Darcy Lewis

FDA approvals of novel agents for molecularly defined subtypes of non–small cell lung cancer (NSCLC) are poised to change both patient outcomes as well as pretreatment testing requirements for those harboring these tumors.

In 2020, the agency approved biomarker-specific therapies for patients whose NSCLC tests positive for 

 exon 14 mutations, marking a big breakthrough for patients with these aberrations. Although the proportion of patients with these genetic alterations is low—estimated at 1% for 

 exon 14 alterations—these groups are primed to experience significantly improved outcomes. In addition, data reported in 2020 about novel, investigational, target-specific therapies in NSCLC indicate that this list will continue to grow in the near future.

“The year 2020 has been phenomenal for us in NSCLC,” Vivek Subbiah, MD, an associate professor in the Investigational Cancer Therapeutics Department, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston, told 

 in an interview. “In May, we had a new FDA approval every week. I think 2021 and 2022 will also be good in this space.”

 gene have been difficult to target for investigators, according to Edward B. Garon, MD, MS, a health sciences associate clinical professor of medicine at David Geffen School of Medicine at UCLA in Los Angeles, California. “Until now, our main agents for these patients have been multitargeted tyrosine kinase inhibitors [TKIs], with limited effectiveness and high toxicities. There wasn’t much enthusiasm [among investigators] until recently in terms of available therapy for this patient population. But now we do have good treatment options for this population.”

Selpercatinib In May, the RET inhibitor selpercatinib (Retevmo) became the first biomarker-specific therapy to earn FDA approval for 

 fusion–positive NSCLC. The approval was based on the results of the open-label phase 1/2 LIBRETTO-001 trial (NCT03157128), which were published in the 

 in August with Subbiah as senior author.

The trial explored selpercatinib in both pretreated and treatment-naive patients with advanced 

 fusion–positive NSCLC across 65 centers in 12 countries. The primary end point was the objective response rate (ORR) as determined by an independent review committee. Secondary end points included the duration of response (DOR).

Initial enrollment consisted of 105 patients with pretreated 

 fusion–positive advanced NSCLC who received treatment across both the phase 1 dose-escalation portion of the trial (n = 49) and the phase 1 dose-expansion or phase 2 portion of the trial (n = 56). Additionally, the investigators later enrolled 39 previously untreated patients with the same malignancy type.

 fusion–positive NSCLC, nearly two-thirds (64%) responded to treatment per blinded independent central review. Two patients achieved a complete response (CR), 62% had a partial response (PR), and an additional 29% had stable disease (SD). At a median follow-up of 12.1 months, 63% of the responses were ongoing. The median DOR was 17.5 months (95% CI, 12.0-not evaluable [NE]).

Among the 39 previously untreated patients, 85% responded to treatment (95% CI, 70%-94%), and 90% of these responses continued at 6 months. Responses in this cohort comprised PRs exclusively, and 10% of patients had SD. The median duration of response was not yet reached (95% CI, 12.0 months-NE).

Eleven patients had baseline central nervous system metastases at enrollment, and nearly all of them experienced an intracranial ORR (91%; 95% CI, 59%-100%). This included 3 patients with CRs (27%), as well as 7 patients with PRs (64%). The remaining patient had SD. The median CNS DOR was 10.1 months (95% CI, 6.7-NE).

“Selpercatinib had durable efficacy, including intracranial activity, with mainly low-grade toxic effects in patients with 

 fusion–positive NSCLC,” Subbiah said. “Our data clearly show that patients benefitted from this treatment.”

 fusion–positive NSCLC may also be treated with the selective RET kinase inhibitor pralsetinib (Gavreto), which gained accelerated approval from the FDA in September for the treatment of patients with 

 fusion–positive NSCLC based on the global registrational phase 1/2 ARROW trial (NCT03037385), which is ongoing.

The trial is examining pralsetinib in patients with advanced solid tumors and 

 fusion–positive NSCLC. Of 179 patients with 

 fusion– positive NSCLC, 116 were evaluable at the data cutoff in November 2019, and results from this group of patients were presented at the American Society of Clinical Oncology 2020 Virtual Scientific Program (ASCO 2020).

According to blinded independent central review, response-evaluable patients had an ORR of 65% (95% CI, 55%-73%). Six percent of evaluable patients achieved a CR and 59% experienced a PR. Among treatment-naïve patients (n = 26), the ORR was 73% (95% CI, 52%-88%), with a 12% CR and a 62% PR rate. Among 80 patients who had been pretreated for NSCLC, the ORR was 61% (95% CI, 50%-72%), with 5% CRs and 56% PRs.

The investigators found that 96% of evaluable patients had tumor reductions, including 100% of patients who were treatment naïve.

The median duration of response was not reached (NR; 95% CI, 11.3 months-NR). Of the pretreated patients, 80% of responding patients had responses lasting at least 6 months. Among treatment-naïve patients, 58% of responding patients had responses lasting 6 months or longer. At the time of presentation, 75% of responding patients were still on treatment.

Nine patients had measurable central nervous system metastases at baseline. Blinded central reviewers found that the intracranial ORR was 56%. Additionally, 3 of these patients obtained an intracranial CR.

