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European Lung Cancer Congress

EGFR TKIs, such as erlotinib, afatinib, and gefitinib, have become the lynchpin of first-line targeted treatment of 

-mutated lung cancer. Their use is supported by data from several studies showing substantial improvements versus chemotherapy. Now, a new generation of TKIs are poised to take their position, according to David Planchard MD, PhD.

“Drug resistance limits the long-term success of even the most effective targeted therapies,” according to Planchard, from the Department of Cancer Medicine at the Institute Gustav Roussy in Villejuif, France, during the 2016 European Lung Cancer Conference (ELCC).

“Third-generation TKIs offer a higher level of selectivity towards 

 versus wild type, allowing a wider therapeutic range, and a better tolerability profile,” he said. “Expect a prolonged control of the disease compared to currently available TKIs.”

Planchard described the odyssey of treatments for patients with 

-mutated lung cancer who develop resistance to frontline TKIs, usually a result of acquired resistance through the T790M mutation. This has led to the development of third-generation TKIs that selectively bind to 

 T790M mutations, such as osimertinib (Tagrisso) and rociletinib. Pretreated patients with T790M-positive tumors have experienced a median progression-free survival (PFS) of 9.7 to 11 months with osimertinib at 80 mg and 8.0 months with rociletinib at 625 mg.

Planchard offered the possibility that the best sequence may actually be to reverse these lines of therapy and to start with a third-generation TKI.

“Prevention or delay of resistance may be a better strategy than treating resistance,” he said and detailed a strategy of ‘hitting harder’ the 

 mutation target with third-generation TKIs.

Planchard proceeded to make a strong case for T790M inhibition in the first-line, explaining that this strategy inhibits mutant 

 with sensitizing mutation exon 19 or L858R, as well as dual mutant 

 having either de novo or secondary T790M resistance mutation. Third-generation TKIs have the advantage of greater selectivity, better tolerability, and also allow for optimized brain penetration. They have demonstrated longer PFS and prolonged the development of resistance, according to Planchard.

With available EGFR first-generation TKIs, rash and diarrhea have been observed in approximately 80% of patients with grade 3/4 seen in nearly 20% of patients. In contrast, osimertinib has shown low rates of all-cause adverse events (AEs) in phase I and II trials. Similar findings were seen with rociletinib, in which grade 1 or 2 diarrhea was noted in 20% of patients, with no reports of diarrhea of grade 3 or higher.

Third-generation TKIs show optimized brain penetration, and are therefore more likely to have activity in brain metastases, which develop within a year of treatment in many patients. Planchard also cited a case study from his practice demonstrating tumor shrinkage in the brain of a patient with lung cancer and said that phase II trial data have shown efficacy in patients with a history of brain metastases.

Osimertinib has been evaluated as first-line treatment in the AURA trial in patients with locally advanced or metastatic 

-mutated NSCLC. Thirty patients each received 80 mg per day and 160 mg per day in the first-line setting. At median follow-up of 16.6 months, the ORR was 77%. Median PFS was 19.3 months for the 160-mg dose and has not yet been reached for the 80 mg-dose.

Osimertinib was well tolerated at both dose levels, though at the recommended 80-mg dose, just 10% of patients required dose reduction and no grade 3 or higher AEs of rash, diarrhea, and other AEs were reported; there was one report of grade 3 nausea.

Planchard pointed out that first-line osimertinib will be evaluated in the FLAURA study and the phase III SOLAR study (NCT02588261). He also noted that the clinical development of rociletinib is ongoing in the TIGER-X, -1, -2, and -3 trials.

Possible pitfalls of first-line third-generation TKIs could be the type of resistance that develops. The C797S mutation is known to impact the sensitivity of these treatment strategies, as it blocks the binding site of osimertinib. Also, the magnitude of PFS and overall survival response is unknown.

“Tumor heterogeneity has important clinical implications and may also enter into the equation,” Planchard commented.

Combination treatment may be the way forward to counter this pitfall. Osimertinib in combination or alternating with gefitinib as first-line in patients with 

-mutant lung cancer is currently being evaluated. Co-targeting EGFR and MEK has shown prolonged time to the development of resistance.

