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European Lung Cancer Congress

Atezolizumab (Tecentriq) plus bevacizumab (Avastin), carboplatin, and paclitaxel (ABCP) has emerged as a potential new standard of care for patients with 

-positive metastatic nonsquamous non—small cell lung cancer (NSCLC) who have failed on TKI treatment, according to an exploratory analysis from the phase III IMpower150 trial presented at the 2019 European Lung Cancer Congress (ELCC).

The data, which were also recently published in 

 showed that ABCP reduced the risk of death by 39% compared with a regimen of bevacizumab, carboplatin, and paclitaxel (BCP). The median OS was not yet reached with ABCP compared with 18.7 months (95% CI, 13.4-NE) with BCP (HR, 0.61; 95% CI, 0.29-1.28).

“IMpower150 is the first phase III immunotherapy-based combination study to demonstrate a statistically significant and clinically meaningful improvement in OS in patients with metastatic nonsquamous NSCLC and 

 mutation, providing a potential new standard of care for these patients,” said Martin Reck MD, PhD, Department of Thoracic Oncology at the Lung Clinic Grosshansdorf in Grosshansdorf, Germany.

The IMpower150 trial overall enrolled 1202 patients who were randomized equally to receive atezolizumab at 1200&thinsp;mg plus carboplatin AUC 6 plus paclitaxel at 200&thinsp;mg/m

 (arm A); atezolizumab plus bevacizumab at 15&thinsp;mg/kg plus chemotherapy (arm B); or bevacizumab plus chemotherapy (arm C). The agents were administered by IV every 3 weeks for 4 or 6 cycles per investigator decision, followed by maintenance with atezolizumab plus bevacizumab or single-agent atezolizumab or bevacizumab, respectively. The primary endpoints were OS and investigatory-assessed progression-free survival in the ITT—wild-type population.

“The trial explored these combinations because atezolizumab inhibits PD-L1 to restore anticancer immunity and may be enhanced through bevacizumab’s inhibition of VEGF immunosuppression and by promoting T-cell tumor infiltration, while the chemotherapy of carboplatin plus paclitaxel may induce immune responses,” Reck said while explaining the study rationale.

Reck presented findings at the 2019 ELCC from the IMpower150 exploratory analyses, which included patients with 

-mt patients with prior TKI therapy. The exploratory analyses occurred at ≥20 months’ follow-up and included 79 patients overall (

-mt population), of whom 58 (73%) comprised the 

-mts subgroup, and 50 (63%) comprised the subgroup who had received prior TKI therapy. The baseline characteristics of the 

-mt patients across treatment arms were generally comparable to those in the ITT population.

For the comparison of OS with ABCP (Arm B) versus BCP (Arm C), all HRs favored the quadruplet across the 3 subgroups. In 

mt patients, the median OS was not reached in arm B versus 18.7 months in arm C (HR, 0.61; 95% CI, 0.29-1.28); in 

-mts patients, the median OS was not reached versus 17.5 months, respectively (HR, 0.31; 95% CI, 0.11-0.83); and in patients receiving prior TKIs, the median OS was not reached versus 17.5 months (HR, 0.39; 95% CI, 0.14-1.07). 

-mt patients were 36%, 71%, and 42%, and the median duration of response was 5.6 months (range, 2.6-15.2), 11.1 months (range, 2.8-18.0), and 4.7 months (range, 2.6-13.5) in arms A, B, and C, respectively.

Adverse events (AEs) included reporting of serious AEs and immunological AEs, which were similar between the treatment arms. In the 

-mt patients, the safety analysis comprised 44 patients in arm A, 33 patients in arm B, and 44 patients in arm C. Treatment-related AEs (TRAEs) occurred in 89%, 100%, and 96% of patients in arms A, B, and C, respectively; grade 3/4 TRAEs were reported in 57%, 64%, and 57% of patients in the respective groups. One grade 5 TRAE occurred in arm C.

Immune-related AEs were rash in 36%, 30%, and 11% of patients and hypothyroidism in 2%, 18%, and 2% of patients in arms A, B, and C, respectively.

“Adding atezolizumab to standard-of-care bevacizumab and chemotherapy provided a survival benefit in 

-mt patients who have failed previous TKIs; this regimen may represent a new treatment option for this patient population.”

Reck M, Jotte R, Mok TSK, et al. IMpower150: an exploratory analysis of efficacy outcomes in patients with EGFR mutations. Presented at: 2019 European Lung Cancer Congress; April 11 to 13, 2019; Geneva, Switzerland. Abstract 104O.

Reck M, Mok TSK, Nishio M et al. Atezolizumab plus bevacizumab and chemotherapy in non-small cell lung cancer (IMpower150): key subgroup analysis of patients with EGFR mutations or liver metastasis in a randomised, open label phase 3 trial. 

. 2019 Mar 25. pii: S2213-2600(19)30084-0. doi: 10.1016/S2213-2600(19)30084-0.

Atezolizumab plus bevacizumab, carboplatin, and paclitaxel has emerged as a potential new standard of care for patients with EGFR-positive metastatic nonsquamous non–small cell lung cancer who have failed prior TKIs.