“Patients have had beautiful responses to pralsetinib characterized by the resolution of all lesions, regardless of the presence of brain metastases, which is extremely uncommon in NSCLC,” Subbiah said. “These patients had no good treatment options before this approval.”

In May, the FDA approved capmatinib (Tabrecta), a selective inhibitor of the MET receptor, for use in patients with NSCLC tumors harboring 

 amplifications. Approval was based on the multicohort phase 2 Geometry Mono-1 trial (NCT02414139), the results of which were published in the 

The trial evaluated capmatinib in 364 patients with 

-dysregulated advanced NSCLC. Investigators assigned patients to cohorts based on their previous lines of therapy and 

 status. ORR was the primary end point and DOR was a key secondary outcome measure, both assessed by blinded central review.

 exon 14 skipping mutations, reviewers identified a response in 41% of pretreated patients (n = 69; 95% CI, 29%- 53%). Among those who were treatment naive (n = 28), 68% (95% CI, 48%-84%) responded to treatment. The median DOR was 9.7 months (95% CI, 5.6-13.0) among pretreated patients and 12.6 months (95% CI, 5.6-NE) among treatment-naive patients.

The investigators observed limited efficacy among previously treated patients with 

 amplification who had a gene copy number less than 10 (overall response in 7% to 12% of patients). Among pretreated patients with 

 amplification and a gene copy number of 10 or higher, nearly one-third of patients responded to treatment (29%; 95% CI, 19%-41%). Among patients without prior treatment, 40% experienced a response (95% CI, 16%-68%).

Garon, who was one of the investigators on the Geometry Mono-1 trial, appreciated the opportunity to study the role of MET as an oncogenic driver. “The fact that this trial evaluated both amplification as well as the exon 14 skipping mutation gave us a broader understanding of the role of MET as a biomarker in lung cancer,” he said. “One question that remains is whether this is an agent to use in the frontline setting. I would argue the data are not entirely clear, partly because we don’t know how well this patient population does with standard therapies.”

Meanwhile, work continues to explore the potential applicability of targeted therapies for oncogenes that do not currently have available options for biomarker-specific application. Promising trials abound, but no FDA approvals have yet materialized for either HER2- or 

Trastuzumab deruxtecan (T-DXd; Enhertu) is a novel antibody-drug conjugate that consists of 3 components: a humanized, anti-HER2, IgG1 monoclonal antibody and a topoisomerase I inhibitor payload that are connected by a tetrapeptide-based cleavable linker. Results of the open-label, multicohort phase 2 DESTINYLung01 trial (NCT03505710) exploring the agent in patients with HER-positive tumors were presented at ASCO 2020.

Patients enrolled in the trial must have received no prior HER2-targeted therapies, with the exception of pan-HER TKIs. ORR confirmed by an independent central committee was the primary end point. One cohort consisted of patients who had HER2-expressing tumors; the other included patients whose tumors harbored a HER2 mutation

At data cutoff in November 2019, the ORR in 26 patients confirmed by independent review was 61.9% (95% CI, 45.6%-76.4%). One patient had a CR (2.4%), 25 had a PR (59%), and an additional 12 patients had SD (28.6%). With only 2 patients either having progressive disease or being NE, the disease control rate was 90% (95% CI, 77.4%- 97.3%). The median DOR was not reached. The median follow-up was 8.0 months (range, 1.4-14.2 months) and the median duration of exposure to the drug was 7.8 months.

Investigators have expanded enrollment by 50 patients in the HER2-mutated cohort to better characterize the risk-benefit ratio of T-DXd. The FDA awarded T-DXd a breakthrough therapy designation in May for metastatic HER2-mutated NSCLC based on these data.

Garon noted that HER2 has been a difficult therapeutic target to date in NSCLC. “Unlike in breast cancer, [in which] HER2 tends to be amplified, in lung cancer there tends to be specific mutations. They tend to be in exon 20, which is somewhat structurally analogous to exon 20 mutations in 

, which have traditionally been a difficult target for drugs,” he said. “But the DESTINY-Lung01 data to date have been quite as promising in a population that is somewhat difficult to treat.”

 mutations are believed to account for about 13% of NSCLC cases. Sotorasib, a small molecule that selectively and irreversibly targets 

 G12C, is considered a promising therapy. A variety of clinical trials are currently underway under the CodeBreak clinical trial umbrella.

In the phase 1 CodeBreak 100 trial (NCT03600883), results of which appeared in the New England Journal of Medicine, investigators enrolled 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) in dose-escalation/-expansion cohorts.

The investigators observed no dose-limiting toxic effects or treatment-related deaths. In the subgroup with NSCLC, nearly one-third of patients (32.2%) had a confirmed objective response, whereas 88.1% of patients (n = 52) had disease control. The median progression-free survival was 6.3 months (range, 0.0-14.9).

More recently, Amgen has announced positive topline phase 2 results for sotorasib in a press release. Calling the trial “potentially registrational,” the company said that detailed results will be released at the International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer in January 2021.

