Julia Wilkerson

Mitosis is not a key target of microtubule agents in patient tumors

Mitosis-specific agents have, to date, not been clinically successful. By contrast, microtubule-targeting agents (MTAs) have a long record of success, usually attributed to the induction of mitotic arrest. Indeed, it was this success that led to the search for mitosis-specific inhibitors. We believe the clinical disappointment of mitosis-specific inhibitors stands as evidence that MTAs have been successful not only by interfering with mitosis but, more importantly, by disrupting essential interphase cellular mechanisms. In this Perspective we will review literature that supports a paradigm shift in how we think about one of our most widely used classes of chemotherapeutics—MTAs. We believe that the steady presence and constant physiological role of microtubules are responsible for the overall success of MTAs. While mitosis-specific inhibitors are effective on only a small fraction of the tumor mass (dividing cells), MTAs target tubulin, a protein that has crucial roles in both mitotic and non-mitotic cells.

Gefitinib and Erlotinib in Metastatic Non-Small Cell Lung Cancer: A Meta-Analysis of Toxicity and Efficacy of Randomized Clinical Trials

BACKGROUND Tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) have been evaluated in patients with metastatic and advanced non-small cell lung cancer (NSCLC). The U.S. Food and Drug Administration initially granted accelerated approval to gefitinib but subsequently rescinded the authorization. Erlotinib and afatinib are similar compounds approved for the treatment of metastatic NSCLC. The objective of this study was to compare the efficacy and toxicity of erlotinib, gefitinib, and afatinib in NSCLC. METHODS We tabulated efficacy variables including overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) and quantitated toxicities and rates of dose reductions and discontinuation. Summary odds ratios were calculated using random and fixed-effects models. An odds ratio was the summary measure used for pooling of studies. RESULTS We examined 28 studies including three randomized trials with afatinib. Clinical toxicities, including pruritus, rash, anorexia, diarrhea, nausea, fatigue, mucositis, paronychia, and anemia, were similar between erlotinib and gefitinib, although some statistical differences were observed. Afatinib treatment resulted in more diarrhea, rash, and paronychia compared with erlotinib and gefitinib. Regarding efficacy, similar outcomes were recorded for ORR, PFS, or OS in the total population and in specific subgroups of patients between erlotinib and gefitinib. All three TKIs demonstrated higher ORRs in first line in tumors harboring EGFR mutations. CONCLUSION Gefitinib has similar activity and toxicity compared with erlotinib and offers a valuable alternative to patients with NSCLC. Afatinib has similar efficacy compared with erlotinib and gefitinib in first-line treatment of tumors harboring EGFR mutations but may be associated with more toxicity, although further studies are needed. Gefitinib deserves consideration for U.S. marketing as a primary treatment for EGFR-mutant NSCLC.

Microtubule-targeting agents augment the toxicity of DNA-damaging agents by disrupting intracellular trafficking of DNA repair proteins

Significance Drugs targeting microtubules are among the most active anticancer agents. In vitro and in preclinical models, these agents are said to interfere with mitosis. However human tumors divide too slowly for this paradigm to apply, evidenced by the failure of over a dozen well-designed antimitotic agents targeting the aurora kinases and kinesin spindle protein that had minimal antitumor activity but caused severe bone marrow suppression. We have proposed that microtubule-targeting agents interfere with the trafficking of critical proteins in interphase microtubules. If true, then one must identify critical proteins whose traffic on microtubules is impacted. We identify nine DNA repair proteins that traffic on microtubules, explaining why combinations of a microtubule-targeting agent and a DNA-damaging agent are frequently used in cancer therapy. The paradigm that microtubule-targeting agents (MTAs) cause cell death via mitotic arrest applies to rapidly dividing cells but cannot explain MTA activity in slowly growing human cancers. Many preferred cancer regimens combine a MTA with a DNA-damaging agent (DDA). We hypothesized that MTAs synergize with DDAs by interfering with trafficking of DNA repair proteins on interphase microtubules. We investigated nine proteins involved in DNA repair: ATM, ATR, DNA-PK, Rad50, Mre11, p95/NBS1, p53, 53BP1, and p63. The proteins were sequestered in the cytoplasm by vincristine and paclitaxel but not by an aurora kinase inhibitor, colocalized with tubulin by confocal microscopy and coimmunoprecipitated with the microtubule motor dynein. Furthermore, adding MTAs to radiation, doxorubicin, or etoposide led to more sustained γ-H2AX levels. We conclude DNA damage-repair proteins traffic on microtubules and addition of MTAs sequesters them in the cytoplasm, explaining why MTA/DDA combinations are common anticancer regimens.

