The OBR Blog

September 30, 2014 - 11:09 am Posted in ESMO / ECC Conference Coverage comments0 Comments

By: Len Kusdra, Analyst, Clinical & Scientific Assessment, Kantar Health, Tatiana Spicakova, Consultant, Clinical & Scientific Assessment, Kantar Health, Greg Wolfe, Senior Consultant, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Senior Director, Clinical & Scientific Assessment, Kantar Health

The role of Programmed Death-1 (PD-1) pathway in suppression of antitumor immunity has become one of the hottest topics in oncology over the past couple of years. PD-1 is a key immune checkpoint receptor expressed on activated T-cells, and binding of PD-1 to its ligand (PD-L1) results in the suppression of the immune response. While the PD-1 pathway normally plays a protective role by attenuating immune-mediated destruction of healthy tissue, the pathway can be exploited by cancer cells to protect themselves from the attack by tumor-specific T-cells. A number of immune checkpoint inhibitors are in late-stage clinical development; these agents work by blocking the interaction between PD-1 and PD-L1, thereby activating the immune system against cancer cells.

PD-1 Pathway Inhibitors in Phase III Development

Drug Manufacturer Antibody Target Development Stage Ongoing pivotal trials
Keytruda Merck Humanized IgG4 PD-1 Approved in Yervoy-treated melanoma (U.S.); Phase III Melanoma, NSCLC, Head and Neck
Opdivo BMS Human IgG4 PD-1 Filed in Yervoy-treated melanoma (US/EU)

Filed in squamous 3rd line NSCLC (US/EU); Phase III

Melanoma, NSCLC, RCC, Head and Neck
MPDL3280A Roche Human IgG1 PD-L1 Phase III Bladder, NSCLC
MEDI-4736 AstraZeneca Human IgG1 PD-L1 Phase III NSCLC

For these novel immune checkpoint inhibitors, the fight to capture the lead in high-profile tumor types such as melanoma and non-small cell lung cancer (NSCLC) is becoming increasingly fierce. But their clinical development does not end there and, in fact, continues to expand into other indications, such as renal cell carcinoma (RCC), urothelial cancer, head and neck cancer, gastrointestinal cancer and hematological malignancies. Data continued to report promising activity across different tumor types at the annual 2014 European Society for Medical Oncology (ESMO), as summarized below.

Opdivo improves response rate versus chemotherapy in Yervoy-treated melanoma in a Phase III randomized trial – is its efficacy superior to the already approved Keytruda?

(Weber, Abstract LBA3)

Past oncology meetings have highlighted the promise of Opdivo™ (nivolumab, Bristol-Myers Squibb) in melanoma. Opdivo demonstrated impressive early clinical data that suggested improved overall response rate (ORR) with fewer toxicities when compared with historical data for Yervoy® (ipilimumab, Bristol-Myers Squibb), a CTLA-4 immune checkpoint inhibitor. At ASCO 2014, another anti-PD-1 monoclonal antibody, Keytruda® (pembrolizumab, Merck), took center stage with impressive Phase II data that ultimately led to its approval in the U.S. in September 2014 as therapy for Yervoy-treated melanoma patients.

Recognizing the urgency of getting to market as soon as possible, BMS submitted U.S./EU regulatory applications for Opdivo for Yervoy-treated melanoma, with expected U.S. approval in March 2015. Once Opdivo becomes approved, physicians will look to efficacy and safety data to drive their decision when choosing between the two agents. At ESMO, highly anticipated data from a randomized Phase III study (Opdivo versus chemotherapy of choice) were presented for 405 previously treated (including Yervoy) unresectable Stage III/IV melanoma patients.

The ORR was 32% for Opdivo versus 11% for chemotherapy, with benefit observed across all subgroups, including PD-L1 negative patients. Grade 3/4 toxicities were reported in 9% of patients in the Opdivo arm versus 31% in the chemotherapy arm, with no new safety signals reported. Unfortunately, the progression-free survival (PFS) and overall survival (OS) data were not yet available at the time of analysis, but duration of response among responding patients suggests prolonged benefit (3.6 months in the chemotherapy arm versus median not reached in the Opdivo arm but with 95% of responders still benefiting at six months). So how does Opdivo compare to Keytruda in this patient population? As shown below, the activity appears very similar between the drugs, and no dramatic differences exist in their safety profiles.

