ASCO 2018: Top Oncologists Select Key, Practice-Changing Abstracts

The oncology community will soon be seeing the much-anticipated data being presented at the 2018 ASCO Annual Meeting. More than 5000 submitted abstracts will showcase findings across tumor types, which include practice-changing research in screening, immunotherapy, targeted agents, chimeric antigen receptor (CAR) T-cell therapy, and more.

Key opinion leaders spoke with OncLive ahead of the conference to share the top abstracts they believe could have the greatest impact on clinical practice and patient outcomes across lymphomas, gastrointestinal cancers, genitourinary cancers, and lung cancer.

LYMPHOMAS

Anas Younes, MD, PhD, medical oncologist, chief, Lymphoma Service, Memorial Sloan Kettering Cancer Center

Activity and tolerability of the first-in-class anti-CD47 antibody Hu5F9-G4 with rituximab (Rituxan) tolerated in relapsed/refractory non-Hodgkin lymphoma (NHL): Initial phase Ib/II results (Abstract 7504)

Anas Younes, MD, PhD

In a 3+3 dose-escalation design, heavily pretreated patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) were treated with Hu5F9-G4, a first-in-class humanized CD47-targeted antibody and maintenance rituximab (NCT02953509). The combination was found to be well tolerated and the maximum-tolerated dose of Hu5F9-G4 was not reached up to 30 mg/kg weekly in the phase Ib portion.

Results with the recommended phase II dose showed that the overall response rate (ORR) was 50%, and the complete response (CR) rate was 32%. As of the data cutoff in January 2018, 90% of patients who responded continued to be in response. Phase II cohorts are ongoing for patients with indolent lymphoma and DLBCL.

“This is a small study but provides promising data on the potential therapeutic value of CD47-targeted therapy. Recently, the FDA granted Hu5F9-G4 fast track designation for relapsed DLBCL and FL.”

Updated safety and long-term clinical outcomes in TRANSCEND NHL 001, pivotal trial of lisocabtagene maraleucel (liso-cel; JCAR017) in relapsed/refractory aggressive NHL (Abstract 7505)

Phase I results of this study previously showed that treatment with the CAR T-cell product JCAR017 demonstrated a CR rate of 59% and an ORR of 86% for patients with relapsed/refractory DLBCL (NCT02631044). In the findings to be presented at this meeting, researchers reported data from all patients in the DLBCL cohort, the FULL cohort, which includes DLBCL NOS (de novo or transformed from FL); primary mediastinal B-cell lymphoma; and follicular lymphoma grade 3B treated with liso-cel at various doses. Data from a CORE cohort comprises patients meeting inclusion criteria for the pivotal cohort, including those with DLBCL NOS and high-grade lymphoma.

Results showed that the best ORR in the FULL and CORE cohorts was 74% and 80%, respectively, and the best CR was 52% in FULL and 55% in CORE. There was an increase in durability of response at the second dose level (DL2; 108 CAR T cells) in the CORE population; the 6-month ORR and CR rate was 50% and 50% with DL2 versus 40% and 30% at dose level 1. Long-term efficacy will be reported at the meeting, as well.

Among 91 patients across the study evaluable for safety, 35% of patients had cytokine release syndrome (CRS); however only 1 patients had grade 3/4 CRS. Nineteen percent of patients had neurotoxicty of any grade, with 12% having grade 3/4. However, at the data cutoff all except one event had been resolved.

"This study demonstrates that the safety profile of different CD19 CAR T-cell therapies may vary among different products. In this case, the incidence of grade 3/4 cytokine release syndrome and neurotoxicity seems to be lower than what has been previously reported with other products. If confirmed, outpatient CAR T-cell therapy may become reality for selected patients."