Atezolizumab Regimen Improves OS After TKI Failure in EGFR+ NSCLC 

Niels Reinmuth, MD, PhD, leader of the Thoracic Oncology Department, of the Asklepios Lung Clinic, discusses the results of the phase III MYSTIC study (NCT02453282), which evaluated the efficacy and safety of first-line durvalumab (Imfinzi) plus tremelimumab versus platinum-based chemotherapy in patients with metastatic non—small cell lung cancer.

Overall survival was analyzed in subgroups based on baseline clinical characteristics. Unfortunately, there was no single clinical characteristic identified. Although durvalumab was effective across all subgroups, it was not found to be statistically significant. This was predetermined, says Reinmuth, because there were 3 primary endpoints.

However, it appears that subsequent immunotherapy might have impaired the overall survival (OS) benefit of durvalumab in the first-line. About two-thirds of patients crossed over to receive a form of immunotherapy, although durvalumab was not permitted as a cross-over option. If statistical methods are applied, it appears that this subsequent immunotherapy may have led to improved outcomes in the chemotherapy-treated group.

Niels Reinmuth, MD, PhD, discusses the results of the MYSTIC study, which evaluated first-line durvalumab plus tremelimumab versus platinum-based chemotherapy in patients with metastatic non–small cell lung cancer.

Dr. Reinmuth on Findings from the MYSTIC Study

James Chih-Hsin Yang, MD, director, Graduate Institute of Oncology, director, Department of Oncology at National Taiwan University Hospital, discusses the final safety and efficacy results from 2 phase I expansion cohorts from the phase I/II AURA trial (NCT01802632). Both cohorts received osimertinib (Tagrisso) at a dose of either 80 mg or 160 mg for advanced 

 mutation-positive advanced non—small cell lung cancer (NSCLC).

For the trial, investigators sought to determine the durability of response for these patients. Results showed that the response rate has been high for both groups, at 67% and 87% for the 80-mg cohort and the 160-mg cohort, respectively. The median duration of response is approximately 20 months, which Yang explained is consistent with findings from the phase III FLAURA trial (NCT02296125).

At the time of data cutoff, May 1, 2018, 11 patients were still receiving the study drug. At 3 years, 25% of patients were still receiving treatment, and at 4 years, 18% of patients had durable response. In terms of progression-free survival, at a cutoff of 3 months, 20% of patients were progression-free. At 4 years, 14% of patients are still progression-free, as estimated by Kaplan—Meier curves. These results, Yang explains, provide confidence that osimertinib may induce durable response in at least some of these patients in the first line.

James Chih-Hsin Yang, MD, discusses the final safety and efficacy results from 2 phase I expansion cohorts from the phase I/II AURA trial.

Dr. Yang on Osimertinib as First-Line Therapy for EGFR-Positive NSCLC

Results from a final analysis of the phase III KEYNOTE-042 trial have confirmed the benefit of pembrolizumab (Keytruda) monotherapy in patients with non—small cell lung cancer (NSCLC), said Tony Mok, MD.

The FDA recently expanded the label for pembrolizumab monotherapy for the frontline treatment of patients with stage III NSCLC who are ineligible for surgery or definitive chemoradiation, as well as for patients with metastatic disease with a PD-L1 expression tumor proportion score (TPS) level of 1% or greater who do not harbor 

The regulatory decision was based on positive findings from the phase III KEYNOTE-042 study, in which investigators randomized 1274 patients with locally advanced or metastatic NSCLC to receive either pembrolizumab or chemotherapy.

Results from the trial showed that frontline pembrolizumab demonstrated a median overall survival (OS) of 16.7 months versus just 12.1 months with standard chemotherapy in those with advanced or metastatic disease and a TPS ≥1%.

 Further, data from an exploratory analysis, which examined all patients with PD-L1 TPS of 1% to 49%, showed a median OS was 13.4 months with pembrolizumab compared with 12.1 months with chemotherapy.

At the 2019 European Lung Cancer Congress, Mok, a professor in the department of clinical oncology at the Chinese University of Hong Kong, presented results from the final analysis of the trial, which showed that with an additional 6 months follow-up, pembrolizumab demonstrated continued OS benefit compared with chemotherapy.  

, Mok discussed the study and the implications of its findings, and shed light on the evolving role of immunotherapy in NSCLC.

: Could you discuss the findings from the final analysis of the phase III KEYNOTE-042 trial?

: KEYNOTE-042 is the sister study of KEYNOTE-024. KEYNOTE-024 study selected patients who had PD-L1 over 50% and randomized them to receive either pembrolizumab or standard chemotherapy, using progression-free survival (PFS) as the primary endpoint. KEYNOTE-042 selected patients [with PD-L1] over 1%, and then did the same randomization of pembrolizumab versus chemotherapy, but the primary endpoint was overall survival (OS), looking at the 1% cutoff, the 20% cutoff, and the 50% cutoff. That’s the distinction between the 2 trials. Obviously, OS is the primary endpoint and the sample size is larger in KEYNOTE-042.