Meanwhile, CodeBreak 200 (NCT04303780), a global, phase 3, randomized, active-controlled confirmatory study comparing sotorasib to docetaxel in 

 G12C–mutant NSCLC, has begun recruiting. Investigators shared complete study details in a poster at the European Society for Medical Oncology Virtual Congress 2020.

“The fact that KRAS is now druggable has opened up our field,” Subbiah said. “With the phase 3 trial enrolling more than 500 patients in its first 6 months, I won’t be surprised if there’s a 2021 approval in store for us.”

1. FDA approves selpercatinib for lung and thyroid cancers with RET gene mutations or fusions. FDA. Updated May 11, 2020. Accessed November 14, 2020. https://bit.ly/2K7qf8n

2. Drilon A, Oxnard GR, Tan DSW, et al. Efficacy of selpercatinib in 

 fusion–positive non–small-cell lung cancer. 

. 2020;383(9):813-24. doi:10.1056/NEJMoa2005653

3. FDA approves pralsetinib for lung cancer with RET gene fusions. FDA. Updated September 8, 2020. Accessed November 14, 2020. https://bit.ly/3kFME9w

4. Gainor JF, Curigliano G, Kim DW, et al. Registrational dataset from the phase I/II ARROW trial of pralsetinib (BLU-667) in patients (pts) with advanced 

 fusion+ non-small cell lung cancer (NSCLC). 

. 2020;38(suppl 15):9515. doi:10.1200/JCO.2020.38.15_suppl.9515

5. FDA grants accelerated approval to capmatinib for metastatic non-small cell lung cancer. FDA. May 6, 2020. Accessed November 14, 2020. https://bit.ly/2Uy6hpm

6. Wolf J, Seto T, Han JY, et al; GEOMETRY mono-1 Investigators. Capmatinib in 

-amplified non–small-cell lung cancer. 

. 2020;383(10):944-957. doi:10.1056/NEJMoa2002787

7. Smit EF, Nakagawa K, Nagasaka M, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-mutated metastatic non-small cell lung cancer (NSCLC): interim results of DESTINY-Lung01. 

. 2020;38(suppl 15):9504. doi:10.1200/JCO.2020.38.15_suppl.9504

8. Enhertu granted breakthrough therapy designation in the US for HER2-mutant metastatic non-small cell lung cancer. News release. AstraZeneca. May 18, 2020. Accessed November 16, 2020. https://bit.ly/3kMoDhe

9. Hong DS, Fakih MG, Strickler JH, et al. KRASG12C inhibition with sotorasib in advanced solid tumors. 

. 2020;383(13):1207-1217. doi:10.1056/NEJMoa1917239

10. Amgen announces positive topline phase 2 results for investigational KRAS G12C inhibitor sotorasib in advanced non-small cell lung cancer. News release. Amgen. October 5, 2020. Accessed November 16, 2020. https://bit.ly/3f9rkbt

11. Reck M, Spira A, Besse B, et al. CodeBreak 200: a phase III, multicenter study of sotorasib (AMG 510), a KRAS(G12C) inhibitor, versus docetaxel in patients with previously treated advanced non-small cell lung cancer (NSCLC) harboring KRAS p.G12C mutation. 

. 2020;31(suppl 4):S894-S895. doi:10.1016j.annonc.2020.08.1730

Articles

FDA approvals of novel agents for molecularly defined subtypes of non–small cell lung cancer are poised to change both patient outcomes as well as pretreatment testing requirements for those harboring these tumors.

RET, MET Inhibitors Advance Targeted Therapies in NSCLC

When patients with myelofibrosis (MF) who required hematopoietic stem cell transplant (HSCT) received a conditioning regimen of thiotepa, busulfan, and fludarabine (TBF) along with 2 two alkylating agents, the subsequent transplants were nearly all successful. These findings are from a single-center, retrospective analysis published recently in 

Twenty-nine consecutive patients with MF were enrolled at a single institution. The results show that of the patients enrolled, all but 2 patients successfully engrafted following the TBF conditioning regimen and no patients relapsed.

About half the patients (n = 15, 52%) were classified as high risk. Peripheral blood stem cells were the graft source in 27 patients. Donor types were as follows: HLA-matched related (n = 5), matched unrelated (n = 16), mismatched unrelated (n = 1), and haploidentical (n = 7).

About one-fifth of patients (21%) experienced grade II–IV acute graft-versus-host disease (GVHD; 95% Confidence Interval [CI], 10–42) by day 100. At 3 years, the cumulative incidence of chronic GVHD was 39% (95% CI, 23–65). Median follow-up was 39 months (range 14–60). At 3 years, overall survival (OS) was 69% (95% CI, 50–83).

“Our findings show that TBF is a valid and safe conditioning regimen providing good disease control and a promising OS,” wrote the authors, led by Mara Memoli, MD, of Saint Antoine Hospital, Paris, France, where the study took place. “Overall, our results indicate that the combination of two alkylating agents and the use of thiotepa in the conditioning regimen provide [a] high chance of achieving full donor chimerism engraftment, good disease control and promising OS in MF patients undergoing HSCT.