RELEVANCE: Phase III randomized study of lenalidomide (Revlimid) plus rituximab (R²) versus chemotherapy plus rituximab, followed by rituximab maintenance, in patients with previously untreated follicular lymphoma (Abstract 7500)

Following promising phase II data with lenalidomide and rituximab, the global phase III RELEVANCE trial examined R² compared with rituximab plus chemotherapy followed by rituximab in previously untreated grade 1 to 3A patients with follicular lymphoma (NCT01650701). Findings showed that neither coprimary endpoint of progression-free survival (PFS) or CR/unconfirmed CR favored R²; the efficacy was similar in both arms. However, the safety data differed; grade 3/4 laboratory abnormalities and febrile neutropenia were higher with rituximab/chemotherapy at 34% versus 50%, and 2% versus 6%, respectively. Meanwhile, there were higher grade 3/4 cutaneous events with R² at 7% vs 1%.

"Although the chemotherapy-free regimen was not superior to chemotherapy, it is remarkable that the efficacy was similar. These results may provide future options for patients who may not tolerate chemotherapy."

GASTROINTESTINAL CANCERS

Tanios Bekaii-Saab, MD, medical oncologist, Mayo Clinic

Unicancer GI PRODIGE 24/CCTG PA.6 trial: a multicenter international randomized phase III trial of adjuvant mFOLFIRINOX versus gemcitabine in patients with resected pancreatic ductal adenocarcinomas (Abstract LBA4001)

Anticipated findings of this late-breaking abstract, for which no details have yet been released, will demonstrate superiority with either adjuvant mFOLFIRINOX or gemcitabine in patients with resectable pancreatic ductal adenocarcinoma.

Tanios Bekaii-Saab, MD

“This long-awaited study of mFOLFIRINOX versus gemcitabine in adjuvant resected pancreas cancer will be relatively practice changing, if positive. Unfortunately, the comparator arm is not standard of care since ESPAC-4 established the superiority of gemcitabine and capecitabine. We are also eagerly awaiting the results of APACT with gemcitabine and nab-paclitaxel versus gemcitabine in the adjuvant setting that should be coming later this year.

“Overall, it will be challenging to administer these intense regimens in the adjuvant setting—for gemcitabine and nab-paclitaxel, perhaps consider a biweekly schedule? At our institution we favor a total neoadjuvant approach where patients are more likely to tolerate intense regimens.”

FOLFIRINOX until progression, FOLFIRINOX with maintenance treatment, or sequential treatment with gemcitabine and FOLFIRI.3 for first-line treatment of metastatic pancreatic cancer: a randomized phase II trial (PRODIGE 35-PANOPTIMOX; Abstract 4000)

Researchers evaluated a “stop-and-go” strategy with oxaliplatin and an alternative sequential strategy in patients with metastatic pancreatic cancer in this randomized phase II trial (NCT02352337). Previous data with the PRODIGE4-ACCORD11 trial showed an improvement in PFS with FOLFIRINOX versus gemcitabine at 6.4 versus 3.3 months (HR, 0.47; 95% CI, 0.37-0.59; P <.001). In this phase II trial, there were 3 arms: 6 months of FOLFIRINOX (A); 4 months of FOLFIRINOX followed by LV5FU2 maintenance and reintroduction of treatment at disease progression (B); and sequential treatment alternating gemcitabine and FOLFIRI.3 every 2 months (C).

Six-month PFS rates were 47%, 44%, and 34% in arms A, B, and C, respectively. Moreover, 4-month ORR was 35%, 41%, and 17% in A, B, and C, respectively. Median PFS was 6.3 months in arm A, 5.7 months in B, and 4.5 months in arm C; median overall survival (OS) was 10.1 months, 11.2, and 7.3 months in arms A, B, and C, respectively.

“This study is an attempt to understand whether a stop-and-go approach was feasible in pancreas cancer patients receiving FOLFIRINOX. The 2 arms of primary interest are arms A (6 months of FOLFIRINOX) and B (FOLFIRINOX for 4 months followed by infusional 5-FU and then reintroduction of irinotecan/oxaliplatin at progression).

"This study failed to show that a stop-and-go strategy was any better than limiting exposure to FOLFIRINOX to 6 months given no difference in PFS/OS and worse neuropathy in arm B. In practical terms, the way I interpret this study is that if you chose to start with mFOLFIRINOX, then allow 3 to 4 months of therapy followed by a fluoropyrimidine for maintenance. What is less clear is whether there is any benefit with reinitiating irinotecan/oxaliplatin or switch therapy. In my practice, I continue to favor gemcitabine and nab-paclitaxel in first-line followed by nanoliposomal irinotecan and 5-FU upon progression of disease for most patients."