Another strategy being tested is the inhibition of anti-apototic factors BCL-xL and BCL-2.

Other combination strategies have shown promising activity, as in the TATTON trial of osimertinib plus durvalumab, a high-affinity human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80. This study was conducted in patients with confirmed T790M mutations but was offset by elevated incidence of pneumonitis.

With all these new options and possibilities for combinations, Planchard said, toxicity must remain top-of-mind for physicians and researchers alike.

“Toxicity represents another pitfall of new treatment strategies and must be minimized in treating patients.”

View more from the 2016 European Lung Cancer Conference

A new generation of EGFR-targeted TKIs are poised to displace traditional agents as frontline therapies for patients with lung cancer. 

Third-Generation EGFR TKIs Move to Frontline in Lung Cancer

John Haanen, MD PhD, department of Medical Oncology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, discusses the role of PD-L1 as a biomarker in lung cancer.

PD-L1 expression can be very dynamic, says Haanen. Therefore, PD-L1 expression may appear to be different depending on when the test was conducted.

PD-L1 expression of tumor cells or within the tumor microenvironment can be induced by the interaction between the immune system, T-cells, and the tumor. T-cells are activated when they recognize the tumor, a process which can sometimes induce PD-L1 expression, explains Haanen. This does not necessarily mean that PD-L1 is expressed all the time. Because PD-L1 is not always present in the tumor, it is not a reliable biomarker, says Haanen.

There does appear to be an association between outcomes and PD-L1 expression, especially with the PD-L1-directed agents; however it is not clear-cut, and therefor should not be used as a biomarker at this time in lung cancer, says Haanen.

John Haanen, MD PhD, epartment of Medical Oncology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, discussed the role of PD-L1 as a biomarker in lung cancer.

Dr. John Haanen on the Role of PD-L1 in Lung Cancer

First-line treatment with single-agent osimertinib (Tagrisso) induced a response rate of 77% in patients with 

-mutated non—small cell lung cancer (NSCLC), according to phase I data

 presented at the 2016 European Lung Cancer Conference (ELCC).

The median progression-free survival (PFS) was 19.3 months for patients receiving osimertinib at 160 mg once daily (n = 30) and was not yet reached for patients receiving the third-generation EGFR TKI at a dose of 80 mg once daily (n = 30). The median duration of response was 16.7 months with 160 mg and non-calculable in the 80-mg group.

“The overall response rate was among the best reported for first-line therapy of 

-mutated NSCLC,” lead author Suresh Ramalingam, MD, professor of Hematology and Medical Oncology at Emory School of Medicine and deputy director of Winship Cancer Institute, said in a statement.

“The PFS results are exciting, well exceeding the historical control rates of 10 to 13 months with first or second generation drugs. Many of the patients have not had disease progression on the study and are still benefitting from treatment.”

Osimertinib (80 mg once daily) is currently approved by the FDA for patients with advanced 

 T790M mutation—positive NSCLC following progression on an EGFR TKI. Updated data

 were also presented at the ELCC for the drug in this setting.

The frontline findings came from a study comprising 60 treatment-naïve patients with locally advanced or metastatic EGFR+ NSCLC from 2 phase I expansion cohorts of the phase I/II AURA trial. Seventy-five percent of patients were female and 72% were Asian. Patients had a WHO performance status of 0 to 1 and were still eligible if they had asymptomatic brain metastases.

 mutation status was determined through local and/or central laboratory testing (cobas EGFR Mutation Test). Forty percent of patients had EGFR exon 19 deletions and 42% had L858R mutations. There were 5 patients with 

 T790M mutations at the start of the study.

The median follow-up was 16.6 months at the January 4, 2016, data cutoff. The overall response rate (ORR) was 67% (95% CI, 47-83) and 87% (95% CI, 69-96) in the 80- and 160-mg groups, respectively. The overall disease control rate (complete response [CR] + partial response [PR] + stable disease [SD]) was 97% (95% CI, 88.5-99.6), including 93% (95% CI, 78-99) and 100% (95% CI, 88-100) in the 80- and 160-mg cohorts, respectively.

