens for 156 patients.

The TBP trial found that on the capecitabine + trastuzumab combination, the overall response rate (ORR) was 48% compared to 23% for capecitabine monotherapy, with 75.3% clinical benefit compared to 54% for capecitabine alone, with the median time to progression (TTP)(the primary endpoint) hazard ration being .69, increased to 8.2 months compared to 5.6 months for capecitabine monotherapy, and with a trend toward an increase in overall survival (OS) extending to 25.5 months compared with 20.4 months on monotherapy. Capecitabine plus trastuzumab was well tolerated, with mild to moderate (grade 1/2) anemia and hand/foot syndrome (HFS) more common on the combination, otherwise the toxicity profiles were comparable in both the continued trastuzumab and capecitabine arm and the capecitabine-alone arm.

Breast Cancer Watch Commentary: Clinical Lessons

1. This provides a robust warrant for clinicians to continue anti-HER2 past first-line therapy as it indicates that continued trastuzumab beyond progression (TBP) improves efficacy of second-line capecitabine in patients with metastatic or locally advanced BC compared with capecitabine alone, and indeed several studies suggest confirm the benefit of continued HER2-inhibition (with trastuzumab or other drugs anti-HER2 agents) is a better approach, making discontinuation of anti-HER2 therapy increasingly problematic.

2. Still unanswered is (1) whether it would be more beneficial to add a third drug such as capecitabine, to trastuzumab and lapatinib, or (2) whether capecitabine + trastuzumab may have been just or at least as effective as capecitabine plus lapatinib, although as Kathy Miller has suggested recently in interview, a reasonable strategy in practice is that patients who progress on capecitabine plus lapatinib will commonly be switched back to another trastuzumab-containing regimen.

New Biological Therapies: Trastuzumab + Pertuzumab

In their phase II trial, Karen Gelmon with the British Columbia Cancer Agency and colleagues⁹ studied pertuzumab plus trastuzumab in HER2-positive metastatic breast cancer patients whose tumors had progressed on prior trastuzumab therapy, obtaining 24% objective response to treatment, with 24% of the patients progression-free through 6 months of therapy, including a partial response rate of 16% and a complete response rate of 8%, with half of the participants experiencing a clinical benefit; most adverse events were grade 2 or less in severity, the most common side effects being diarrhea (64%), fatigue (33%), nausea/vomiting (27%), rash (26%), and headache (20%), and some mucositis. Only 3 of 66 patients (less than 5%) experienced falling LVEF.

Breast Cancer Watch Commentary:
Understanding Pertuzumab:
Pertuzumab is a humanized monoclonal antibody (MoAb), targeting part of the ECD or extracellular domain (subdomain-2 , the extracellular dimerization domain (EDD)) of HER2 different than that targeted by trastuzumab (subdomain-4 of HER2), allowing it to block certain interactions between HER2 and EGFR (HER1), or HER2/3/4, and hence with potential of activity even in non-HER2-overexpressing tumor. Pertuzumab inhibits ligand-dependent growth of breast cancer cell lines apparently independently of the level of immunohistochemical expression of HER2. Because of this, pertuzumab is now considered the first in a new class of what's called HDIs or HER2 dimerization inhibitors which inhibit the 'pairing' (dimerization) of the HER2 protein with other members of the HER family of receptors, as we know that in many cases HER1 and HER3 form heterodimers with HER2 in response to mitogenic signals, the formed heterodimers then acting as themselves strong oncogenic signals. What is exceptional is that pertuzumab only requires HER2 expression but is not dependent on HER2 amplification or overexpression, making it deployable in a wide range of tumor types, given that most human epithelial cells express HER2, and there is some speculation that pertuzumab may be able to overcome trastuzumab resistance.

There are several points to note in connection with the Gelmon study. Although only less than 5% of the patients experienced falling LVEF, this may underestimate the nature of cardiotoxicity that may be involved: the recent NCI cardiotoxicity study of Chia Portera and colleagues¹⁰ found that out of 11 HER2+ MBC patients, six (54%) experienced a LVEF reduction, three with grade 1, two with grade 2, and one with grade 3 left ventricular systolic dysfunction (LVSD), and of these six, two patients had a LVEF reduction of >= 15%. This suggests continued caution in dealing with potentially cardiotoxic agents and regimens.

In addition, I observe that preliminary data suggests HER3 inhibition may be more clinically relevant than inhibition of EGFR in HER2-amplified breast cancer, as per the recent findings of the Genetech team of Howard Stern and Si Tuen Lee-Hoeflich and colleagues¹¹ whose findings suggest that EGFR is dispensable in HER2-amplified breast cancers and may have no clinically important role in HER2 signaling, and who therefore used in this connection pertuzumab to directly block the HER2/HER3 interaction by binding to the domain II dimerization arm of HER2.