Pembrolizumab versus paclitaxel for previously treated advanced gastric or gastroesophageal junction (G/GEJ) cancer: Phase III KEYNOTE-061 trial (Abstract 4062)

The phase III study is the confirmatory trial for the accelerated approval by the FDA in September 2017 for pembrolizumab for the treatment of patients with PD-L1—positive recurrent or advanced G/GEJ adenocarcinoma who have received 2 or more lines of chemotherapy, including fluoropyrimidine- and platinum-containing chemotherapy, and, if appropriate, HER2/neu-targeted therapy. The accelerated approval was based on findings from the phase II KEYNOTE-059 study.

Results of KEYNOTE-061 showed that pembrolizumab reduced the risk of death by 18% compared with paclitaxel in patients with previously treated G/GEJ cancer and PD-L1 positivity ≥1% (NCT02370498). However, this was not found to be statistically significant.

"Pembrolizumab is now approved in the United States for patients with refractory PD-L1—positive G/GEJ cancer based on a nonrandomized phase II study: KEYNOTE-059. KEYNOTE-061 fails to confirm an advantage for administering pembrolizumab versus paclitaxel in this patient population. A study with a similar design but with avelumab (Bavencio; JAVELIN 100) failed, as well."

"Both studies are even more disappointing when we are reminded that paclitaxel is a substandard control arm, since the current standard—at least in the United States&mdash;is paclitaxel and ramucirumab (Cyramza). It is likely that PD-1 inhibitors have a meaningful role in a subset of patients, such as microsatellite instability—high and Epstein-Barr virus–positive patients. Outside these settings, the use of PD-1 inhibitors in gastric and GEJ cancer patients should be limited to clinical trials when possible&mdash;many [of which] are currently ongoing."

A randomized phase II study of weekly paclitaxel ± trastuzumab in patients with HER2-positive advanced gastric or gastroesophageal junction cancer refractory to trastuzumab (Herceptin) combined with fluoropyrimidine and platinum: WJOG7112G (T-ACT; Abstract 4011)

Continuation of trastuzumab beyond progression in this patient population was not found to have the similar outcomes as it does for patients with HER2-positive breast cancer. Results of WJOG112G (UMIN000009297) showed that the median PFS was 3.19 months (95% CI 2.86-3.48) in the paclitaxel arm and 3.68 months (95% CI 2.76-4.53) in the paclitaxel/trastuzumab arm, respectively (HR, 0.91; 95% CI, 0.67-1.22; P = .33). The median OS was 9.95 months in the paclitaxel arm and 10.2 months in the paclitaxel/trastuzumab arm (HR, 1.23; 95% CI, 0.75-1.99; P = .20). The ORRs were 31.6% and 33.3% (P = 1.00) and the disease control rates were 71.1% and 61.5% (P = .47), in the paclitaxel and paclitaxel/trastuzumab arms respectively.

"This is a very important study given that continuation of trastuzumab beyond progression in gastric/GEJ cancer patients is widely used in the United States without any supporting data. This phase II randomized study suggests a lack of benefit from continuation of trastuzumab beyond progression in patients with HER2-positive disease. This is practice changing, since it informs us about limiting exposure to [trastuzumab] to the first-line setting only."

REACH-2: A randomized, double-blind, placebo-controlled phase III study of ramucirumab (Cyramza) versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated baseline alpha-fetoprotein (AFP) following first-line sorafenib (Nexavar; Abstract 4003)

REACH-2 is a follow-up to the phase III REACH trial, which showed that second-line treatment with ramucirumab did not improve OS versus placebo in the overall population of patients with advanced HCC. However, a subgroup analysis of REACH showed that patients with high expression of AFP did experience an OS benefit with ramucirumab. Findings of REACH-2 showed that ramucirumab was associated with a 29% reduction in the risk of death in patients with HCC and AFP ≥ 400 ng/mL who progressed on or were intolerant to sorafenib (NCT02435433).