Overall, 72% of patients were alive and progression-free at 12 months, including 75% of patients in the 80-mg arm and 69% of patients in the 160-mg arm. Fifty-five percent of patients were progression-free at 18 months, including 57% and 53% in the lower- and higher-dose cohorts, respectively.

Outcomes were also reported for the 5 patients with T790M mutations at diagnosis. All 5 patients had a PR with a response duration ranging from 12.2 to 20.7 months. Ramalingam said these data may help explain the favorable efficacy of frontline osimertinib, which targets the T790M mutation. “We may be changing the biology of the disease with the use of first-line osimertinib.”

Dose reductions to manage AEs were needed for 3 patients (10%) in the lower-dose arm and 14 patients (47%) in the higher-dose cohort. “Overall, we found that the 80-mg dose was better tolerated than the 160-mg dose,” Ramalingam said at a press conference held during the ELCC by AstraZeneca, the manufacturer of osimertinib.

The most common all-grade adverse events (AEs) were rash (70% with 80 mg; 87% with 160 mg), diarrhea (60%, 87%), dry skin (57%, 60%), stomatitis (43%, 50%), and paronychia (37%, 63%). Grade ≥3 AEs for the 160-mg arm included diarrhea (7%), paronychia (7%), rash (3%), and stomatitis (3%). One patient in the 80 mg-arm had grade ≥3 nausea.

The ongoing phase III FLAURA study is further examining these early-stage findings. In the double-blind trial, treatment naïve patients with EGFR+ locally advanced or metastatic NSCLC will be randomized to either osimertinib (80 mg or 40 mg orally once daily) or a standard of care EGFR TKI—erlotinib (Tarceva) or gefitinib (Iressa).

Update Confirms Results in Pretreated Patients

“The results with osimertinib in the first-line look promising. The ongoing randomized trial will define the role of osimertinib in the treatment of EGFR mutated patients who are treatment-naïve,” Enriqueta Felip, MD, PhD, a medical oncologist at Vall d`Hebron University Hospital in Barcelona, Spain, who was not directly involved with the study, commented in an ELCC release.

New osimertinib data presented at ELCC confirmed the drug’s efficacy for its approved indication in patients with 

 T790M mutation—positive NSCLC who progressed on an EGFR TKI.

At the 80-mg recommended dose in this setting, the ORR was 71% (95% CI, 57-82) in a phase I dose expansion cohort (n = 63) and 66% (95% CI, 61-71) in a pooled analysis of 411 patients from 2 phase II studies. The median PFS was 9.7 months (95% CI, 8.3-13.6) and 11 months (95%, CI 9.6-12.4) for the expansion cohort and pooled results, respectively.

“In this mature pooled analysis for T790M-positive 

-mutant patients who have progressed on prior EGFR TKI, we were able to show a high overall response rate, encouraging duration of response, and good tolerability profile. PFS was long compared to the 4 to 5 months provided by chemotherapy,” lead author James Yang, MD, PhD, said in a statement.

 mutations who have failed EGFR TKI, for whom osimertinib is now standard of care. Molecular diagnosis for T790M must now be the standard, as well,” added Yang, who is director of the Department of Oncology and Department of Medical Research in the National Taiwan University Hospital, Taipei.

The pooled cohort included 210 patients from the phase II AURA2 study and 201 patients from the phase II part of the phase I/II AURA trial. The initial data for these 411 patients were evaluated by the FDA in granting the accelerated approval to osimertinib in the pretreated setting. The 63-patient group was an expansion cohort from the phase I part of the AURA trial.

All 474 patients in the analysis had T790M-positive advanced NSCLC and had progressed on an EGFR TKI. Over 60% of the patients were female and over two-thirds were never-smokers. The median age was 60 and 63 years in the phase I and phase II groups, respectively.