New Biological Therapies: Lapatinib Plus Pazopanib

Dennis Slamon and colleagues¹² conducted a short (12-week) preliminary randomized open-label phase II study of non-chemotherapy dual all-oral multikinase inhibitor (MKI) therapy using lapatinib (Tykerb, 1500mg/d) and the anti-VEGF agent pazopanib (400mg/d) compared with lapatinib alone in 141 HER2-positive advanced and metastatic BC (metastatic breast cancer); after 12 weeks, any patients with aggressive or stable disease were taken off dual MKI therapy and placed on trastuzumab (Herceptin). With a primary endpoint was 12-week progression, it was clear that pazopanib enhanced the antitumor efficacy of lapatinib: the dual MKI arm was associated with a a significant increase in target lesion response, and with 84% PFS (progression-free survival) compared to 63% PFS in the lapatinib monotherapy arm (hazard ratio of 0.41), although data for all patients was not available at the time of the ASCO 2008 presentation - efficacy data was missing on 20% or more of the studied patients. As to cardiotoxicity, of concern was the fact that four patients suffered a > 20% decrease in LVEF, all in the dual MKI combination arm, three of whom had previous anthracyclines treatment; all cases resolved upon discontinuation.

In addition, estimated week 12 disease progression rate was 15.9% for the dual MKI arm vs 36.8% for lapatinib monotherapy, with responses of 36.2% and 22.2%, respectively, as well as a significantly greater week 12 decrease in maximum target lesion diameter on dual MKI therapy compared with lapatinib monotherapy (almost all patients in the dual MKI arm experienced a lesion diameter decrease)). The dual MKI therapy was associated with an acceptable safety profile.

Breast Cancer Watch Commentary

This study provides proof of concept on the potential efficacy of dual MKI (multikinase inhibitor) therapy for HER2+ MBC using both HER2 + angiogenesis blockade, motivated in that HER2 tumors have increased levels of VEGF, so that the investigational agent pazopanib and lapatinib affect different crosstalking pathways, and previous phase I and II trials have independently established the activity of trastuzumab plus the anti-VEGF agent bevacizumab (Avastin), also being evaluated in the in-progress ECOG 1105 clinical trial. In addition it should be noted that pazopanib is more than just a VEGF inhibitor: it is a small-molecule multiple protein tyrosine kinase inhibitor of the c-kit and PDGF (platelet-derived growth factor) receptor.

In addition, Pegram and colleagues¹³ tested a parallel concept of dual HER2/VEGF pathway inhibition using two intravenously administered monoclonal antibodies, trastuzumab (Herceptin) and bevacizumab (Avastin) as first-line therapy in 30 of 50 patients with HER2-amplified metastatic or locally-relapsed disease, finding objective clinical responses (all partial responses) in 46% (13 of 28) evaluable patients, with an additional 9 of 28 patients with stable disease at week 8 (11 patients remain on active treatment). And the BETH trial¹⁴ will test the same dual strategy, trastuzumab (Herceptin) and bevacizumab (Avastin) in combination with chemotherapy , in the adjuvant setting.

And I conclude by noting that pazopanib has also shown considerable promise in STS (soft tissue sarcoma), epithelial ovarian cancer, NSCLC (non small cell lung cancer), and RCC (renal cell carcinoma), and is in a phase III clinical trial for IBC - inflammatory breast cancer¹⁵.

New Biological Therapies: HSP90 Tanespimycin

The heat shock protein (HSP90) inhibitors are a novel class of drugs that appear capable of lowering HER2 cell surface expression, and thus might potentiate the effects of anti-HER2 treatment. To study that possibility in patients, Shanu Modi at Memorial Sloan-Kettering Cancer Center (MSKCC) and colleagues¹⁶ conducted a phase 2 trial of the HSP90 inhibitor, tanespimycin, in combination with trastuzumab in patients with tumor progression despite prior trastuzumab therapy, finding that the overall response rate (ORR) was 26% in the 27 evaluable patients, with fatigue, nausea, and diarrhea as the most common treatment-related side effects although grade 3 toxicity was uncommon except grade 3 elevations in transaminases (alanine transaminase (ALT) and aspartate transaminase (AST)) were noted in several patients.

Breast Cancer Watch Commentary

Heat shock protein 90 (HSP90) is a molecular chaperone (one which binds and stabilize proteins at various intermediate stages including self-assembly called folding) required for the stability and function of several signaling proteins including ones which promote cancer cell growth and/or survival (the name derives from the fact that all cells produce them in response to many environmental insults or "stresses" - including heat, oxidation and hypoxia, acidosis, and toxic agent exposure, so they are in effect necessary for cell survival during stress). HSP90 inhibitors are unique in that, although they are directed toward a specific molecular target, they simultaneously inhibit multiple signaling pathways that frequently interact to promote cancer cell survival. Indeed, HSP90 inhibitors may be able to concurrently target the six hallmarks of a cancer cell: self-sufficiency in growth signals, insensitivity to antigrowth signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis¹⁷.