"This study was a follow-up to the REACH, where an observation was made regarding AFP >400 ng/mL and an improvement in patients' outcomes. The results of REACH-2 suggest that in this group of patients, OS was superior with ramucirumab versus placebo. The difference, however, was very modest and historically not in line with what we have observed in patients receiving regorafenib (Stivarga) or cabozantinib (Cabometyx) in their respective phase III studies—although no data is available in the AFP >400 group. From REACH-2, one can conclude that ramucirumab is an additional option complicating, on a positive connotation, the landscape of how we treat patients with HCC who are refractory to sorafenib."

Long-term results of the ADORE trial: Adjuvant oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) versus 5-fluorouracil and leucovorin (FL) after preoperative chemoradiotherapy and surgery for locally advanced rectal cancer (Abstract 3501)

This phase II trial (NCT00807911) randomized patients to 4 months of FOLFOX or FL. At a median follow-up of 74.1 months, the 6-year DFS rate was 68.2% with FOLFOX and 56.8% with FL (HR, 0.63; 95% CI, 0.43-0.93, P = .018). Subgroup analyses will provide additional data on the patient population.

"This study confirms the disease-free survival benefits of adjuvant FOLFOX versus 5-FU in patients with yp stage II/III rectal cancer who received preoperative chemoradiation (CRT). What remains unclear is whether this will translate into an OS benefit. It is also likely that 3 months of FOLFOX (or preferably XELOX, given the results of the IDEA trial) will be sufficient, especially when considering the time spent on neoadjuvant CRT."

GENITOURINARY CANCERS

Toni K. Choueiri, MD, director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute

Olaparib (Lynparza) combined with abiraterone (Zytiga) in patients with metastatic castration-resistant prostate cancer (mCRPC): a randomized phase II trial (Abstract 5003)

This phase II, placebo-controlled study randomized patients to olaparib at 300 mg twice daily plus abiraterone acetate or placebo plus abiraterone following therapy with docetaxel (NCT01972217). The primary endpoint was investigator-assessed radiological PFS (rPFS). Results showed that there was an improvement in rPFS with the olaparib/abiraterone versus placebo/abiraterone, regardless of homologous recombination repair mutation status (HRRm; P = .03). The median OS was 23.3 versus 20.9 months in the olaparib arm versus placebo, respectively (HR, 0.89; 95% CI, 0.58-1.35). Authors noted that this is the first clinical trial to demonstrate a clinical benefit for patients with mCRPC who were treated with a combination of PARP inhibition and abiraterone, regardless of HRRm status; however, safety data were better in the placebo arm.

Toni K. Choueiri, MD

"First evidence that a PARP inhibitor in combination with abiraterone leads to an increase in PFS. Though caution is advised 3-fold: 1, no OS benefit; 2, the PARP inhibitor did not select for a biomarker (here, HRR mutation); and 3, almost double serious and cardiovascular events. I do not think this is ready for clinical adoption."

The PROPHECY trial: Multicenter prospective trial of circulating tumor cell AR-V7 detection in men with mCRPC receiving abiraterone or enzalutamide (Xtandi; Abstract 5004)

To determine whether detection of circulating tumor cell AR-V7 is a valid predictive biomarker for response to abiraterone or enzalutamide, researchers conducted the multicenter prospective PROPHECY study (NCT02269982) in patients with high-risk mCRPC on abiraterone or enzalutamide. Researchers used association of baseline AR-V7 with radiographic or baseline PFS with the Johns Hopkins modified-AdnaTest CTC AR-V7 mRNA assay as well as the Epic Sciences CTC nuclear AR-V7 protein assay. Results showed that AR-V7 detection is an independent CTC-adjusted negative predictive biomarker of short PFS and OS with abiraterone or enzalutamide treatment in these patients.

"This is an important study that highlights AR-V7 as a biomarker in CRPC using 2 assays. Both assays were confirmed to be independently associated with worse outcomes in patients treated with abiraterone or enzalutamide. Furthermore, AR-V7-positive patients seem to have a distinct genomic profile."

