Immune Checkpoint Drug Active in NSCLC

Tumors with at least 50% PD-L1 expression associated with unexpected improvement..

Patients with advanced non-small cell lung cancer (NSCLC) had almost a 50% response rate to an immune checkpoint inhibitor if their tumors tested positive for the checkpoint protein, according to data reported here.

Overall response to pembrolizumab (Keytruda) was 45.2% in patients whose tumors exhibited PD-L1 (programmed death-ligand 1) expression in at least 50% of cells. Patients who received the PD-L1 inhibitor as initial therapy had a 50% response rate.

The response rate fell off dramatically (17% or less) in tumors that had lower levels of PD-L1 expression, Edward B. Garon, MD, of the University of California Los Angeles, said at the American Association for Cancer Research (AACR) meeting. A fourth of the tumors met the 50% cutoff for PD-L1 expression.

“I think that, with this data, we can now confidently say that in previously treated patients, who have PD-L1 expression in at least half of their cells … pembrolizumab is associated with superior clinical outcomes, clearly, than would be anticipated with cytotoxic chemotherapy,” Garon said during an AACR press briefing.

“The outcomes in patients with lesser degrees of staining, in certain clinical scenarios, may also be better than what is seen with comparators, but complete data on that will require data from randomized studies.”

The results were reported simultaneously in the New England Journal of Medicine.

The PD-1 (L1) receptor/ligand system has a braking effect on immune function, specially T-cell function. Tumor cells that express PD-L1 effectively block the immune system’s ability to attack the tumor. In describing immune checkpoint inhibitors, such as pembrolizumab, researchers have often used the analogy of “taking the foot off the brakes” of the immune system and “giving it the gas.”

Approved in 2014 for advanced melanoma, pembrolizumab has demonstrated activity in multiple types of solid tumors, including NSCLC. Garon reported findings from a phase I study to examine the safety and efficacy of the PD-L1 inhibitor only in patients with advanced NSCLC and to validate PD-L1 expression as a biomarker to identify patients who are more likely to respond to the drug.

Investigators enrolled and treated 495 patients with one of three doses of pembrolizumab and subsequently randomized them to a training group (n=182) or a validation group (n=313) for the biomarker analysis. PD-L1 expression was determined from immunohistochemical staining of tumor samples, and results were reported as the proportion of tumor cells that stained positive for membranous PD-L1.

The training cohort comprised 171 previously treated patients and 11 with no prior therapy. After exclusions, 129 patients remained for PD-L1 expression cutoff values. In the validation cohort, 223 patients had received prior therapy, 90 had no prior treatment, and 156 were included in the PD-L1 expression analysis.

Overall, 19.4% of the patients had objective responses to treatment with pembrolizumab. The patients had a median duration of response was 12.5 months, median progression-free survival (PFS) of 3.7 months, and median overall survival (OS) of 12.0 months. None of the outcomes differed appreciably by dosage.

In the validation cohort, patients whose tumors had at least 50% staining for PD-L1 had an response rate of 45.2%, including 50% in patients with no prior therapy. Patients with PD-L1 expression in 1% to 49% of tumor cells had a response rate of 16.5% (19.2% in untreated patients), and the response rate declined to 10.7% for patients with <1% of cells that expressed PD-L1.

PD-L1 expression ≥50% was associated with a median PFS of 6.3 months, almost double the PFS associated with 1% to 49% expression (3.3 months) and nearly triple the PFS of patients whose tumors had the least PD-L1 expression (2.3 months). Patients with no prior treatment and ≥50% PD-L1 expression had a median PFS of 12.5 months.

Median OS has yet to be reached in the patients with ≥50% PD-L1 expression, regardless of treatment history. For patients with 1% to 49% PD-L1 expression, median OS was 7.3 months in previously treated patients and 16.2 months in the previously untreated subgroup. For the lowest level of PD-L1 expression, median survival was 8.6 and 10.4 months in the previously treated and untreated patients, respectively.

Garon said pembrolizumab was well tolerated. The most common adverse event was fatigue, occurring in about 20% of all patients (all grades). About 10% of patients developed pruritus and decreased appetite. No other adverse event occurred in as many as 10% of patients. Most adverse events were mild or moderate in severity.

Noting that three-fourths of the patients in the study had progressed on prior therapy, press briefing moderator Suzanne Topalian, MD, of Johns Hopkins Medicine in Baltimore, said pembrolizumab exceeded conventional expectations for second- and third-line therapy in advanced NSCLC.

“This is a very difficult-to-treat patient population where the impact of second- and third-line agents is generally not expected to prolong survival,” she said. “These results are especially impressive in this particular treatment setting.”