Progression-free survival is simply a measure of a drug's effect while administered and is not a surrogate for overall survival.

Since 1992, the Food and Drug Administration has allowed for accelerated approval of cancer drugs in cases where a statistically significant and clinically meaningful improvement in survival or side effect over alternative therapies is clearly demonstrated in controlled randomized trials. To this effect, endpoints other than overall survival (OS) are accepted as surrogate markers for survival. A lack of consensus exists regarding the validity of progression-free survival (PFS) as a true measure of outcome due to treatment. To quantitatively evaluate the correlation between the magnitude of the difference in PFS and that of OS in randomized trials conducted in patients with metastatic solid tumors, we performed electronic searches for trials that reported a statistically significant improvement in PFS, OS, or both for 1 treatment arm over another. We cataloged variables of interest such as the hazard ratio (HR) for PFS and HR for OS from 66 studies that met inclusion criteria and calculated the difference (delta) in response rate (RR), PFS, and OS. We performed linear regressions between the differences in OS and the differences in PFS as well as between both those values and RR. We also examined the correlations of HR for PFS and HR for OS. Regression analysis of both delta PFS/delta OS (R2 = 0.49; P < 0. 0001) and HR PFS/HR OS (R2 = 0.62, P < 0.0001) showed strong statistical evidence that an increase in PFS is associated with an increase in OS of the same magnitude. Both PFS and OS showed strong association with RR. These results were reinforced when we looked at the 3 largest subgroups by cancer type. We found very little overlap in comparative analyses of genes annotated to terms of cell growth and death. We conclude that PFS is not a surrogate for OS; rather it is a straightforward measure of on-therapy benefit and is not predictive of tumor growth after the cessation of treatment. The magnitude of the improvement in PFS is the magnitude of the improvement in OS. PFS is simply a measure of a drug’s effect on tumor growth while it is administered and is not a surrogate for OS. Although PFS should not replace OS in regulatory approval consideration should be given to studies that treat beyond current definitions of progressive disease as a strategy to augment OS.

MAPK pathway activation leads to Bim loss and histone deacetylase inhibitor resistance: rationale to combine romidepsin with an MEK inhibitor

To identify molecular determinants of histone deacetylase inhibitor (HDI) resistance, we selected HuT78 cutaneous T-cell lymphoma (CTCL) cells with romidepsin in the presence of P-glycoprotein inhibitors to prevent transporter upregulation. Resistant sublines were 250- to 385-fold resistant to romidepsin and were resistant to apoptosis induced by apicidin, entinostat, panobinostat, belinostat, and vorinostat. A custom TaqMan array identified increased insulin receptor (INSR) gene expression; immunoblot analysis confirmed increased protein expression and a four- to eightfold increase in mitogen-activated protein kinase (MAPK) kinase (MEK) phosphorylation in resistant cells compared with parental cells. Resistant cells were exquisitely sensitive to MEK inhibitors, and apoptosis correlated with restoration of proapoptotic Bim. Romidepsin combined with MEK inhibitors yielded greater apoptosis in cells expressing mutant KRAS compared with romidepsin treatment alone. Gene expression analysis of samples obtained from patients with CTCL enrolled on the NCI1312 phase 2 study of romidepsin in T-cell lymphoma suggested perturbation of the MAPK pathway by romidepsin. Immunohistochemical analysis of Bim expression demonstrated decreased expression in some skin biopsies at disease progression. These findings implicate increased activation of MEK and decreased Bim expression as a resistance mechanism to HDIs, supporting combination of romidepsin with MEK inhibitors in clinical trials.