The stability of the ErbB2 protein is inherently and uniquely dependent on HSP90, and inhibition of HSP90 causes a dramatic decrease in ErbB2 protein level, both in cultured cells and in animal tumor models, as suggested early by Wanping Xu at the NCI and colleagues¹⁸. In addition, HSP90 inhibitors have potential to circumvent the genetic plasticity allowing tumor cells to evade the cytotoxicity of many oncotherapeutic agents¹⁹.

The HSP90 inhibitor tanespimycin (formerly, 17-AAG) used in the MSKCC trial is a new non-Cremophor suspension formulation of a former more toxic Cremophor-based product. Since HER2 and related proteins require HSP90 for proper self-assembly ("folding"), these are degraded by HSP90 inhibitors like tanespimycin, and it may be as suggested by Katerina Sidera at the Hellenic Pasteur Institute (Athens) and colleagues²⁰ that there is a novel interaction between surface HSP90 and the extracellular domain (ECD) of HER-2, and as we have observed above, Modi and colleagues found a response rate of about 26%, and an impressive 57 to 63% overall benefit rate, and an encouraging potential to still provide significant benefit to tumors that are wholly trastuzumab-resistance. These are important developments, since HSPs are critical in malignant progression of breast carcinoma and high HSP90 expression in primary breast cancer defines a population of patients with decreased survival²¹. It is also highly encouraging that myelosuppression was not a dose-limiting toxicity in HSP trials to date, facilitating coadministration with chemotherapy, and I note finally that there may be a role for HSP90 inhibition in BRCA1-deficient breast cancer²².

New Biological Therapies: Trastuzumab-DM1

At ASCO 2008, Howard Burris with the Sarah Cannon Cancer Center in Nashville and coresearchers²³ presented Phase I findings with the investigational agent T-DM1 (trastuzumab-DM1), a conjugate of trastuzumab (Herceptin) and the antimicrotubule DM1, with T-DM1 administered in 24 metastatic BC HER2-positive patients (once per 21-day cycle for a median of 91.6 weeks), with rather dramatic results: six objective responses, including one partial remission with a 36% shrinkage in the mediastinal area after just two cycles, and responses were exceptional: the response rate for patients who had measurable disease was 44%, and additional patients had stable disease. A companion Phase I T-DM1 study²⁴ was also presented on the safety and pharmacokinetics of T-DM1 given IV once weekly to advanced HER2+breast cancer patients who have progressed on a trastuzumab- containing regimen. For those who received the weekly schedule, the response rate was 53%, an exceptionally high rate in a population with a median of 5 prior therapies, and almost two years of prior trastuzumab before reintroduction of trastuzumab in the T-DM1 conjugate. The MTD for T-DM1 was established at 3.6 mg/kg, with objective tumor responses observed at doses at or below the MTD, and with adverse events of grade 2 or higher being infrequent and manageable. T-DM1 PK is compatible with q3-week dosing.

Breast Cancer watch Commentary

T-DM1 (trastuzumab-DM1) is an investigational ADC, or antibody-drug conjugate, meaning a monoclonal antibody linked with a cytotoxic agent for the selective kill, intracellularly, of tumor cells, minimizing the impact on normal tissue. This ADC has a proposed dual mechanism of action: anti-HER2 activity and targeted intracellular delivery of DM1, derivative of maytansine (derived naturally from a fungus), a potent antimicrotubule agent. The DM1 component is attached to trastuzumab by what's called the MCC linker molecule, with the goal of target intracellular delivery of both drugs with high specificity to tumor-only tissue.

ADCs (antibody-drug conjugates) are a novel cytotoxic immunotherapy approach to treating trastuzumab-resistant disease. Ian Krop at Dana-Farber and colleagues²⁵ had previously conducted a phase 1 dose-escalation study T-DM1 in 24 patients with trastuzumab-refractory breast cancer which found T-DM1 relatively well tolerated, associated with transient transaminitis and transient thrombocytopenia which both however resolved over time; 12 of 15 patients treated at MTD had stable disease or a partial response, and 5 with sustained stable diseases lasting from 130 to 250 days, exceptional with single-agent therapy (similar findings were presented at ASCO 2007²⁶). Given these positive findings, the future looks quite promising for ADCs (antibody-drug conjugates) as novel cytotoxic immunotherapy, both for overcoming trastuzumab resistance and for active anti-HER2 therapy.


brain mets	triple neg	current issue