Since our presentation at the 2018 ASCO Annual Meeting, we reported our final analysis at the European Lung Cancer Congress this year. At this time, we confirmed the improvement in OS of 20 months versus 13 months in the [PD-L1] over 50% subgroup. Similarly, in the 20% subgroup and the 1% subgroup, we also had an improvement in OS with a positive hazard ratio.

In the exploratory analysis, we also looked at the 1% to 49%, where we did not observe an improvement in OS. What does that mean? That a lot of the benefit is driven by the 50% subgroup. One caveat that we can take from this is that in the 50% subgroup, the standard treatment is single-agent [pembrolizumab]. However, in the 1% to 49% subgroup, the standard treatment should be chemotherapy or chemotherapy with pembrolizumab as per KEYNOTE-189.

On the other hand, for patients who cannot receive chemotherapy, then these data may support consideration of the use of single-agent pembrolizumab because it’s not actually inferior. Although this is not an inferiority analysis, the data suggest that it’s possible to consider this option.

What are the next steps for this research with pembrolizumab?

That’s an important question. Right now, on the standard indication, with the number of studies available, it’s use is pretty well-defined as either a single-agent or in combination with chemotherapy.

I think the next wave is, number 1, how do we manage resistance to single-agent pembrolizumab? There tends to be, potentially, continuation of the drug or combination with other drugs.

The second part of this is, do we use pembrolizumab as a frame—a so-called skeleton&mdash;and add on other immunotherapy agents? Obviously, it’s still very risky business because there are several negative data that have already come out, so we have to do this a lot smarter. If we see an advantage, we must make use of it.

The third part of it is, although I like PD-L1 expression, I still don’t think that it’s a perfect biomarker. We still have to work hard to understand the science a little bit more so that we can choose patients smarter. We’ve made it clinical, relevant, and applicable, but it’s still not the perfect one. Just like 

 mutation, before we found that mutation, we had used FISH. FISH was actually popular for a little while, but eventually we were able to find the 

 mutation. Hopefully we’ll find a more specific biomarker in the future.

What are some of the other key advances made with immunotherapy that are being presented during this congress? 

I think there are several discussions on tumor mutational burden (TMB), and the relevance of TMB was discussed on the basis of the MYSTIC data. That was cross-referenced with the TMB data from CheckMate-227.

How we’re going to apply that information is actually quite important, because there are other randomized studies, such as the B-FAST study, which will use TMB as a selective biomarker for patients to go on atezolizumab (Tecentriq). I think more work has to be done in this regard, number 1.

Number 2, there was another great talk about tumor heterogenicity, especially about the microenvironment and the immune reaction based on this heterogenicity. I think that was outstanding. In some ways, we treat lung cancer like a single disease, but inside this tumor, there are actually many inhabitants, and we have to recognize the behavior of these different inhabitants to determine how to deal with them.

Mok TSK, Wu Y-L, Kowalski DM, et al. Final analysis of the phase III KEYNOTE-042 study: pembrolizumab (pembro) versus platinum-based chemotherapy (chemo) as first-line therapy for patients (pts) with PD-L1—positive locally advanced/metastatic NSCLC. 

. 2019;30(suppl 2; abstr 1020). doi: 10.1093/annonc/mdz063.

Lopes G, Wu Y-L, Kudaba I, et al. Pembrolizumab (pembro) versus platinum-based chemotherapy (chemo) as first-line therapy for advanced/metastatic NSCLC with a PD-L1 tumor proportion score (TPS) ≥ 1%: open-label, phase 3 KEYNOTE-042 study. 

. 2018;36(suppl 18; abstr LBA4). doi: 10.1200/JCO.2018.36.18_suppl.LBA4.

Tony Mok, MD, discusses the KEYNOTE-042 trial and the implications of its findings, and sheds light on the evolving role of immunotherapy in non–small cell lung cancer.

Mok Provides Pembrolizumab Update, Next Steps With Immunotherapy in NSCLC

No overall survival advantage was obtained from maintenance therapy comprising nivolumab (Opdivo) alone or in combination with ipilimumab (Yervoy) over placebo in patients with extensive-stage small cell lung cancer (SCLC), according to findings

from the phase III CheckMate-451 trial presented at the 2019 European Lung Cancer Congress.

Overall survival (OS) was not significantly prolonged with nivolumab plus ipilimumab compared to placebo (HR, 0.92; 95% CI, 0.75-1.12; 

= .3693), nor was OS improved with nivolumab monotherapy compared to placebo (HR, 0.84; 95% CI, 0.69-1.02).

Taofeek Owonikoko, MD, PhD, Co-Chair of the Clinical and Translational Review Committee, Winship Cancer Institute of Emory University, explained that there is a high unmet need for new treatments in the second-line setting and beyond for patients with SCLC.

“Approximately 60% to 70% of patients with SCLC have extensive disease at the time of diagnosis, meaning it has spread beyond a single lung and nearby lymph nodes and cannot be treated with radiotherapy,” said Owonikoko. “There is generally a good initial response to chemotherapy; however, the responses are often not durable and most patients experience disease progression within a short time. Currently intervention is begun after tumor growth.”