Analyzing the Pivotal Trial That Compared Sunitinib and IFN-α in Renal Cell Carcinoma, Using a Method That Assesses Tumor Regression and Growth

Purpose: We applied a method that analyzes tumor response, quantifying the rates of tumor growth (g) and regression (d), using tumor measurements obtained while patients receive therapy. We used data from the phase III trial comparing sunitinib and IFN-α in metastatic renal cell carcinoma (mRCC) patients. Methods: The analysis used an equation that extracts d and g. Results: For sunitinib, overall survival (OS) was strongly correlated with log g (Rsq = 0.44, P < 0.0001); much less with log d (Rsq = 0.04; P = 0.0002). The median g of tumors in these patients (0.00082 per days; log g = −3.09) was about half that (P < 0.001) of tumors in patients receiving IFN-α (0.0015 per day; log g = −2.81). With IFN-α, the OS/log g correlation (Rsq = 0.14) was weaker. Values of g from measurements obtained by study investigators or central review were highly correlated (Rsq = 0.80). No advantage resulted in including data from central review in regressions. Furthermore, g can be estimated accurately four months before treatment discontinuation. Extrapolating g in a model that incorporates survival generates the hypothesis that g increased after discontinuation of sunitinib but did not accelerate. Conclusions: In patients with mRCC, sunitinib reduced tumor growth rate, g, more than did IFN-α. Correlating g with OS confirms earlier analyses suggesting g may be an important clinical trial endpoint, to be explored prospectively and in individual patients. Clin Cancer Res; 18(8); 2374–81. ©2012 AACR.

Sunitinib Does Not Accelerate Tumor Growth in Patients with Metastatic Renal Cell Carcinoma

SUMMARY Preclinical studies have suggested that sunitinib accelerates metastases in animals, ascribing this to inhibition of the vascular endothelial growth factor receptor or the tumor’s adaptation. To address whether sunitinib accelerates tumors in humans, we analyzed data from the pivotal randomized phase III trial comparing sunitinib and interferon alfa in patients with metastatic renal cell carcinoma. The evidence clearly shows that sunitinib was not harm- ful, did not accelerate tumor growth, and did not shorten survival. Specifically, neither longer sunitinib treatment nor a greater effect of sunitinib on tumors reduced survival. Sunitinib did reduce the tumor’s growth rate while administered, thereby improving survival, without appearing to alter tumor biology after discontinuation. Concerns arising from animal models do not apply to patients receiving sunitinib and likely will not apply to similar agents.

The VEGF inhibitor axitinib has limited effectiveness as a therapy for adrenocortical cancer

CONTEXT Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis in need of more effective treatment options. Published evidence indicates many ACCs express the vascular endothelial growth factor receptor (VEGFR), suggesting inhibiting vascular endothelial growth factor signaling could potentially impact tumor growth. OBJECTIVE The objective of the study was to determine the antitumor efficacy of axitinib (AG-013736), a potent, selective inhibitor of VEGFR1, -2, and -3. DESIGN This was a phase II, open-label trial using a two-stage design. PATIENTS Thirteen patients with metastatic ACC previously treated with at least one chemotherapy regimen with or without mitotane participated in the study. INTERVENTION Starting axitinib dose was 5 mg orally twice daily. Dose escalations were permitted if the administered dose was tolerable. RESULTS Thirteen patients were enrolled. Dose escalation was possible in seven patients, but the majority could not tolerate a dose higher than the starting 5 mg, twice-daily dose for prolonged periods of time. All patients experienced known grade 1/2 toxicities, and 10 of 13 patients had at least one grade 3/4 adverse event. No patient tumor could be scored as a Response Evaluation Criteria in Solid Tumors response, although the growth rate on therapy compared with that prior to starting axitinib was reduced in 4 of the 13 patients. The median progression-free survival was 5.48 months, and the median overall survival was longer than 13.7 months. CONCLUSION Axitinib has limited effectiveness in ACC. Together with 48 patients previously reported who received either sorafenib or sunitinib, a total of 61 ACC patients have now been treated with a VEGFR tyrosine kinase inhibitor without an objective Response Evaluation Criteria in Solid Tumors response. Future trials in ACC should look to other targets for possible active agents.