Topalian pointed out that the PD-L1 expression data are clear-cut, given that patients with less than 50% expression “still had notable response rates.” Garon agreed and said that one of the shortfalls of research on PD-L1 expression has been the inability to identify groups of patients who clearly will not respond to PD-L1 inhibition.

“The data are exciting and will be valuable for practitioners and patients to stratify their likelihood of benefiting,” he added.

Ibrutinib versus Ofatumumab in Previously Treated Chronic Lymphoid Leukemia.

Chronic lymphoid leukemia (CLL) is characterized by a variable natural history that is partly predicted by clinical and genomic features.1 Therapy for CLL has evolved from monotherapy with alkylating agents to chemoimmunotherapy.2,3 Each of the combination regimens has shown prolonged rates of progression-free survival, as compared with similar regimens that do not contain antibodies.
Treatment of patients with relapsed CLL often includes regimens such as bendamustine and rituximab,4ofatumumab,5 or investigational agents.6-8 Ofatumumab was approved by the Food and Drug Administration (FDA) and the European Medicines Agency on the basis of a single-group study involving patients who had resistance to fludarabine and alemtuzumab therapy; with an overall response rate of 58%,5 ofatumumab has been recommended in international consensus guidelines as a therapeutic option for patients with previously treated CLL.9,10
A short duration of response to initial therapy or adverse cytogenetic abnormalities have been associated with a poor outcome among patients receiving conventional therapy.9,11,12 Identifying new therapies that prolong survival remains an important need for these patients.
Ibrutinib (Imbruvica, Pharmacyclics and Janssen) is a first-in-class, oral covalent inhibitor of Bruton’s tyrosine kinase, an essential enzyme in B-cell receptor signaling, homing, and adhesion.13-15 On the basis of response rates in single-group, phase 2 studies, ibrutinib was recognized by the FDA as a breakthrough therapy and was granted accelerated approval for patients with mantle-cell lymphoma (in November 2013) and CLL (in February 2014) who had received at least one previous therapy. Among patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL), those who received ibrutinib had a response rate of 71%, according to investigator assessment, and a progression-free survival rate of 75% at 2 years.13 In this study, drug toxicity did not result in the discontinuation of ibrutinib in most patients. On the basis of early results of the phase 2 trial, we initiated a multicenter, open-label, randomized, phase 3 trial, the Study of Ibrutinib versus Ofatumumab in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (RESONATE), to compare once-daily oral ibrutinib with an active control single-agent therapy, ofatumumab, in patients with relapsed or refractory CLL or SLL.
Among patients with relapsed CLL or SLL, including those who had a short duration of response to prior therapy or who had adverse cytogenetic abnormalities, ibrutinib was superior to ofatumumab with respect to progression-free survival, overall survival, and response rate at a median follow-up of 9.4 months. The positive effect of ibrutinib was observed in subgroups of patients with a high-risk chromosome 17p13.1 deletion and with resistance to previous purine analogue therapy. Similar benefits with respect to progression-free survival were observed regardless of age, clinical stage, and factors such as status with respect to mutations in IGHV. The effect of ibrutinib on overall survival was significant, an effect that was robust despite the crossover of 57 patients to the ibrutinib group after they had disease progression while receiving ofatumumab; this effect was also observed in subgroup and sensitivity analyses.
Except for a few differences, our findings are largely similar to those of other trials of ibrutinib or ofatumumab. In each of the two groups in our study, the response rate as determined by independent assessors was lower than the response rate as determined by investigators. In the phase 2 study of ibrutinib monotherapy,13 in which response was assessed by investigators, the response rate was 71%, which is similar to the 70% response rate assessed by investigators in our study. The independently assessed response rate in the ofatumumab group in our study appears to be lower than that in the pivotal study that was based on 1996 National Cancer Institute guidelines for CLL,23 which did not require CT scanning to confirm response.24 This difference may be due in part to the requirement in our study for serial CT scanning, which was performed every 12 weeks, to confirm response. Another ofatumumab study that compared response assessment between patients who underwent CT scanning and those who did not undergo CT scanning showed substantial differences in the rates of response between the two subgroups, with lower response rates seen in the group that underwent CT scanning.25 Furthermore, the investigator-assessed response rate among patients in the ofatumumab group in our study (21%) was similar to the rate (23%) in a recent study that used 2008 criteria of the International Workshop on Chronic Lymphocytic Leukemia.26 Reassuringly, the results with respect to progression-free survival in the ofatumumab group in our study (median, 8.1 months) are similar to those in historical reports (median, approximately 6 months).5
Previous reports of ofatumumab therapy showed that patients with refractory CLL had a median survival of 12 months26 and 15 months,5 with no plateau in deaths. With a median follow-up of 9.4 months in our study, an early separation in the curves for overall survival favored ibrutinib; however, the median was not reached in either study group. At later time points, the survival curve for ofatumumab began to flatten, which may in part be a reflection of the influence of ibrutinib on patients in the ofatumumab group who crossed over to ibrutinib therapy.
Ibrutinib was associated with toxic effects that were expected on the basis of the results of phase 2 studies. It appears that the drug can be safely administered even in a heavily pretreated and elderly population with baseline coexisting conditions, such as the one in our study. In the ibrutinib group, 32% of the patients had a decreased creatinine clearance, 64% had cytopenias, and 32% had a score on the Cumulative Illness Rating Scale of more than 6 (ranging from 0 to 52, with higher scores indicating worse health status). Toxic effects did not result in frequent dose reductions or treatment discontinuations.
One strength of a randomized, controlled trial is that background disease-related complications may be differentiated from a treatment effect with a new agent. However, it is important to note that patients in the ibrutinib group had a reporting period for adverse events that was more than 3 months longer than that in the ofatumumab group (median duration, 8.6 months vs. 5.3 months), and no exposure-adjusted analysis of adverse events was performed.
The frequencies of renal complications and increased creatinine levels were similar in the two study groups. Although the overall rate of infections was higher in the ibrutinib group, the frequency of infections of grade 3 or higher did not differ significantly between the two groups. Ocular symptoms were collected proactively and were reported more frequently among patients in the ibrutinib group, including a small proportion of patients who reported blurred vision. The development of cataracts in 3% of the patients receiving ibrutinib (as compared with 1% in the control group) bears noting, since longer exposure may be associated with an increased risk.
Atrial fibrillation of any grade was noted in 10 patients in the ibrutinib group, as compared with 1 patient in the ofatumumab group, and led to the discontinuation of ibrutinib in 1 patient. Potential reasons for the higher rate of atrial fibrillation among patients receiving ibrutinib are being explored. In clinical studies in which serial electrocardiographic studies were performed, no evidence of arrhythmias was observed among patients receiving ibrutinib.13,27
An adverse event of interest with ibrutinib from early studies was major hemorrhage, including subdural hematoma. In our study, we excluded patients requiring warfarin but not those requiring other forms of anticoagulation. The rate of major hemorrhage was similar in the two study groups, with one subdural hematoma noted in a patient receiving ibrutinib. Although mild bleeding episodes were more common in the ibrutinib group, adherence to appropriate drug-withholding guidelines perioperatively and precautions regarding the use of antiplatelet agents and anticoagulants resulted in no unexpected major bleeding complications in the ibrutinib group. Further studies of the mechanism of bleeding, including bruising, that was observed among patients receiving ibrutinib have been conducted28 or are planned.
In conclusion, ibrutinib was superior to ofatumumab in difficult-to-treat patients with relapsed or refractory CLL or SLL, as measured by progression-free survival, overall survival, and response. The improvement was observed across all subgroups that were examined, including patients who were resistant to chemoimmunotherapy and those with a chromosome 17p13.1 deletion, which confirms single-agent ibrutinib as an effective therapy for CLL or SLL. Phase 3 studies examining the effect of ibrutinib in previously untreated patients with CLL or SLL are ongoing