Owonikoko and colleagues investigated whether administering maintenance therapy following successful chemotherapy and prior to disease progression could improve OS in this patient population.

The double-blind, randomized, phase III CheckMate-451 trial (NCT02538666) enrolled 834 patients with extensive-stage SCLC who achieved stable disease after 4 cycles of chemotherapy. The patients were randomly assigned 1:1:1 to receive nivolumab plus ipilimumab, nivolumab alone, or placebo for up to 2 years or until disease progression. In the combination arm, 279 patients received a maximum of 4 cycles of nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg every 3 weeks. Nivolumab monotherapy was administered at 240 mg every 2 weeks to 280 patients, and placebo was delivered to 275 patients.

Patient baseline characteristics were well balanced across treatment arms; 23%, 22%, and 22% of patients in the combination, nivolumab, and placebo arms had received prior postchemotherapy immunotherapy, and 63%, 66%, and 58% of patients in the respective arms had received first-line carboplatin-based chemotherapy. The best response to chemotherapy was complete response in 3%, 2%, and 2%, and partial response in 72%, 69%, and 70% of patients in the combination, nivolumab, and placebo arms, respectively. In the respective groups, 25%, 29%, and 28% of patients showed stable disease following chemotherapy.

The primary endpoint, significantly improved OS with maintenance therapy versus placebo, was not met.

Subgroup analysis of OS revealed similar consistent results across subgroups defined by age, ECOG performance status, baseline LDH levels, the presence of liver metastasis at baseline, and the best response to prior chemotherapy. Only the subgroup of patients aged <65 years demonstrated OS that favored the combination over placebo (median OS, 10.2 versus 8.9 months, respectively; HR, 0.72).

Owonikoko called the overall results a “big disappointment; however, there was an indication that, compared to placebo, it took longer for the cancer to progress in patients who received either combination immunotherapy or nivolumab alone.”

In responding patients, the duration of response during maintenance therapy was 10 months with the combination, 11 months for nivolumab, and 8 months for placebo.

The invited discussant at the session, Luiz Paz-Ares, MD, PhD, chair of the Medical Oncology Department at the Hospital 12 de Octubre, and Head of the Lung Cancer Unit at the CNIO (National Oncology Research Center) in Madrid, Spain, pointed out that the OS Kaplan-Meier curves began to show separation at around 1 year, suggesting a possible long-term effect of delaying progression with immunotherapy maintenance.

The rates of adverse events (AEs) were high with immunotherapy; AEs occurred in 86% of patients receiving the nivolumab/ipilimumab combination compared to 61% of patients treated with nivolumab alone, and 50% of patients on placebo. Twenty-nine percent of patients receiving the combination discontinued the study due to a treatment-related AE, compared with 8% of patients in the nivolumab arm and <1% of patients on placebo. Seven (2.5%) treatment-related deaths occurred with nivolumab plus ipilimumab, and 1 patient each died in the nivolumab and placebo groups.

Owonikoko noted that, “Patients who began maintenance therapy sooner after completion of chemotherapy did appear to derive greater benefit.”

Patients beginning maintenance therapy ≤5 weeks postchemotherapy showed a median OS of 9.1 months (95% CI, 7.3-12.1) with combination therapy, 12.1 months (95% CI, 9.6-12.1) with nivolumab, and 8.9 months (95% CI, 7.3-11.0) with placebo (HR, 0.83; 95% CI, 0.65-1.18, for combination versus placebo. HR, 0.66; 95% CI, 0.49-0.91, for nivolumab versus placebo).

“These data suggest there is some activity with immunotherapy in the maintenance phase,” Owonikoko said.

Owonikoko T, Kim H, Govindan R, et al. Nivolumab (nivo) plus ipilimumab (ipi), nivo, or placebo (pbo) as maintenance therapy in patients (pts) with extensive disease small cell lung cancer (ED-SCLC) after first-line (1L) platinum-based chemotherapy (chemo): Results from the double-blind, randomized phase III CheckMate 451 study. Presented at: 2019 European Lung Cancer Congress; April 11 to 13, 2019; Geneva, Switzerland. Abstract LBA1.

No overall survival advantage was obtained from maintenance therapy comprising nivolumab (Opdivo) alone or in combination with ipilimumab (Yervoy) over placebo in patients with extensive-stage small cell lung cancer.

Nivolumab/Ipilimumab Falls Short as Maintenance Therapy in SCLC

The encouraging activity with osimertinib (Tagrisso) for patients with 

-mutant non—small cell lung cancer (NSCLC) continues to be highlighted in the form of prolonged progression-free survival (PFS); however, next steps are focusing on understanding the primary and acquired resistance mechanisms to the third-generation EGFR inhibitor.

Regarding its benefit, frontline osimertinib continued to show extended PFS in patients with advanced 

-mutant NSCLC, according to final efficacy and safety results from phase I expansion cohorts of the AURA trial that were presented at the 2019 European Lung Cancer Congress (ELCC).

