BACKGROUND Most patients with non-small-cell lung cancer have no response to the tyrosine kinase inhibitor gefitinib, which targets the epidermal growth factor receptor (EGFR). However, about 10 percent of patients have a rapid and often dramatic clinical response. The molecular mechanisms underlying sensitivity to gefitinib are unknown. METHODS We searched for mutations in the EGFR gene in primary tumors from patients with non-small-cell lung cancer who had a response to gefitinib, those who did not have a response, and those who had not been exposed to gefitinib. The functional consequences of identified mutations were evaluated after the mutant proteins were expressed in cultured cells. RESULTS Somatic mutations were identified in the tyrosine kinase domain of the EGFR gene in eight of nine patients with gefitinib-responsive lung cancer, as compared with none of the seven patients with no response (P<0.001). Mutations were either small, in-frame deletions or amino acid substitutions clustered around the ATP-binding pocket of the tyrosine kinase domain. Similar mutations were detected in tumors from 2 of 25 patients with primary non-small-cell lung cancer who had not been exposed to gefitinib (8 percent). All mutations were heterozygous, and identical mutations were observed in multiple patients, suggesting an additive specific gain of function. In vitro, EGFR mutants demonstrated enhanced tyrosine kinase activity in response to epidermal growth factor and increased sensitivity to inhibition by gefitinib. CONCLUSIONS A subgroup of patients with non-small-cell lung cancer have specific mutations in the EGFR gene, which correlate with clinical responsiveness to the tyrosine kinase inhibitor gefitinib. These mutations lead to increased growth factor signaling and confer susceptibility to the inhibitor. Screening for such mutations in lung cancers may identify patients who will have a response to gefitinib.

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Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib

Secret History: Return of the Black Death Channel 4, 7-8pm In 1348 the Black Death swept through London, killing people within days of the appearance of their first symptoms. Exactly how many died, and why, has long been a mystery. This Secret History documentary follows experts as they pick through the evidence and reveal why the plague killed on such a scale. And they ask, what might be coming next?

Medscape

Each year, the American Cancer Society estimates the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute and mortality data from the National Center for Health Statistics. Incidence and death rates are age-standardized to the 2000 US standard million population. A total of 1,399,790 new cancer cases and 564,830 deaths from cancer are expected in the United States in 2006. When deaths are aggregated by age, cancer has surpassed heart disease as the leading cause of death for those younger than age 85 since 1999. Delay-adjusted cancer incidence rates stabilized in men from 1995 through 2002, but continued to increase by 0.3% per year from 1987 through 2002 in women. Between 2002 and 2003, the actual number of recorded cancer deaths decreased by 778 in men, but increased by 409 in women, resulting in a net decrease of 369, the first decrease in the total number of cancer deaths since national mortality record keeping was instituted in 1930. The death rate from all cancers combined has decreased by 1.5% per year since 1993 among men and by 0.8% per year since 1992 among women. The mortality rate has also continued to decrease for the three most common cancer sites in men (lung and bronchus, colon and rectum, and prostate) and for breast and colon and rectum cancers in women. Lung cancer mortality among women continues to increase slightly. In analyses by race and ethnicity, African American men and women have 40% and 18% higher death rates from all cancers combined than White men and women, respectively. Cancer incidence and death rates are lower in other racial and ethnic groups than in Whites and African Americans for all sites combined and for the four major cancer sites. However, these groups generally have higher rates for stomach, liver, and cervical cancers than Whites. Furthermore, minority populations are more likely to be diagnosed with advanced stage disease than are Whites. Progress in reducing the burden of suffering and death from cancer can be accelerated by applying existing cancer control knowledge across all segments of the population.

https://onlinelibrary.wiley.com/doi/pdf/10.3322/canjclin.56.2.106

Cancer statistics, 2006.