The TBF conditioning regimen varied slightly as the hospital’s policy evolved. The first 3 patients received a total dose of 10 mg/kg of thiotepa (5 mg/kg on days -7 and -6). This dose was reduced to 5 mg/kg (at day -6) in all remaining patients per revised hospital policy. All patients received a total dose of 150 mg/m2 of fludarabine (30 mg/m2 from day -5 to day -1). The total dose of intravenous busulfan was 6.4 mg/kg (on days -4 and -3) or 9.6 mg/kg (3.2 mg/kg/day on days -4, -3, and -2) based on the patient’s age, comorbidities and performance status. All patients received cyclosporine A and mycophenolate as GVHD prophylaxis.

OS was the study’s primary endpoint. Secondary endpoints included the cumulative incidences of acute and chronic GVHD neutrophil and platelet engraftment, non-relapse mortality (NRM), and disease-free survival (DFS).

Patients’ median age was 56 years (range 42–70) and patients were divided nearly equally among those who had primary MF (n = 14, 48%) and secondary MF (n = 15, 52%). Among these, 6 had previously had polycythemia vera and 9 had essential thrombocythemia.

More than half the patients (n = 18, 62%) had a 

 mutation, including 2 with an associated 

 mutation. Six patients (21%) had a single 

 mutation and 4 patients (14%) were triple negative. Eight patients (27%) underwent next-generation sequencing. Among the 3 patients with 

 co-mutation. In the 2 triple negative patients according to standard molecular biology, 1 had 

 mutation, and 1 patient did not present with any mutation.

Nineteen patients had splenomegaly; 16 of them received ruxolitinib (Jakafi). Among these, 11 received treatment for more than three months. Two tolerated ruxolitinib but took it for less than 3 months due to the start of the conditioning regimen. Three patients had to stop treatment for severe thrombocytopenia before day 30. Most patients had evidence of disease progression or symptom persistence before HSCT but patients were not required to have a clinical response to ruxolitinib to progress to HSCT.

Among the patients who engrafted, the median time to neutrophil recovery was 14 days (range 9–34). The median times to achieve platelet engraftment of at least 20 x 109/L was 17 days (range 1–65) and 19 days (range, 8-185) to reach at least 50 x 109/L. The cumulative incidence of neutrophil engraftment at 30 days was 96% (95% CI, 80–99). The 2 patients who did not engraft died during aplasia, one at day 19 from infection and the other one at day 12 from multi-organ failure.

Among the patients who engrafted, all except two had a full donor chimerism at day 90. Three patients needed and received a successful CD34+-selected stem cell boost from their original donor, according to hospital center policy. Nine patients received the thrombopoietin mimetic agent eltrombopag.

The authors observed a trend toward better OS among patients who underwent transplant before the median time period of 11 months (<11 months 86%; > 11 months 53%; P = 0.05). They also observed lower OS among patients who received ruxolitinib before transplant compared to patients who did not (50% versus 92%, P = 0.02). Among the one-third of patients who died (n = 9), the cause of death was infection in 5 and GVHD and multi-organ failure in 2 each.

Memoli et al noted that the main limitations of their study were the sample size and its retrospective design. “However, this is the largest study on [the] TBF conditioning regimen before allo-HSCT for MF,” they wrote. “Further prospective studies of larger scale are needed to assess the use of [the] TBF conditioning regimen in specific patient settings.”

Memolia M, Paviglianitia A, Malarda F, et al. Thiotepa-busulfan-fludarabine as a conditioning regimen for patients with myelofibrosis undergoing allogeneic hematopoietic transplantation: a single center experience. 

. Published online October 5, 2020. DOI: 10.1080/10428194.2020.1827246. 

When patients with myelofibrosis who required hematopoietic stem cell transplant received a conditioning regimen of thiotepa, busulfan, and fludarabine along with 2 two alkylating agents, the subsequent transplants were nearly all successful.

Conditioning with Thiotepa-busulfan-fludarabine Improves Outcomes for Patients with MF Undergoing ASCT

Dramatic improvements in efficacy outcomes for patients with non–small cell lung cancer (NSCLC) have been a reason for celebration over the last decade, as FDA approvals of immunotherapy-plus-chemotherapy combinations as well as oncogenic-targeting drugs have transformed the treatment landscape.

The FDA frequently issues approvals for drugs and biologics based on surrogate end points such as progression- free survival (PFS) or objective response rate (ORR) instead of overall survival (OS). These end points are employed for the purposes of expediting drug approvals so that patients with metastatic cancer can receive the newest, cutting-edge therapies. But with the FDA requiring confirmatory trials in many cases to validate data leading to regulatory actions, OS remains the ultimate benchmark of efficacy.

Recently, investigators have released 3-, 4-, and 5-year OS data for key pivotal trials in NSCLC, and the news is good. Updates from 6 clinical trials further emphasize how beneficial these therapies, now established as standard-of-care agents, have been for patients with advanced NSCLC.

“We have had a sense in our clinics for a while that patients with targeted therapies are clearly living longer,” Edward B. Garon, MD, MS, said in an interview with 

. “It had been difficult to exactly quantify, but we have now seen in multiple datasets that there are significant improvements in survival in lung cancer, and that at least some of that improvement is based on better treatments for advanced-stage disease.”