Colorectal Cancer Survival Gains and Novel Treatment Regimens: A Systematic Review and Analysis

IMPORTANCE The past 2 decades have witnessed progress in the management of metastatic colorectal cancer (mCRC) with more effective agents and better surgical, medical, and supportive care. While substantial progress has been made, much more must be achieved to prolong the lives of patients. OBJECTIVE To conduct a systematic review to ascertain what percentage of the life expectancy gain in locally advanced and mCRC over the past 2 decades is due to novel therapies vs improvements in supportive care or secular trends and to thus inform treatment development strategies. EVIDENCE REVIEW We searched Cochrane Controlled Trials Register, Medline, Embase, CancerLit, and Healthstar electronic databases for trials covering the period 1993 to 2015, scanned reference lists of articles, and searched recent conference abstracts. Ninety-six phase 3 trials and large (>50 patients) phase 2 trials in mCRC were examined. Outcomes evaluated in the experimental arms (EAs) and control arms (CAs) included overall response rate, stable disease, progression-free survival (PFS), and overall survival (OS). FINDINGS Over the period covered by the studies, the OS in EAs increased at a mean (95% CI) rate of 0.80 (0.67-0.93) mo/y. Importantly, OS in the CAs improved 0.63 (0.51-0.75) mo/y, reflecting in part the use of experimental regimens in subsequent studies. Chemotherapy contributed only partly to the gains in OS, given that (1) mean (95% CI) improvements in PFS were only 0.31 (0.22-0.39) mo/y in the EAs and 0.23 (0.15-0.31) mo/y in CAs; (2) gains in survival not directly attributable to the protocol were greater than gains in PFS (0.46 [0.36-0.57] mo/y in EAs and 0.39 [0.29-0.49] mo/y in CAs; and (3) effects on OS were much lower in second-line trials (median [interquartile range] response rates, 8.6% [0%-11.0%] in EAs and 7.5% [3.8%-12.8%] in CAs) compared with first-line trials (39.5% [24.0%-50.2%] for EAs and 29.4% [16.4%-39.4%] for CAs). CONCLUSIONS AND RELEVANCE The OS of patients with mCRC has improved gradually over the past 2 decades, with gains from chemotherapy occurring alongside gains from lead-time bias and improved locoregional approaches and supportive care. Gains from first-line therapies have been modest but consistent; however, gains from second-line therapies have been disappointing. We believe that future progress will be greater if emphasis is placed on enrolling patients in experimental trials to explore and develop alternative first-line regimens and better second-line therapies.

Continuing a cancer treatment despite tumor growth may be valuable: sunitinib in renal cell carcinoma as example.

Background The US FDA and the EMA have approved seven agents for the treatment of renal cell carcinoma, primarily based on differences in progression-free survival (PFS). Because PFS is an arbitrary endpoint we hypothesized that an analysis would demonstrate the growth rate of tumors remained constant at the time of RECIST-defined disease progression. Methods We previously estimated the growth (g) and regression (d) rates and the stability of g using data from the Phase III trial comparing sunitinib and interferon. Results Sufficient data were available and rate constants statistically valid in 321 of 374 patients randomized to sunitinib. Median d was 0•0052 days−1; in 53 patients no tumor growth was recorded. Median g was 0•00082 days-1 and was stable for a median of 275 days on therapy, remaining stable beyond 300, 600 and 900 days in 122, 65 and 27 patients, respectively. A possible increase in g while receiving sunitinib could be discerned in only 18 of 321 patients. Given a median g of 0•00082 days−1 the estimated median time to a second progression were sunitinib continued past RECIST-defined progression was 7.3 months. At 100, 200, and 300 days after starting therapy, an estimated 47%, 27%, and 13% of tumor remains sunitinib sensitive and could explain a RECIST-defined response to a new TKI. Conclusion Prolonged stability of g with sunitinib suggests continued sunitinib beyond RECIST-defined progression may provide a beneficial outcome. Randomized trials in patients whose disease has “progressed” on sunitinib are needed to test this hypothesis.