Efficacy in Previously-Treated Metastatic Melanoma

Opdivo (n=120) 32% 3% ND
Chemotherapy (47) 11% 0% ND
Keytruda (n=197)1 28% 2% 5.6 mos

1Ribas, Abstract LBA9000, ASCO 2014

While response rate is a valid and informative endpoint about the drug’s efficacy, PFS and OS data ultimately might help decide which of the two will become the winner. This is especially important for Opdivo’s trial, in which OS was the co-primary endpoint. Will the improved response rates translate into a statistically significant OS benefit that supports the regulatory applications? The expected answer is yes, although due to immature data we now continue to wait with bated breath for this data. While Keytruda already demonstrated that PD-1 inhibitor works in Yervoy-treated melanoma patients, the results from the Opdivo trial were significant in that it presented, for the first time, data from a randomized Phase III study. Commercially, Keytruda will have a six-month time-to-market advantage over Opdivo and will likely amass a strong foothold in the Yervoy-pretreated setting by the time Opdivo launches. Will having overall survival data from a randomized study (assuming it is available by the time of launch) sway physicians to forgo Keytruda in favor of Opdivo, or will physicians interpret a positive survival benefit for Opdivo to be a surrogate for similar expectations with Keytruda?

Is Keytruda leading the PD-1 pack in NSCLC?

(Garon, Abstract LBA43)

Safety and efficacy data for Keytruda were reported for previously treated and treatment-naive NSCLC patients enrolled in Phase I study expansion cohorts. In 262 patients, treatment-related adverse events included (any grade; Grade 3/4) fatigue (20%; <1%), pruritus (9%; 0%) and pneumonitis (4%, 2%). In 236 evaluable patients, the ORR was 21% (26% in treatment-naïve and 20% in previously treated patients).  Curiously, current/former smokers appeared to achieve a better response compared to never smokers (27% vs 9%), although the underlying reasons for this observation remain unknown. Median PFS and OS also appeared better for treatment-naïve versus previously treated patients (mPFS: 27 weeks vs. 10 weeks; mOS: not reached vs. 8.2 months).

The study evaluated whether the expression of PD-L1 biomarker correlates with outcomes. Strong PD-L1 expression was defined as 50% or higher membrane staining in tumor cells and weak expression as 1-49%. The ORR correlated with the level of PD-L1 expression (37% for strong positive, 17% for weak positive and 10% for negative). PFS was also longer for patients with strong versus weak PD-L1 expression (HR 0.52), as was OS (HR 0.59). While the efficacy certainly appears better for PD-L1 positive patients, it is not a black-and-white scenario, and many unresolved issues remain. Namely, differences exist in how the PD-L1 biomarker is measured in the different assays that the various manufactures are developing (what antibody is used), how tissue is collected (old, frozen tissue versus fresh biopsy), where it is measured (tumor cells versus tumor-infiltrating immune cells) and which cutoff threshold is used (1% versus 5% versus others). More importantly, a subset of PD-L1 negative patients still derive a benefit from these inhibitors, yet many of the pivotal trials in NSCLC are conducted in PD-L1 positive tumors. How will that affect the real-world patients, and will the biomarker-negative patients be denied treatment if the drugs receive PD-L1 positive labels (especially outside of the U.S., where payers tend to impose stricter rules)? Keytruda is exclusively targeting PD-L1 positive patients in its pivotal NSCLC trials, while BMS chose to target both PD-L1 positive patients as well as all-comers (including squamous and non-squamous histologies). If those trials are positive, perhaps the inclusion of these patients will enable BMS to have a competitive marketing edge over Keytruda.