A look at these data reveal continuous positive changes in the NSCLC space. 

When investigators published 5-year OS data from the phase 1 KEYNOTE-001 trial (NCT01295827) in June 2019, the results represented the longest follow-up for single-agent pembrolizumab (Keytruda) in advanced or metastatic NSCLC. Total enrollment in KEYNOTE-001 consisted of 550 patients with locally advanced or metastatic NSCLC, including 101 treatment-naive patients and 449 pretreated patients.

At data cutoff in November 2018, median follow-up in this trial was 60.6 months. The median OS was 22.3 months (95% CI, 17.1-32.3) in treatment-naive patients and 10.5 months (95% CI, 8.6-13.2) in those who were previously treated. Corresponding estimated 5-year OS rates were 23.2% and 15.5%. In patients with a PD-L1 tumor proportion score (TPS) of 50% or more the 5-year OS rates were 29.6% and 25.0%, respectively.

“That 5-year OS is unprecedented in any kind of metastatic lung cancer trial,” said Andreas Saltos, MD, of the University of South Florida and Moffitt Cancer Center in Tampa. “These data speak to what we tell patients. We see patients every day now who were diagnosed with stage IV lung cancer years ago and are still doing well.”

The KEYNOTE-001 5-year follow-up study notes that 450 patients (82%) in the original cohort had died as of late 2018. “The fact that any patients who were in the early KEYNOTE and CheckMate trials are going on their seventh or eighth year of survival is very encouraging to see,” Saltos said.

In September, investigators presented 5-year OS data from the KEYNOTE-024 trial (NCT02142738) at the European Society for Medical Oncology (ESMO) Virtual Congress 2020.

The phase 3 trial, which randomized 305 patients to receive either pembrolizumab (n = 154) or physician’s choice standard-ofcare chemotherapy (n = 151), earned pembrolizumab FDA approval as a first-line treatment for patients with PD-L1–positive NSCLC in 2016.

Patients treated on the trial had previously untreated metastatic NSCLC with PD-L1 TPS of 50% or greater and no targetable EGFR or ALK alterations. At data cutoff in June 2020, the median follow-up was 59.9 months. In the pembrolizumab arm, the median OS was 26.3 months versus 13.4 months in the chemotherapy arm (HR, 0.62; 95% CI, 0.48-0.81). The Kaplan-Meier estimate of the 5-year OS rate was 31.9% in the pembrolizumab group and 16.3% in the chemotherapy group.

Trial protocol permitted patients in the chemotherapy arm to cross over to receive pembrolizumab upon disease progression. The authors reported that 83 patients, or slightly more than half the cohort randomized to chemotherapy, later crossed over to pembrolizumab. Patients who completed 2 years of pembrolizumab therapy also were permitted to resume treatment with pembrolizumab if their disease later progressed.

In total, 39 patients completed the planned 2 years of therapy. At data cutoff, 32 of these patients were still alive with progressive disease leading to death in the remaining 7 patients. The ORR was 82.1% in this patient subgroup, which included 4 patients (10.3%) who experienced a complete response and 28 (71.8%) who had a partial response. Six patients (15.4%) experienced stable disease. Investigators determined that 18 of the patients still alive had not experienced progressive disease at the time of data cutoff.

“Of new data that were recently presented, perhaps the most substantial in terms of informing the community were the 5-year survival data from KEYNOTE-024,” Garon said. “In the original KEYNOTE-001 study, the treatment-na.ve population had a 5-year survival [rate] that was approximately 30%. Now, KEYNOTE-024 confirms that about 30% of these patients with high staining for PD-L1 will be alive 5 years after [starting immunotherapy with single-agent pembrolizumab].”

Also presented at ESMO 2020, the phase 2 POPLAR (NCT01903993) and the phase 3 OAK (NCT02008227) trial investigators presented 4-year OS data for both trials, which compared the anti–PD-L1 cancer immunotherapy atezolizumab (Tecentriq) with docetaxel in patients with pretreated NSCLC.4 Both randomized, open-label trials formed the basis for the FDA approval of atezolizumab for the treatment of patients with metastatic NSCLC whose disease progressed during or following platinum-containing chemotherapy.

The 2 studies enrolled a total of 1512 patients with locally advanced or metastatic NSCLC who had experienced disease progression during or after prior platinum-based therapy (POPLAR, n = 287; OAK, n = 1225). Patients were randomized to receive either atezolizumab or docetaxel until disease progression. Median follow-up duration was 48.6 months on the POPLAR trial and 47.7 in OAK.

In POPLAR, the 4-year OS rate was 15% in the atezolizumab group with a median OS of 12.6 months. This was compared against docetaxel, with a corresponding OS rate of 8% and a median OS of 9.7 months (HR, 0.76; 95% CI, 0.58-1.00; 

In OAK, patients in the atezolizumab group experienced a median OS of 13.3 months and a 4-year OS rate of 16%. In the docetaxel group, corresponding data were 9% and 9.8 months (HR, 0.78; 95% CI, 0.68-0.89; 

Saltos noted that the OS results from POPLAR and OAK results are comparable to those observed in the pretreated pembrolizumab arms of KEYNOTE-001. “The higher the PD-L1 level, the higher the chance of a response which is one aspect to consider when comparing these trials to each other to help guide our clinical decision-making process,” he said. “Importantly, while PD-L1 is a good biomarker prognostically, the needle is still moving for patients without PD-L1 expression to have a better chance of long-term survival.”