In the planned interim analysis of data for the first 200 patients, progression-free survival was significantly longer in the gefitinib group than in the standard-chemotherapy group (hazard ratio for death or disease progression with gefitinib, 0.36; P<0.001), resulting in early termination of the study. The gefitinib group had a significantly longer median progression-free survival (10.8 months, vs. 5.4 months in the chemotherapy group; hazard ratio, 0.30; 95% confidence interval, 0.22 to 0.41; P<0.001), as well as a higher response rate (73.7% vs. 30.7%, P<0.001). The median overall survival was 30.5 months in the gefitinib group and 23.6 months in the chemotherapy group (P = 0.31). The most common adverse events in the gefitinib group were rash (71.1%) and elevated amino transferase levels (55.3%), and in the chemotherapy group, neutropenia (77.0%), anemia (64.6%), appetite loss (56.6%), and sensory neuropathy (54.9%). One patient receiving gefitinib died from interstitial lung disease. CONCLUSIONS First-line gefitinib for patients with advanced non–small-cell lung cancer who were selected on the basis of EGFR mutations improved progression-free survival, with acceptable toxicity, as compared with standard chemotherapy. (UMIN-CTR number, C000000376.)

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Gefitinib or Chemotherapy for Non–Small-Cell Lung Cancer with Mutated EGFR

Background We conducted a phase 3, randomized, double-blind, placebo-controlled trial of sorafenib, a multikinase inhibitor of tumor-cell proliferation and angiogenesis, in patients with advanced clear-cell renal-cell carcinoma. Methods From November 2003 to March 2005, we randomly assigned 903 patients with renal-cell carcinoma that was resistant to standard therapy to receive either continuous treatment with oral sorafenib (at a dose of 400 mg twice daily) or placebo; 451 patients received sorafenib and 452 received placebo. The primary end point was overall survival. A single planned analysis of progression-free survival in January 2005 showed a statistically significant benefit of sorafenib over placebo. Consequently, crossover was permitted from placebo to sorafenib, beginning in May 2005. Results At the January 2005 cutoff, the median progression-free survival was 5.5 months in the sorafenib group and 2.8 months in the placebo group (hazard ratio for disease progression in the sorafenib group, 0.44;...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa060655

Sorafenib in advanced clear-cell renal-cell carcinoma.

e13602 Background: Treatment-free survival (TFS) with and without (w/o) toxicity are outcome measures that describe health states where patients are experiencing clinically stable disease while off anti-cancer treatment, a clinically meaningful attribute seen with some immune-oncology (IO) regimens. We sought to characterize TFS with and w/o ongoing toxicity in addition to time on protocol therapy (combination and monotherapy) in trials of frontline IO-VEGF tyrosine kinase inhibitor (TKI) combinations in pts with advanced renal cell carcinoma (aRCC). Methods: We pooled randomized trials submitted to FDA evaluating IO-TKI combination in treatment-naïve aRCC with at least 30 months (mos) of median follow-up. OS was partitioned into health states, including TFS, defined as area between Kaplan-Meier curves for 2 time-to-event endpoints originating at randomization: 1) time to all protocol therapy cessation and 2) time to subsequent systemic therapy initiation or death. Health state areas under the curve were estimated by 30-mo restricted mean times. We pooled data by treatment arm. Results: Three trials (KEYNOTE-426, JAVELIN Renal 100, CheckMate 9ER) met criteria for analysis; in total, 1183 pts received IO-TKI vs. 1184 on control arms receiving sunitinib (SUN). IO-TKI and SUN groups spent 9% (2.7 mos [95% confidence interval (CI): 1.8, 3.5]) and 10% (2.9 mos [95% CI: 2.1, 3.8]) of the 30-mo period alive and treatment-free. Mean TFS with grade ≥3 toxicity were 1 and 0.6 mos in the IO-TKI and SUN groups, respectively. Mean TFS w/o grade ≥3 toxicity were 1.7 and 2.3 mos in IO-TKI and SUN groups, respectively. In IO-TKI group, the 30-mo mean time on combination therapy was 13.7 mos (46% of 30-mo period) and 3.9 mos on monotherapy (13% of 30-mo period). Following cessation of one drug in IO-TKI arm, monotherapy duration of TKI was longer than IO: 2.9 and 1 mos, respectively. Conclusions: In this descriptive, exploratory analysis, TFS and TFS w/o toxicity were similar in IO-TKI group compared to SUN group, in contrast to improved TFS in IO-IO vs. SUN seen in published literature. Among pts on IO-TKI, more time was spent on TKI monotherapy than IO monotherapy. These findings may reflect continuation of TKI until progression per protocol design in all trials and discontinuation of IO after 2 years in 2 trials, and may inform individual pt choice of IO-IO vs. IO-TKI. [Table: see text]

Richard Pazdur

Papers

FDA analysis of treatment-free survival in frontline advanced immuno-oncology–VEGF TKI renal cell carcinoma trials.