Multicenter randomized phase II trial of paclitaxel, ifosfamide, and cisplatin (TIP) versus bleomycin, etoposide, and cisplatin (BEP) for first-line treatment of patients with intermediate- or poor-risk germ cell tumors (GCT; Abstract 4508)

Encouraging single-arm phase II findings led to this study, which investigated 4 cycles of TIP against standard BEP in patients with treatment-naive, IGCCCG intermediate- or poor-risk GCT (NCT01873326). Subtypes included nonseminoma and seminoma, with primary sites in the testis (n = 69), mediastinum (n = 19), and retroperitoneum (n = 3). At a median follow-up of 1.71 years, the estimated 1-year PFS was similar in both arms. Additional data are expected to be reported at the meeting.

"This was an important study that looks at an alternative to BEP in intermediate, poor risk-GCT, building on [Memorial Sloan Kettering Cancer Center] experience with a single-arm ITP regimen. First-line TIP versus BEP had similar efficacy. [This may be] a reasonable alternative in patients who cannot get bleomycin [due to pulmonary problems]."

Pembrolizumab monotherapy as first-line therapy in advanced clear cell renal cell carcinoma (accRCC): Results from cohort A of KEYNOTE-427 (Abstract 4500)

In 107 treatment-naive patients receiving pembrolizumab, at a median follow-up of 7.2 months, the confirmed ORR by independent central review was 33.6% (95% CI, 24.8-43.4) with 1 complete response and 35 partial responses (PRs; NCT02853344). Additionally, the ORR was 27.5% for favorable-risk patients and 37.3% for those with intermediate- and poor-risk disease. The median duration of response was also not reached. The data presented at the meeting will also include potential tissue-based biomarkers.

"This is the first evidence showing single-agent pembrolizumab data in untreated clear cell RCC. Though this is a single-arm study, responses are high and seems to be durable, begging the question if there is a population of mRCC patients [who] can just benefit from single-agent immunotherapy, rather than a combination with a VEGF inhibitor or another immunotherapy drug."

Updated results from the enfortumab vedotin phase I (EV-101) study in patients with metastatic urothelial cancer (mUC; Abstract 4504)

The antibody-drug conjugate enfortumab vedotin showed preliminary activity and tolerability in a study (NCT02091999) in patients with mUC expressing Nectin-4. Updated results at the recommended phase II dose of 1.25 mg/kg demonstrated that the agent was overall well tolerated, and the ORR was 33% (95% CI, 24.7-42.9). Moreover, confirmed CRs and PRs were reported in 3 and 34 patients, respectively. The ORRs across subgroups were 32% (prior treatment with a checkpoint inhibitor), 37% (checkpoint inhibitor-naïve), and 26% (prior treatment with a checkpoint inhibitor and had liver metastases). In the overall population, the median PFS and OS were 23.1 weeks and 12.5 months, respectively. The median duration of response was 24.3 weeks.

“There is a void of new targets after cytotoxic chemotherapy and PD-1/PD-L1 inhibitors in metastatic bladder cancer. The antibody-drug conjugate enfortumab vedotin data—with a [greater than] 30% ORR (including post-immunotherapy)&mdash;is very encouraging, justifying further development. Other chemotherapy agents (non-platinum) do yield <10% ORR.”

LUNG CANCER

H. “Jack” West, MD, thoracic oncologist, Swedish Cancer Institute at Swedish Medical Center

Pembrolizumab versus platinum-based chemotherapy as first-line therapy for advanced/metastatic non—small cell lung cancer (NSCLC) with a PD-L1 tumor proportion score ≥ 1%: Open-label, phase III KEYNOTE-042 study. (Abstract LBA4)

The randomized trial (NCT02220894) evaluated the efficacy and safety of frontline pembrolizumab compared with platinum-doublet chemotherapy in patients with non—small cell lung cancer (NSCLC) who have PD-L1 expression and either squamous or nonsquamous histology. Patients were randomized 1:1 and were given pembrolizumab at 200 mg every 3 weeks or investigator’s choice of chemotherapy with carboplatin/paclitaxel or carboplatin/pemetrexed. The primary endpoint was OS in patients with a PD-L1 expression ≥50%.

Previously, results from the phase III KEYNOTE-024 trial showed that frontline pembrolizumab more than doubled the median OS versus standard chemotherapy in patients with NSCLC and a PD-L1 expression level ≥50%.