The double-blinded phase 3 PACIFIC trial (NCT02125461) randomized patients with unresectable, stage III NSCLC to durvalumab (Imfinzi) or placebo following chemoradiotherapy, regardless of their PD-L1 status.6 Patients disease could not have progressed following concurrent platinum-based chemotherapy plus radiation. These data led to FDA approval of durvalumab for this indication in NSCLC.

Of 713 patients, 476 received durvalumab and 237 received placebo. As of the March 2020 data cutoff, the median follow-up was 34.2 months. The key results remained consistent with earlier reports, which showed that both PFS (stratified HR, 0.55; 95% CI, 0.44-0.67) and OS (stratified HR, 0.71; 95% CI, 0.57-0.88) favored the durvalumab arm.

The median OS of the durvalumab arm was announced during ESMO 2020, at 47.5 months compared with 29.1 months for placebo. The 48-month OS rates were 49.6% for durvalumab and 36.3% for placebo. PFS rates at 48 months were 35.3% versus 19.5%, respectively. Updated patient subgroup treatment effects will be reported in the future.

“PACIFIC’s maximum treatment course was 1 year, but these responses have been sustained for at least 3 years now, suggesting that a higher number of these patients may be cured of their disease,” Saltos said. “These data show about half of patients treated with durvalumab survived 4 years, and an estimated 35% had not progressed, a significant advance.”

Earlier this year, investigators published long-term OS data for the FLAURA trial (NCT02296125) in the 

 This phase 3 trial compared firstline osimertinib (Tagrisso) with standard-of-care EGFR tyrosine kinase inhibitors (TKIs) in patients with 

 mutation–positive advanced NSCLC. These data served as the basis of the FDA’s approval of osimertinib for first-line treatment of metastatic NSCLC with most common 

In total, 556 patients with previously untreated advanced NSCLC with an EGFR mutation (exon 19 deletion or L858R allele) were randomized to receive either osimertinib or treatment with a first-generation EGFR TKI, either gefitinib (Iressa) or erlotinib (Tarceva). In the osimertinib group, the median OS was 38.6 months and 31.8 months in the comparator group (HR, 0.80; 95.05% CI, 0.64-1.00; 

The median exposure was 20.7 months in the osimertinib group and 11.5 months in the comparator group. Nearly 30% of osimertinib treated patients (n = 79, 28%) continued to receive therapy at 3 years, while only 26 (9%) in the comparator group did.

The new FLAURA data confirm an impression that Garon has held regarding well-tolerated, effective therapy. “From a progression-free survival perspective, the events were reasonably mature previous to overall survival. Fortunately, those results have lagged because this population has seen substantial outcome improvements,” he said. “The data from FLAURA have clearly changed practice, and we continue to see an improvement in outcomes for patients with these targets.”

Updated OS results for the ALEX trial (NCT02075840), which compared alectinib (Alecensa) with crizotinib (Xalkori) in patients with treatment-na.ve 

-positive NSCLC, appeared in the Annals of Oncology earlier this year.10 ALEX was the first global randomized study to show clinically meaningful improvement in OS for a next-generation ALK TKI versus crizotinib in the treatment of patients with 

-positive NSCLC who had no prior therapies. These data served as the basis of the 2017 FDA approval of alectinib as frontline therapy for 

ALEX randomized 303 patients with stage III or IV ALK-positive NSCLC to receive alectinib (n = 152) or crizotinib (n = 151) until disease progression, toxicity, withdrawal, or death. Investigator-assessed PFS was the trial’s primary end point.

At the time of the 5-year OS data cutoff in November 2019, the median duration of OS follow-up was 48.2 months in the alectinib arm versus 23.3 months in the crizotinib arm. OS data remain immature with 37% of survival events occurring as of data cutoff; the target maturity for survival is 50%, per the trial protocol. The median OS was not reached with alectinib versus 57.4 months with crizotinib (stratified HR, 0.67; 95% CI, 0.46-0.98.

With alectinib, the 5-year OS rate was 62.5% versus 45.5% with crizotinib. Corresponding median treatment duration was 28.1 months and 10.8 months. At data cutoff, 34.9% of patients in  the alectinib group and 8.6% of patients in the crizotinib group were still on study treatment.

Patients who had central nervous system metastases at baseline saw an OS benefit from alectinib (HR, 0.58; 95% CI, 0.35-1.00), which Saltos pronounced a “significant development” in this population. He said “this recent report adds weight to the idea that alectinib up front is superior” to other available agents in this patient population.

Indeed, the study authors noted that the use of next-generation ALK TKIs as salvage therapy is “feasible,” but their impact on OS in this population remains uncertain.