At a median follow-up of 19.1 months, the median PFS in patients who received the third-generation EGFR inhibitor at 80 mg was 22.1 months (95% CI, 12.3-30.2) and was 19.3 months (95% CI, 11.1-26.0) for those who received it at 160 mg, leading to an overall median PFS of 20.5 months (95% CI, 13.7-26.1).

The FDA approved osimertinib as a first-line treatment for patients with NSCLC whose tumors harbor 

 mutations (exon 19 deletions or exon 21 L858R substitution mutations) in April 2018.

However, studies have emerged exploring primary and acquired resistance mechanisms to osimertinib. A Chinese study presented at the meeting evaluated targeted next-generation sequencing of patients with stage IIIb-IV 

-mutant T790M NSCLC to detect molecular marker status.

Findings showed that of the 117 patients who received osimertinib, 82.91% developed acquired resistance, and 7.69% had primary resistance.

 From the baseline samples, it was determined that there were 3 (33.33%) patients with 

 mutation, and 2 (22.22%) patients with unknown status. The data suggest that the mechanisms of this resistance could be highly heterogeneous.

“Acquired resistance to EGFR TKIs, or any other TKI for that matter, is matter of fact: it happens,” said Suresh S. Ramalingam, MD. “What we’re beginning to learn is what the resistance mechanisms to osimertinib are.”

 during the 2019 ELCC, Ramalingam, professor of hematology and medical oncology at the Emory University School of Medicine, described these findings with osimertinib, and discussed the emerging body of data exploring primary and acquired resistance mechanisms to the third-generation agent.

: Could you discuss the data we have with frontline osimertinib in EGFR-mutant NSCLC?

: The FLAURA study demonstrated that osimertinib was superior in terms of PFS compared with either erlotinib (Tarceva) or gefitinib (Iressa). This has resulted in FDA approval of osimertinib in the United States and many other countries in the world. The study itself was a randomized, phase III trial in 556 patients who were randomized 1:1. Osimertinib was given at 80 mg per day in the experimental arm, and patients received standard doses of either erlotinib or gefitinib.

The primary endpoint was PFS, and we had independent assessment of radiographic images. Patients in the control group could cross over if they had progression and developed a T790M mechanism of resistance, and then receive osimertinib.

It was a very well-designed, phase III clinical trial that we reported, and it showed that the median PFS with osimertinib was 18.9 months, and the median PFS in the control group was 10.2 months. This represented a 54% reduction in the risk of disease progression or death for patients treated with osimertinib.

We also saw a very favorable toxicity profile for osimertinib. Since it’s a mutation-specific inhibitor, it has less of an effect on the wild-type receptor. Finally, the overall survival (OS) data suggested that there was a favorable outcome, though, from a statistical standpoint, the results are still very immature. We found a positive hazard ratio of 0.63, which did not quite meet the statistical significance at that level of low maturity, but it was still very promising regardless. Therefore, from all standpoints, we found that osimertinib came out ahead.

One problem that we see in lung cancer—specifically in 

-mutated patients—is brain metastases. Therefore, any agent we choose, we want to be effective against brain metastases. We saw that in the FLAURA study with osimertinib; we saw intracranial responses. For about 20% of the patients who came into the study with brain metastases, their PFS hazard ratio was similar to the overall patient population. We also saw less disease progression in the brain for patients with osimertinib. Therefore, another key piece of information that came out from the FLAURA study is that osimertinib has activity in the brain.

Another study being presented at the 2019 ELCC focuses on real-world data on long-term survival in patients with stage IV NSCLC who harbor T790M and were treated with osimertinib. Why is this study notable?

What we’re now beginning to see, now that osimertinib has been around for almost 4 years in clinical practice, is more outcome data from a real-world setting. In the second-line setting, that was the first indication for osimertinib in clinical practice for patients with T790M acquired resistance to a first- or second-generation TKI. This is the setting where the AURA3 trial had demonstrated superiority for osimertinib over platinum-based chemotherapy.

It’s encouraging to see these long-term survival data come up. We will soon hear the survival data from the AURA3 trial sometime maybe this year or early next year, and what this all tells us is that patients with 

-mutated NSCLC are living longer because of better treatment options.

Another study being presented addresses potential resistance mechanisms in patients with EGFR-mutant NSCLC who develop T790M. What is important to note about this trial?

We have to think about it in two different ways. What are the resistance mechanisms when osimertinib is used in the frontline setting for 

-mutated disease? What are the resistance mechanisms when it’s used in the second-line setting after someone has T790M?

In the frontline setting, when we looked at the plasma samples from patients on the FLAURA study, there was not a single case of T790-mediated acquired resistance, which, mechanistically, speaks to how effective osimertinib is at blocking both the EGFR exon 19 and 21 mutations, and also T790M.

 mutations, in the form of C797S, and we saw 

 pathway amplification; approximately 20% to 25% of the patients have 1 of these mechanisms of resistance. We’re still too early in the era of frontline osimertinib to know the full spectrum of resistance mechanisms.