H. Jack West, MD

"It directly compares pembrolizumab monotherapy to histology appropriate doublet chemotherapy for either squamous or nonsquamous NSCLC in patients with PD-L1 expression 1% or greater. This has an OS benefit for pembrolizumab, but what we’ll need to see is whether the benefit is quite compelling for patients with lower PD-L1 status. We already know that patients with PD-L1 [expression] 50% or greater do very well with pembrolizumab monotherapy. We already have an approval based on the KEYNOTE-024 study from a couple years ago. So, the question is, [with] PD-L1 expression of 1% or greater, or 20% or greater, do those patients get a benefit that is as impressive—that would lead us to favor pembrolizumab monotherapy&mdash;or is this trial positive because it’s being carried by the patients with the highest level of PD-L1? Those with lower PD-L1 [expression may] not do as well. We’ll need to see about that because in addition to the long-standing option of chemotherapy followed by [second-line] immunotherapy, we also have a number of growing options of chemotherapy and immunotherapy."

Phase III study of carboplatin-paclitaxel/nab-paclitaxel with or without pembrolizumab for patients with metastatic squamous NSCLC (Abstract 105)

The phase II IMmotion150 study randomized patients with untreated mRCC to atezolizumab plus bevacizumab, atezolizumab alone, or sunitinib alone. Crossover to atezolizumab plus bevacizumab was allowed following progression on single-agent atezolizumab or sunitinib.

The international, phase III, placebo-controlled KEYNOTE-407 study (NCT02775435) tested the immunotherapy-chemotherapy combination in a 1:1 randomization in 560 treatment-naïve patients with metastatic squamous disease. Additionally, patients were stratified by PD-L1 expression, taxane regimen, and geographical site. Findings show that adding pembrolizumab to chemotherapy nearly doubled the ORR compared with chemotherapy alone, and was also associated with a tolerable safety profile.

In March 2018, a supplemental biologics license application was submitted to the FDA for the use of pembrolizumab in combination with standard chemotherapy as a treatment for this patient population.

"This trial of carboplatin/nab-paclitaxel with pembrolizumab or placebo in patients with advanced squamous NSCLC regardless of tumor PD-L1 expression, was already provocative based on the previously reported significant improvement in response rate in the chemo/immunotherapy arm, particularly after we learned from the abstract that the improvement in ORR was 23% compared to the control arm.

"A key remaining variable was whether the arguably far more relevant clinical endpoints of PFS and OS would also be positive, and we have just learned from a press release that these endpoints have also been found to be significantly superior with pembrolizumab, as well. Running the table with a significant improvement in response rate, PFS, and OS should mean that the combination should receive FDA approval in short order, but also that it will emerge as a leading first-line management option for patients with advanced squamous NSCLC, likely with pembrolizumab monotherapy as a leading alternative."

IMpower131: Primary PFS and safety analysis of a randomized phase III study of atezolizumab (Tecentriq) plus carboplatin and paclitaxel or nab-paclitaxel (Abraxane) versus carboplatin plus nab-paclitaxel as first-line therapy in advanced squamous NSCLC (Abstract LBA9000)

Reports from Genentech (Roche), the manufacturer of atezolizumab, have stated that the addition of atezolizumab to frontline carboplatin and nab-paclitaxel delayed progression or death versus chemotherapy alone for patients with advanced squamous NSCLC. In the multicenter, randomized phase III trial, coprimary endpoints were PFS and OS (NCT02367794). However, a statistically significant OS improvement was not observed at the interim analysis and the study is now continuing according to its design. Moreover, Genentech added that no new safety signals were reported with the atezolizumab combination.

"Looking at the same patient population as KEYNOTE-407, this trial has been previously reported as demonstrating a significant PFS benefit with carboplatin/nab-paclitaxel/atezolizumab compared to the same chemotherapy alone. This is a late-breaking abstract for which we don't have data yet, but the press release highlighting an improvement in ORR, PFS, and OS for the same chemotherapy backbone with pembrolizumab in KEYNOTE-407, as noted above, now significantly raises the ante.