Both Saltos and Garon look ahead to the next round of trial results for these and newer agents with excitement, noting that initial concerns about using genomic data to drive treatment decisions beyond cases of 

“In the past several months, we have seen approvals for gene rearrangements involving the [capmatinib (Tabrecta)] approval for the 

 exon 14 skipping mutation,12 which is a fairly common mutation,” Garon said. “Also on the horizon are multiple agents targeting 

 G12C mutations, which we think are going to turn out to be a group very similar in size to the patients with 

 positivity, particularly in Western populations.”

As intriguing as future therapeutics are in NSCLC, it’s also natural to reflect on how far the profession has come in a relatively short time.

“I’m having different conversations with my patients these days. A lot of the patient information on the web still refers to the average survival rate as 1 year in advanced NSCLC,” Saltos said. “It can take a lot of reassurance to help patients understand how much the landscape has changed. But we all know that we’re seeing many patients live longer than a year thanks to these new therapies (TABLE

1. Garon EB, Hellmann MD, Rizvi NA, et al. Five-year overall survival for patients with advanced non‒small-cell lung cancer treated with pembrolizumab: results from the phase I KEYNOTE-001 study. 

. 2019;37(28):2518-2527. doi:10.1200/JCO.19.00934

2. Brahmer JR, Rodriguez-Abreu D, Robinson AG, et al. KEYNOTE-024 5-year OS update: first-line (1L) pembrolizumab (pembro) vs platinum- based chemotherapy (chemo) in patients (pts) with metastatic NSCLC and PD-L1 tumour proportion score (TPS) ≥50%. 

. 2020;31 (suppl 4):S1142-S1215. Abstract LBA51. doi:10.1016/j.annonc. 2020.08.2284

3. Pembrolizumab (Keytruda) checkpoint inhibitor. News release. FDA. October 24, 2016. Accessed October 18, 2020. https://bit.ly/37qP8Wc

4. Mazieres J, Rittmeyer A, Gadgeel SM, et al. 4-year survival in randomised phase II (POPLAR) and phase III (OAK) studies of atezolizumab vs docetaxel in pre-treated NSCLC. Ann Oncol. 2020;31(suppl 4):S1142-S1215. Abstract 1271P. doi:10.1016/j.annonc.2020.08.1585

5. Atezolizumab (Tecentriq). News release. FDA. October 19, 2016. Accessed October 18, 2020. https://bit.ly/2FLXxIx

6. Faivre-Finn C, Vicente D, Kurata T, et al. Durvalumab after chemoradiotherapy in stage III NSCLC: 4-year survival update from the phase III PACIFIC trial. 

l. 2020;31(suppl 4):S1142-S1215. doi:10.1016/annonc/annonc325

7. FDA approves durvalumab after chemoradiation for unresectable stage III NSCLC. News release. FDA. February 20, 2018. Accessed October 19, 2020. https://bit.ly/37oQGAb

8. Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. 

d. 2020;382(1):41-50. doi:10.1056/NEJMoa1913662

9. FDA approves osimertinib for first-line treatment of metastatic NSCLC with most common EGFR mutations. News release. FDA. April 19, 2018. Accessed October 19, 2020. https://bit.ly/3o9BEUP

10. Mok T, Camidge DR, Gadgeel SM, et al. Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study. 

 2020;31(8):1056-1064. doi:10.1016/j.annonc.2020.04.478

11. Alectinib approved for (ALK) positive metastatic non-small cell lung cancer (NSCLC). News release. FDA. November 7, 2017. Accessed October 19, 2020. https://bit.ly/2T9IXxB

12. FDA grants accelerated approval to capmatinib for metastatic nonsmallcell lung cancer. News release. FDA. May 6, 2020. Accessed October 19, 2020. https://bit.ly/2HkEANq

Dramatic improvements in efficacy outcomes for patients with non–small cell lung cancer have been a reason for celebration over the last decade, as FDA approvals of immunotherapy-plus-chemotherapy combinations as well as oncogenic-targeting drugs have transformed the treatment landscape.






A Long-Term Survival Picture Emerges as Follow-up Data From NSCLC Trials Mature

The frequency of mutations in patients with mantle cell lymphoma (MCL) has a tendency to increase at clinical turning points like disease relapse and progression compared with at the time of diagnosis, according to a systemic review and meta-analysis published in 

A team of authors from the MD Anderson Cancer Center, Mayo Clinic, and Pennsylvania State College of Medicine conducted this analysis to examine the prevalence of genetic mutations in patients with MCL, determine methods of sequencing and genotyping, and demonstrate the possible clinical significance of these mutations.

The authors, led by Michael L. Wang, MD, of MD Anderson, reviewed the genetics of 2275 MCL tumor or bone marrow samples taken at baseline and observed that nearly half (43.5%) contained mutated 

. The next most frequently mutated gene was 

 (20.2%). Cytogenetic methods also detected aberrations in 

 (20.8%). Additional common baseline mutations included 

The study authors also identified the genes with the highest mutational frequency difference (>5%). These include 

TP53, ATM, KMT2A, MAP3K14, BTK, TRAF2, CHD2, TLR2, ARID2, RIMS2, NOTCH2, TET2, SPEN, NSD2, CARD11, CCND1, SP140, CDKN2A,

Based on the pooled analysis, the study authors focused on 32 genes, out of 164, that were found to be frequently mutated in at least one of the studies. Wang et al found the overall probability of having a genetic mutation in these 32 genes to be 11.3% at baseline (95% CI, 9.3%-13.4%). For patients tested again after relapse or progression, the probability of having a mutation in one of these genes had increased to 18.4% (95% CI, 14.9%-22.4%). “The oncogenic role of these aberrations as driver mutations in clonal evolution and expansion should be further studied,” they wrote. “Targeted panels for MCL could be constructed using genes with the highest mutational rate combined with recurrently mutated regions of the genes to understand their clinical relevance in the era of novel precision therapies.”