When you think about second-line osimertinib use, we see a slightly higher prevalence of the C797S mutation. We continue to see 

 amplification, which is an important resistance mechanism in that situation. What does all this mean? Well, we have to now develop combination approaches based on the mechanisms of acquired resistance, so we can either overcome it or prevent it.

We already saw some exciting data at the 2019 AACR Annual Meeting just 2 weeks ago: combination therapy with osimertinib and savolitinib with acquired resistance seem to have a promising response rate of about 35%. When a MET inhibitor was used with osimertinib for patients with 

 amplification, the response rates and duration of response were quite promising. We’re already beginning to see movement in that direction.

What do we know about frontline osimertinib treatment and mechanisms of acquired resistance?

When osimertinib is used in the frontline setting, we see a response rate of about 80%, and the median PFS is 19 months. The key question now is, “Does it result in an improvement in OS?” For that, we are waiting for the full maturation of the FLAURA study data, which we’ll have either later this year or in early 2020.

Also, when somebody develops acquired resistance, how do we overcome that? Now we go to chemotherapy after patients progress on osimertinib, but we’re already learning about 

 pathway amplification, mutations of the renin—angiotensin system, mitogen-activated protein kinase pathway, and secondary 

 mutations. All of these can have potential targeted approaches to overcome that resistance.

We’re also learning to use liquid biopsies to understand resistance mechanisms, and perhaps there’s a possibility down the road to prognosticate patients early on during the course of treatment and be in a position to adapt therapies even before they acquire resistance mechanisms. That is another key area of interest.

The good news is osimertinib is a very well-tolerated drug compared with the previous generations of EGFR inhibitors. That allows us to develop combinations based on osimertinib and have them come at a safe tolerability profile for patients, and that provides new opportunities to understand and develop strategies against resistance mechanisms.

What is next in the clinical management of patients who progress on first-line osimertinib?

The key question is, “Can we go from osimertinib to another TKI based on resistance mechanisms rather than going to chemotherapy?” Early evidence of that came from the TATTON trial that was reported, which recently showed that combining a MET or a MEK inhibitor could be a potential way to delay acquired resistance, or use it to treat acquired resistance mediated by those pathways. That’s clearly the next level of investigation about what is the best way to salvage patients who develop resistance to osimertinib.

I look at it even at a broader setting. Can osimertinib be used in earlier stages of lung cancer to cure patients? A phase III study in patients with locally advanced, surgically unresectable disease has just been launched a few months ago, the LAURA trial, where patients get chemoradiation and are then randomized to osimertinib or no TKI.

The other key study in this space is in the adjuvant therapy setting for patients who’ve had surgical resection. This study, called ADAURA, has already completed accrual, where patients either received osimertinib or not after surgery and adjuvant chemotherapy.

In the United States, we’re pursuing the ALCHEMIST study, which is also asking a similar question of EGFR inhibition versus no EGFR inhibition in patients undergoing surgery. The goal there is now to leverage the exciting results from metastatic disease to improve cure rates for patients with earlier stages of lung cancer.

Yang J, Ramalingam S, Lee C, et al. Osimertinib as first-line (1L) treatment for epidermal growth factor receptor (EGFR) mutation-positive advanced non-small cell lung cancer (NSCLC): Final efficacy and safety results from two phase I expansion cohorts. Presented at: 2019 European Lung Cancer Congress; April 11-13, 2019; Geneva, Switzerland. Abstract 122P.

Xu C, Wang W, Zhu Y, et al. Potential resistance mechanisms using next generation sequencing from Chinese EGFR T790M+ non-small cell lung cancer patients with primary resistance to osimertinib: A multicenter study. Presented at: 2019 European Lung Cancer Congress; April 11-13, 2019; Geneva, Switzerland. Abstract 114O.

Suresh S. Ramalingam, MD, describes findings with osimertinib, and discusses the emerging body of data exploring primary and acquired resistance mechanisms to the third-generation agent.

Ramalingam Discusses Osimertinib Efficacy and the Journey to Overcome Acquired Resistance

Final results from 2 phase I expansion cohorts of frontline osimertinib (Tagrisso) presented at the 2019 European Lung Cancer Congress confirmed the efficacy of the third-generation TKI in patients with 

-positive non&shy;—small cell lung cancer (NSCLC).

The expansion cohort data from the phase I AURA trial showed that at a median follow-up of 19.1&thinsp;months, the objective response rate (ORR) was 67% (95% CI, 47-83) in patients receiving osimertinib at an 80&thinsp;mg dose, and the ORR was 87% (95% CI, 69-96) in patients receiving an elevated dose of 160&thinsp;mg of osimertinib. The ORR was 77% (95% CI, 64- 87) in the overall patient cohort with both doses.

The median best percentage change overall in target lesion size was -48% (range, -100% to +32%); the median change in the low-dose cohort was -46% (range, -81% to +32%), and the median change was -59% (range, -100% to -16%) in the higher dose cohort.