The disease control rate (CR + PR + SD + progressive disease) was 93% (95% CI, 84-98) in the phase I group and 91% (95% CI, 88-94) in the pooled phase II cohort. The median duration of response was 9.6 months and 12.5 months, respectively. The maximum duration of response was 26.3+ months in the phase I group and 15.3+ months in the pooled phase II analysis.

In the phase I cohort, 41, 29, and 17 patients were progression-free at 12, 18, and 24 months, respectively. In the pooled analysis, 48 patients were progression-free at 12 months and results were not reported for 18 or 24 months.

The most common all-grade AEs included rash (37% in the phase I group; 41% in the pooled phase II group), diarrhea (35%, 38%), paronychia (29% each), and dry skin (22%, 30%). In the phase I group, grade ≥3 AEs included diarrhea (n = 2) and paronychia (n = 2). Grade ≥3 AEs in the pooled analysis included rash (n = 3) and diarrhea (n = 2).

“Of note, is that some of these patients [receiving osimertinib] developed interstitial lung disease, which is a class effect for this kind of drug, and some patients developed QT prolongation,” Yang said when presenting at the AstraZeneca press conference. He added that the occurrence of these events was infrequent and similar to rates reported in previous analyses.

Commenting on the findings, Felip said in statement, “The study confirms the good results with osimertinib in this setting. Nowadays, in patients with an 

 mutation who progress after an EGFR TKI, there is a clear need for T790M testing since we now have a highly active agent, osimertinib, for this situation.”

			Ramalingam S, Yang JC, Lee CK, et al. Osimertinib as first-line treatment for EGFR mutation-positive advanced NSCLC: updated efficacy and safety results from two phase I expansion cohorts. Presented at: 2016 European Lung Cancer Conference; April 13-16, 2016; Geneva, Switzerland. Abstract LBA 1.

			Yang JC, Ramalingam S, Jänne PA, et al. Osimertinib (AZD9291) in pre-treated pts with T790M-positive advanced NSCLC: updated phase 1 (p1) and pooled phase 2 (p2) results. Presented at: 2016 European Lung Cancer Conference; April 13-16, 2016; Geneva, Switzerland. Abstract LBA 2.

First-line treatment with single-agent osimertinib (Tagrisso) induced a response rate of 77% in patients with EGFR-mutated nonâ€“small cell lung cancer.

Frontline Osimertinib Approaches 80% Response in EGFR+ NSCLC

Thierry Jahan, MD, professor of medicine at the UCSF Helen Diller Family Comprehensive Cancer Center, discusses the combination of the immunotherapy CRS-207 with chemotherapy as a treatment for patients with malignant pleural mesothelioma (MPM). CRS-207 is a strain of Listeria that contains 2 gene deletions to diminish its pathogenicity. The bacterium has also been engineered to express mesothelin, which is expressed on mesothelioma cells. 

Mesothelioma is a very difficult disease to treat, says Jahan. Chemotherapy, which is the standard of care, yields between a 20% and 40% response rate, with a median survival of about 1 year.

In a phase Ib study, the combination of CRS-207 with chemotherapy demonstrated a 94% disease control rate and a 59% response rate in patients with MPM, said Jahan. Median progression-free survival was 8.5 months. The combination was well-tolerated, with temperature spikes and rigors as the primary adverse events.

Thierry Jahan, MD, professor of medicine at the UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco, discusses CRS-20, a live, attenuated Listeria monocytogenes bacterium which is being investigated with chemotherapy in malignant pleural mesothelioma (MPM).

Dr. Thierry Jahan on CRS-207 With Chemotherapy in Mesothelioma

Patients with non-small cell lung cancer (NSCLC) who had ceased to respond to EGFR TKI therapy demonstrated a rapid and robust response to the investigational agent BI-1482694 (HM61713), according to findings presented at the 2016 European Lung Cancer Conference (ELCC).

BI-1482694 received a breakthrough therapy designation from the FDA in December, 2015 for the treatment of patients with NSCLC based on phase I/II data presented at the 2015 ESMO Asia Congress.