At disease progression, the most common genetic mutations were 

The biggest difference from baseline to disease progression was seen in the 

gene, where the frequency was 26.8% at baseline up to 43.0% at disease progression (Bayesian probability, 0.998).

The authors performed a literature search of 3 major databases for original studies that reported genetic mutations in patients with MCL, including randomized clinical trials, prospective studies, retrospective studies, and case reports. They excluded studies that reported only conventional cytogenetics such as gains, deletions, and translocations, as well as gene expression data without genetic mutation data. 

Extracted data included mutational data (whether a gene was mutated), type of study (observational or experimental), the technology used to analyze mutations, sample collection time point (baseline/diagnosis, relapse, progression), and if a specific treatment or therapy was named in the study. They collected both study-level and patient-level data. After initially identifying 1577 unique studies, Wang et al culled studies that didn’t meet the inclusion criteria until they were left with 32 to include in the final analysis.

The 32 included studies included 2275 samples from 2127 patients. Overall, 2045 of 2127 patients with MCL had baseline samples with genetic mutation information for at least 1 of the 32 genes. Studies from the pre-genomic era generally used techniques such as Sanger sequencing, probed fluorescence in situ hybridization, and polymerase chain reaction to identify mutations. More recent studies have frequently used single-nucleotide polymorphism arrays and next-generation sequencing (NGS).

Wang et al urged the inclusion of all genes with >5% increase in mutational frequency in future genomic and functional studies “to understand their role in the relapse and progression of MCL and be included in targeted NGS panels,” they wrote. “The patient-level data of prevalent mutations in MCL provide additional evidence to existing literature highlighting the importance of molecular variability in advancing precision medicine initiatives in MCL.”

In assessing their paper’s strength and weaknesses, Wang et al emphasized their inclusion of patient-level data as increasing the quality and reliability of their data. Despite their efforts, they note that their study is subject to the small-study effect due to the rarity of MCL and the relatively low number of genetic studies done to date. Additionally, MCL tissue banks are used for many genotyping/sequencing studies, so it’s possible that some patient samples have been used in multiple studies. “However, we believe that each patient observed in the 32 studies was genotyped/sequenced uniquely for that particular study and represents an independent observation,” they wrote.

The authors also noted that additional articles reporting mutations in patients with MCL were published after their study period: “These articles describe prevalent mutations similar to those reported in our analysis, including 

1. Hill HA, Qi X, Jain P, et al. Genetic mutations and features of mantle cell lymphoma: a systematic review and meta-analysis. 

 2020;4(13):2927-2938. doi:10.1182/bloodadvances.2019001350.

2. Jain P, Zhang S, Kanagal-Shamanna R, et al. Genomic profiles and clinical outcomes of de novo blastoid/pleomorphic MCL are distinct from those of transformed MCL. 

 2020;4(6):1038-1050. doi:10.1182/bloodadvances.2019001396

3. Streich L, Sukhanova M, Lu X, et al. Aggressive morphologic variants of mantle cell lymphoma characterized with high genomic instability showing frequent chromothripsis, CDKN2A/B loss, and TP53 mutations: a multi-institutional study. 

 2020;59(8):484-494. doi:10.1002/gcc.22849

4. Swenson S, Gilbreath T, Vahle HE, et al. UBR5 HECT domain mutations in mantle cell lymphoma control maturation of B cells 

. 2020;136(3):299-312. doi:10.1182/blood.2019002102

5. Zhao S, Kanagal-Shamanna R, Navsaria L, et al. Efficacy of venetoclax in high risk relapsed mantle cell lymphoma (MCL) - outcomes and mutation profile from venetoclax resistant MCL patients. 

 2020;95(6):623-629. doi:10.1002/ajh.25796

6. Pararajalingam P, Coyle KM, Arthur S, et al. Coding and non-coding drivers of mantle cell lymphoma identified through exome and genome sequencing. 

. 2020;136(5):572-584. doi:10.1182/blood.2019002385

The frequency of mutations in patients with mantle cell lymphoma has a tendency to increase at clinical turning points like disease relapse and progression compared with at the time of diagnosis, according to a systemic review and meta-analysis.

Darcy Lewis | Authors

Articles

RET, MET Inhibitors Advance Targeted Therapies in NSCLC

Conditioning with Thiotepa-busulfan-fludarabine Improves Outcomes for Patients with MF Undergoing ASCT

A Long-Term Survival Picture Emerges as Follow-up Data From NSCLC Trials Mature

Meta-Analysis Highlights Commonly Mutated Genes in Mantle Cell Lymphoma