Source: NEJM

Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell Lymphoma.


Bruton’s tyrosine kinase (BTK) is a mediator of the B-cell–receptor signaling pathway implicated in the pathogenesis of B-cell cancers. In a phase 1 study, ibrutinib, a BTK inhibitor, showed antitumor activity in several types of non-Hodgkin’s lymphoma, including mantle-cell lymphoma.


In this phase 2 study, we investigated oral ibrutinib, at a daily dose of 560 mg, in 111 patients with relapsed or refractory mantle-cell lymphoma. Patients were enrolled into two groups: those who had previously received at least 2 cycles of bortezomib therapy and those who had received less than 2 complete cycles of bortezomib or had received no prior bortezomib therapy. The primary end point was the overall response rate. Secondary end points were duration of response, progression-free survival, overall survival, and safety.


The median age was 68 years, and 86% of patients had intermediate-risk or high-risk mantle-cell lymphoma according to clinical prognostic factors. Patients had received a median of three prior therapies. The most common treatment-related adverse events were mild or moderate diarrhea, fatigue, and nausea. Grade 3 or higher hematologic events were infrequent and included neutropenia (in 16% of patients), thrombocytopenia (in 11%), and anemia (in 10%). A response rate of 68% (75 patients) was observed, with a complete response rate of 21% and a partial response rate of 47%; prior treatment with bortezomib had no effect on the response rate. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months (95% confidence interval [CI], 15.8 to not reached), the estimated median progression-free survival was 13.9 months (95% CI, 7.0 to not reached), and the median overall survival was not reached. The estimated rate of overall survival was 58% at 18 months.