“Osimertinib is a third-generation, CNS-active EGFR-tyrosine kinase inhibitor that potently and selectively inhibits both 

T790M resistance mutations,” explained lead author James Chih-Hsin Yang MD, director and professor of the Graduate Institute of Oncology at the National Taiwan University in Taipei city, Taiwan.

“Final efficacy and safety data from the first-line cohorts of the AURA study support the use of osimertinib for patients with

 mutation—positive NSCLC,” added Yang.

The FDA approved frontline osimertinib in April 2018 for the treatment of patients with NSCLC whose tumors harbor 

 mutations (exon 19 deletions or exon 21 L858R substitution mutations). The approval was primarily based on the phase III FLAURA study, in which frontline osimertinib  reduced the risk of progression or death by 54% versus standard therapy with either erlotinib (Tarceva) or gefitinib (Iressa).

The median progression-free survival (PFS) was 18.9 months with osimertinib compared with 10.2 months for standard treatment (HR, 0.46; 95% CI, 0.37-0.57; 

The expansion cohorts in the AURA study enrolled 60 treatment-naïve patients with locally advanced/metastatic 

 mutation-positive NSCLC. Key eligibility criteria included measurable disease and WHO performance status 0/1. Patients with stable asymptomatic CNS metastases were eligible. The primary endpoint was ORR, with secondary endpoints including PFS and safety.

Thirty patients were treated with osimertinib at a dose of 80&thinsp;mg once daily and 30 patients received osimertinib at 160&thinsp;mg once daily. Seventy-five percent of patients were female, and 72% were Asian. At study entry, 

 ex19del mutation was detected in 43% of patients, with 48% of patients having 

T790M mutation—positive by central test.

At the data cutoff of May 1, 2018, 11 patients remained on osimertinib; of these 13% and 23% of patients were in the 80 mg and 160 mg cohorts, respectively. The median duration of response (DOR) was 19.3&thinsp;months (95% CI, 12.2-24.7) in the lower dose cohort, compared to 16.7&thinsp;months (95% CI, 9.7-29.0) in the higher dose cohort and 18.0 months (95% CI, 12.5-24.7) in the overall cohort. Forty-eight patients overall experienced disease progression or died at this time point.

The estimated proportion of overall patients remaining in response at 36 months was 25% (95% CI, 14-38) and 18% (95% CI, 7-32) at 48 months.

At 78% data maturity, the median PFS in the 80 mg, 160 mg, and overall cohorts was 22.1&thinsp;months (95% CI, 12.3-30.2), 19.3 months (95% CI, 11.1-26.0), and 20.5&thinsp;months (95% CI, 13.7-26.1). respectively.

Dose reductions were mostly due to adverse events (AEs) and were required in 27% and 60% of patients receiving osimertinib at 80&thinsp;mg and 160&thinsp;mg, respectively.

Any grade AEs occurred in all patients in the overall population. Serious AEs occurred in 45% of patients and grade ≥3 AEs were reported in 68% of patients overall.

Diarrhea (3%) was the most commonly reported grade ≥3 AE among patients receiving osimertinib at 80&thinsp;mg. In the 160-mg cohort, the most common grade ≥3 AEs included diarrhea in 7% of patients, stomatitis in 3%, and paronychia in 10%.

AEs led to treatment discontinuation in 13%, 10%, and 12% of patients in the 80-mg cohort , 160-mg cohort, and overall, respectively. One patient in the osimertinib 160-mg group died due to an AE.

“Our findings are consistent with previous reports that demonstrate first-line osimertinib efficacy in patients with 

 mutation—positive advanced NSCLC. PFS was prolonged at both doses; however, better tolerability was observed at the 80-mg dose,” Yang summarized.

Yang J, Ramalingam S, Lee C, et al. Osimertinib as first-line (1L) treatment for epidermal growth factor receptor (EGFR) mutation-positive advanced non-small cell lung cancer (NSCLC): Final efficacy and safety results from two phase I expansion cohorts. Presented at: 2019 European Lung Cancer Congress; April 11 to 13, 2019; Geneva, Switzerland. Abstract 122P.

Ramalingam S, Reungwetwattana T, Chewaskulyong B, et al. Osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFRm advanced NSCLC: FLAURA. Presented at: 2017 ESMO Congress; Madrid, Spain; September 9-12, 2017. Abstract LBA2_PR.

Final results from 2 phase I expansion cohorts of frontline osimertinib (Tagrisso) presented at the 2019 European Lung Cancer Congress confirmed the efficacy of the third-generation TKI in patients with EGFR-positive non&shy;–small cell lung cancer.

Update Further Supports Osimertinib in Frontline EGFR+ NSCLC

Martin Reck, MD, PhD, head of the department of thoracic oncology at Lung Clinic Grosshansdorf, discusses the rationale for the IMpower150 study, which assessed the combination of atezolizumab (Tecentriq), bevacizumab (Avastin), and chemotherapy in the first-line treatment of patients with nonsquamous non—small-cell lung cancer (NSCLC).