"With trials of chemotherapy doublets and pembrolizumab collecting positive trial results and likely new approvals, we will definitely need to see an OS comparable to that seen with pembrolizumab on KEYNOTE-407, if not have the results with atezolizumab look stronger, to overcome that momentum and have carboplatin/nab-paclitaxel/atezolizumab emerge as a leading consideration in a crowded landscape with competing positive trials."

Nivolumab (Opdivo) plus platinum-doublet chemotherapy versus chemo as first-line treatment for advanced NSCLC with <1% tumor PD-L1 expression: results from CheckMate-227 (Abstract 9001)

Results of this multi-arm trial focused on nivolumab plus chemotherapy (n = 177) versus chemotherapy alone (n = 186) in patients with <1% PD-L1 expression (NCT02477826). Results showed that, at a median follow-up of 11.2 months, there was an improvement in PFS with the combination versus chemotherapy (HR, 0.74; 95% CI, 0.58-0.94). Moreover, the PFS benefit with nivolumab plus chemotherapy was observed across most subgroups. However, the benefit was more pronounced in nonsquamous patients (HR, 0.68) compared with those with squamous disease (HR, 0.92). The combination was also well tolerated.

Part 2 of the study, which is ongoing, is exploring the combination versus chemotherapy alone, irrespective of PD-L1 expression.

Initial findings from another arm of the phase III CheckMate-227 trial, which were presented at the 2018 AACR Annual Meeting and published online in the New England Journal of Medicine, showed that the combination of nivolumab and ipilimumab more than tripled the 1-year PFS rate versus chemotherapy for treatment-naïve patients with NSCLC who have high tumor mutation burden.

"This demonstrated an improvement in PFS with the nivolumab/chemotherapy combination, [with] a hazard ratio of .74. What is interesting from the abstract, they also report, is that the difference was far more pronounced in favor of the chemoimmunotherapy arm for the nonsquamous population, with a hazard ratio of 0.68, but it was only .92 for squamous NSCLC. We need to see more data from this; it is going to be a very limiting issue in the squamous population, because we have other options that I suspect are going to be far more impressive."

Dacomitinib versus gefitinib (Iressa) for first-line treatment of advanced NSCLC (ARCHER 1050): Final OS analysis (Abstract 9004)

This year’s updated findings from the phase III ARCHER 1050 trial (NCT01774721) incorporate OS data, which differs from the PFS and response results with dacomitinib, a second-generation EGFR inhibitor, presented at the 2017 ASCO Annual Meeting.

In the study, patients with advanced EGFR mutation-positive NSCLC were randomized to dacomitinib or gefitinib. Results showed that dacomitinib was associated with a significant improvement in OS versus gefitinib (HR, 0.76; 95% CI, 0.582-0.993; 2-sided P = .044 based on stratified analysis). The median OS was 34.1 months (95% CI, 29.5-37.7) with dacomitinib versus 26.8 months (95% CI, 23.7-32.1) with gefitinib. Thirty-month survival rates were 56.2% with dacomitinib and 46.3% with gefitinib.

Previously released findings showed that dacomitinib reduced the risk of disease progression by more than 40% and resulted in an average 6.5-month improvement in response duration versus gefitinib in the frontline setting for these patients.

"Dr [Tony] Mok already presented this trial—it’s been published, as well&mdash;with the second-generation EGFR inhibitor dacomitinib versus first-generation inhibitor gefitinib in EGFR-mutation—positive patients. That showed an impressive difference in PFS with dacomitinib, but we haven’t seen OS, and toxicity issues with dacomitinib were pretty significant. There were a lot of challenges with that.

"What we’re going to see at [the 2018 ASCO Annual Meeting] presented by Dr Mok are the OS results, which are borderline statistically significant shown in a few different permutations, but are enough that could be convincing to change our view about whether there could be a role for dacomitinib in advanced NSCLC, after all. Obviously, this is a setting where we now have osimertinib (Tagrisso), a third-generation inhibitor just approved, but with dacomitinib coming in with a PFS of about 15 months and a significant improvement in OS that reaches a median 3 years, this is something that could lead to more discussions about whether there is a role for sequencing EGFR inhibitors."