In that study, the objective response rate (ORR) by independent assessment with BI-1482694 was 62% for patients with 

-positive NSCLC. When looking specifically at those with a response confirmed on subsequent scans, the response rate with BI-1482694 was 46%. The overall disease control rate with BI-1482694 was 91% by independent review.

The results presented at ELCC are from an extension cohort where the disease control rate was 91% in 63 patients following treatment with the investigational agent. ORR by independent review was 62%; in 43 responding patients, 27 (84%) patients showed response by treatment cycle 2. Tumor response was confirmed in 32 (46%) patients. The median duration of response was not reached as of data cutoff.

The ORR was similar among patients whether they had received an EGFR TKI or chemotherapy as the last treatment before study entry.

“BI-1482694 is a novel, third-generation, oral EGFR TKI that specifically targets tumors harboring 

 mutations, which are the most common mechanism of acquired resistance seen in about 50% of patients following first- and second-generation EGFR TKI treatent,” explained Jin-Soo Kim, MD, of Seoul National University.

The maximum tolerated dose of 800 mg/day, established in the phase I/II dose escalation studies, was used in the expansion cohort of patients that had previously received EGFR TKIs for advanced EGFR mutation-positive NSCLC. All patients were required to have a documented T790M mutation. The majority (76%) had been treated with gefitinib, followed by erlotinib and afatinib. Patients receiving additional lines of systemic therapy were also eligible

Of the 76 evaluable patients at data cutoff June 30, 2015, 44 were female, 61 had an ECOG performance status ≤1, and 57 had received 2 or more lines of systemic therapy. Treatment duration with BI-1482694 ranged from 1 to 39 weeks; 46 patients remained on the drug at data cutoff.

“At the recommended phase II dose of 800 mg, BI-1482694 showed meaningful clinical activity with a favorable safety profile in T790M-positive patients progressing on initial EGFR TKI treatment,” Kim reported.

“Preliminary signs of activity in metastatic brain disease were observed in a 62-year-old man who achieved a complete response in the target brain lesion by cycle 6,” Kim continued. “The patient continues on treatment and maintains the complete response.”

The most common treatment-related adverse events included diarrhea, reported by 55% of patients, rash (38%), nausea (37%), and pruritis (36%). Grade 3 rash and pruritis were reported by 5% and 1% of patients, respectively.

Drug-related adverse events (DRAEs) occurred in 73 patients, and serious DRAEs were reported in 9 patients. DRAEs led to treatment discontinuation in 3 patients. No cases of QT prolongation syndrome or hyperglycemia were reported. The authors announced that ELUXA 1, a global phase II trial (NCT02485652) further evaluating the efficacy and safety of BI-1482694 in T790M-positive NSCLC, is ongoing and recruiting participants. “The broader ELUXA clinical trial program is in development to assess Bl-1482694 in different settings of EGFR-mutation positive NSCLC,” Kim said.

			Park K, Lee Js, Han JY, et al. Efficacy and safety of BI 1482694 (HM61713), an EGFR mutant-specific inhibitor, in T790M-positive NSCLC at the recommended phase II dose. Presented at: 2016 European Lung Cancer Conference; April 13-16, 2016; Geneva, Switzerland. Abstract 130O.

			Lee J, Park K, Han J, et al. Clinical activity and safety of the EGFR mutant-specific inhibitor, BI1482694, in patients (pts) with T790M-positive NSCLC. Presented at: 2015 ESMO Asia Congress; Singapore; December 18-21, 2015. Abstract 425PD.

Patients with non-small cell lung cancer who had ceased to respond to EGFR TKI therapy demonstrated a rapid and robust response to the investigational agent BI-1482694 (HM61713).

European Lung Cancer Congress | Conference

Third-Generation EGFR TKIs Move to Frontline in Lung Cancer

Dr. John Haanen on the Role of PD-L1 in Lung Cancer

Frontline Osimertinib Approaches 80% Response in EGFR+ NSCLC

Dr. Thierry Jahan on CRS-207 With Chemotherapy in Mesothelioma

High Response Rates Observed With BI-1482694 in T790M+ NSCLC