This trial was unique, explains Reck, in that it investigated a unique combination comprised of a checkpoint inhibitor, chemotherapy, and an antiangiogenic compound on the basis of the idea that the antiangiogenic compound combined with a checkpoint inhibitor could enhance the efficacy of immunotherapy.

Patients were randomized to receive either the standard of care or the combination therapy. In patients who received the combination, a significant and relevant improvement in progression-free survival and overall survival was been observed in the intent-to-treat population, says Reck. The trial was also notable for its inclusion of patients with pretreated 

Martin Reck, MD, PhD, head of the department of thoracic oncology at Lung Clinic Grosshansdorf, discusses the rationale for the IMpower150 study.

Dr. Reck on the Rationale of the Impower150 Study

Luis G. Paz-Ares, MD, PhD, chief physician at the Hospital Universitario Doce De Octubre, discusses results from an integrated analysis of patients with 

 fusion—positive non–small cell lung cancer (NSCLC) enrolled in the STARTRK-2 (NCT02568267), STARTRK-1 (NCT02097810), and ALKA-372-001 (EudraCT 2012-000148-88) trials, which evaluated the safety and efficacy of entrectinib in patients with solid tumors.

The trials enrolled a total of 54 patients with 

 fusions in solid tumors across a variety of histologies, but the analysis conducted by Paz-Ares and his colleagues focused on the 10 patients with NSCLC. Results from the analysis were presented at the 2019 European Lung Cancer Congress.

In these patients, the response rate with entrectinib was 70%. In the 6 patients with NSCLC who also had brain metastases, 4 experienced an intracranial response. The safety profile for entrectinib in this patient population was also similar to that of the overall population.

These findings, says Paz-Ares, led the investigators to conclude that not only is entrectinib active in a variety of tumor types, it is particularly effective in 

 fusion—positive NSCLC and in patients who also have central nervous system disease.

Luis G. Paz-Ares, MD, PhD, chief physician at the Hospital Universitario Doce De Octubre, discusses an integrated analysis of patients with NTRK fusion–positive non–small-cell lung cancer enrolled in the STARTRK-2, STARTRK-1, and ALKA-372-001 trials, which evaluated the safety and efficacy of entrectinib in patients with solid tumors.
 

Dr. Paz-Ares on Entrectinib in NTRK Fusion-Positive NSCLC

-positive non—small cell lung cancer (NSCLC) showed high response rates and durable responses following treatment with entrectinib, according to findings from a pooled analysis of 3 studies presented at the 2019 European Lung Cancer Congress.

Entrectinib demonstrated systemic efficacy with 77.4% of patients in the overall population showing a response. Strong intracranial activity was also demonstrated in a cohort of patients with CNS disease at baseline who showed an overall response rate (ORR) of 73.9%.

“There are high unmet needs in patients with 

 fusion—positive NSCLC. Brain metastases are common in this population and the CNS is a common site of first progression, therefore use of a CNS-penetrant ROS-1 inhibitor in the first-line setting would be beneficial to these patients,” said Fabrice Barlesi MD, PhD, Marseille University, Assistance Publique-Hopital du Marseille in Marseille, France.

Entrectinib is a potent ROS1 inhibitor that also inhibits TRKA/B/C. Entrectinib was designed to cross the blood-brain barrier and effectively penetrate the CNS to achieve therapeutic levels in the CNS, Barlesi explained.

“In preclinical studies, entrectinib provided more potent ROS1 inhibition than crizotinib, “ he noted.

Barlesi presented results from an integrated efficacy analysis from two phase I entrectinib studies—ALKA-372-001 (EudraCT 2012-000148-88] and STARTRK-1 (NCT02097810)&mdash;and the phase II STARTRK-2 (NCT02568267) trial. Based on data from this analysis, the FDA is currently reviewing a new drug application (NDA) for entrectinib as a treatment for patients with metastatic 

-positive NSCLC, as well as patients with 

 fusion—positive locally advanced or metastatic solid tumors. The action date for a decision on the NDA is August 18, 2019.

The 3 trials enrolled patients with NSCLC who had not received prior treatment with a ROS1 inhibitor but harbored a 

 fusion, as determined by nucleic acid—based diagnostic platforms. Tumor assessments were done at week 4 and every 8 weeks thereafter by blinded independent central review (BICR; by RECIST v1.1).

The efficacy population comprised 53 patients with a median age of 53 years (range, 27-73). Sixty-four percent of patients were female, 50.9% were ECOG performance status 1, and 58.5% were never-smokers. At baseline, 43.4% of patients had CNS disease.

The safety-evaluable population included 134 patients who received ≥1 dose of entrectinib and had at least 6 months of follow-up. Patient characteristics were similar in this cohort, with the exception that more (50.0%) patients had CNS disease at baseline.

The primary endpoints of all the studies were ORR and duration of response (DOR). Key secondary endpoints included progression-free survival (PFS) and safety. Additional endpoints were intracranial ORR, DOR in patients with intracranial response, and PFS in patients with or without baseline CNS disease.

Patients with ROS1-positive non–small cell lung cancer showed high response rates and durable responses following treatment with entrectinib.

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