Ibrutinib shows durable single-agent efficacy in relapsed or refractory mantle-cell lymphoma.

Source: NEJM


Interferon-Free Regimen for HCV Genotype 1 Infection: Closer Still.

Despite promising findings, including higher response rates with inclusion of ribavirin in a triple-therapy regimen, response rates are still too low in this group to forgo interferon.
Interferon-free regimens should be available soon for hepatitis C virus (HCV) genotype 2 infection and probably genotype 3 infection. For now, the next-generation regimen for genotype 1 infection will be shorter and more tolerable but will still include interferon.

To continue the search for an effective, interferon-free regimen for HCV genotype 1 infection, researchers conducted an industry-funded, multicenter, randomized, open-label, phase IIb study in 362 treatment-naive patients. Patients received faldaprevir (120 mg once daily) plus deleobuvir (600 mg 2 or 3 times daily) with or without ribavirin (1000–1200 mg daily) for 16, 28, or 40 weeks. The primary endpoint was sustained virologic response at 12 weeks posttreatment (SVR12).

SVR12 did not differ by treatment duration (16 weeks, 59%; 28 weeks, 59%; 40 weeks, 52%) or by deleobuvir dose (69% for twice daily and 59% for three times daily). SVR12 was higher in ribavirin users versus nonusers (59% vs. 39%, P=0.03). SVR12 rates were numerically higher in patients with genotype 1b versus 1a (range across treatment groups, 56% to 85% vs. 11% to 47%) and in patients with IL28B genotype CC versus non-CC (range across treatment groups, 58% to 84% vs. 33% to 64%). Of 75 patients with virologic breakthrough, 73 had resistant HCV variant strains. Discontinuation rates ranged from 5% to 25% across treatment groups; the most common adverse events were rash, photosensitivity, nausea, vomiting, and diarrhea.


We are getting closer to an interferon-free regimen for genotype 1 hepatitis C virus infection, but we are not there yet. Ribavirin will likely still be needed as a part of the regimen. Also, multiple interferon-free regimens might be required, with choice of regimen based on predictors of response such as genotype 1 subtype and IL28B status. Finally, until their sustained virologic response rates approach 80%, interferon-free regimens will likely only be an option for patients for whom interferon-based regimens are intolerable or contraindicated.

 Source: NEJM

Nivolumab plus Ipilimumab in Advanced Melanoma.


In patients with melanoma, ipilimumab (an antibody against cytotoxic T-lymphocyte–associated antigen 4 [CTLA-4]) prolongs overall survival, and nivolumab (an antibody against the programmed death 1 [PD-1] receptor) produced durable tumor regression in a phase 1 trial. On the basis of their distinct immunologic mechanisms of action and supportive preclinical data, we conducted a phase 1 trial of nivolumab combined with ipilimumab in patients with advanced melanoma.



We administered intravenous doses of nivolumab and ipilimumab in patients every 3 weeks for 4 doses, followed by nivolumab alone every 3 weeks for 4 doses (concurrent regimen). The combined treatment was subsequently administered every 12 weeks for up to 8 doses. In a sequenced regimen, patients previously treated with ipilimumab received nivolumab every 2 weeks for up to 48 doses.



A total of 53 patients received concurrent therapy with nivolumab and ipilimumab, and 33 received sequenced treatment. The objective-response rate (according to modified World Health Organization criteria) for all patients in the concurrent-regimen group was 40%. Evidence of clinical activity (conventional, unconfirmed, or immune-related response or stable disease for ≥24 weeks) was observed in 65% of patients. At the maximum doses that were associated with an acceptable level of adverse events (nivolumab at a dose of 1 mg per kilogram of body weight and ipilimumab at a dose of 3 mg per kilogram), 53% of patients had an objective response, all with tumor reduction of 80% or more. Grade 3 or 4 adverse events related to therapy occurred in 53% of patients in the concurrent-regimen group but were qualitatively similar to previous experience with monotherapy and were generally reversible. Among patients in the sequenced-regimen group, 18% had grade 3 or 4 adverse events related to therapy and the objective-response rate was 20%.



Concurrent therapy with nivolumab and ipilimumab had a manageable safety profile and provided clinical activity that appears to be distinct from that in published data on monotherapy, with rapid and deep tumor regression in a substantial proportion of patients.


Source: NEJM