While the data presented for Keytruda was certainly very encouraging, how does it compare with the other key competitors that are also vying to win the NSCLC space? At a first glance, it appears that the agents have similar levels of activity in terms of response rates and survival. But the data are still premature, and the efficacy and safety could start differentiating as more patients are enrolled and longer follow-up becomes available. For now, there is no clear winner in NSCLC, and it has yet to be determined whether targeting the receptor versus ligand may prove to be a more efficacious or safer strategy.




(1st line)

NSCLC ORR (pretreated) mPFS mOS
MPDL3280A1 23% (n=53) ND 23% (n=53) ND ND
MEDI-47362 16% (n=58) ND 16% (n=58) ND ND
Opdivo3 17% (n=129) 30% (n=20) 17% (n=129) 2.3 mos 9.9 mos
Keytruda4 21% (n=236) 26% (n=42) 20% (n=194) 2.5 mos 8.2 mos

1Soria, 1322P, ESMO 2014

2Brahmer, Abstract 8021, ASCO 2014

3Gettinger, Abstract 8024, ASCO 2014

4Garon, LBA43, ESMO 2014

In terms of approval timelines in NSCLC, BMS has an advantage over the other agents as it already submitted a regulatory application in the EU and a rolling submission in the U.S. for Opdivo as a third-line therapy in squamous NSCLC. The submissions were based on data from a Phase II study, and the drug could be approved in both regions next year.

Keytruda shows promising activity in gastric and urothelial cancers

Like BMS, Merck is also pursuing an aggressive development strategy for Keytruda that spans multiple tumor types. Promising preliminary results were reported at ESMO for the gastric cancer (Muro, Abstract LBA15) and urothelial cancer (Plimack, Abstract LBA23) cohorts from the KEYNOTE-012 Phase Ib study. In the gastric cancer presentation, 162 patients with recurrent or metastatic adenocarcinoma of the stomach or gastroesophageal junction (GEJ) were screened to identify 65 (40%) patients with PD-L1 positive tumors, who were then treated with 10 mg/kg Keytruda every two weeks. Keytruda showed an acceptable safety profile in 39 evaluable patients, although there was one incidence each of Grade 4 pneumonitis and Grade 5 (fatal) hypoxia. Keytruda achieved 30.8% ORR (no complete responses) and reduction in tumor size in 41% of patients. Efficacy was similar in Asian and non-Asian patients, and responses were durable. Based on these results, initiation of a Phase II trial in advanced gastric cancer is expected in in the first quarter of 2015.

In the urothelial cancer cohort, 95 patients with recurrent or metastatic cancer of the renal pelvis, ureter, bladder or urethra were screened to identify 61 (64.2%) patients with PD-L1 positive tumors. Thirty-three patients with PD-L1 positive tumors were treated with 10 mg/kg Keytruda every two weeks. Grade 3 or higher adverse events were observed in four patients and included AST increase, dehydration, neuromyopathy, macropapular rash, pruritic rash, rhabdomyolysis, thrombocytopenia, and toxic encephalopathy (n=1 for each, some patients had multiple Grade ≥3 adverse events). The ORR was 24.1% (including three complete responses), and a reduction in tumor size was observed in 64% of patients. Six of the seven responses were ongoing, and median duration of response was not reached at a median follow-up of 11 months. These promising results served as the impetus for the Phase III KEYNOTE-045 trial scheduled to begin by the end of 2014.

MPDL3280A shows promising activity in monotherapy activity in bladder, and activity in RCC in combination with Avastin, but will it succeed in CRC?

Roche/Genentech was awarded breakthrough therapy status for its MPDL3280A in urothelial bladder cancer (UBC) in May 2014. Unlike Opdivo and Keytruda, this antibody targets the ligand (PD-L1) rather than receptor, but it is too early to tell whether this strategy will translate into better efficacy and/or a better safety profile.  Perhaps recognizing the increasing crowdedness and being too late to the melanoma market, Roche’s clinical development strategy has focused on other tumor types, including NSCLC and RCC as well as the less commercially attractive (in the eyes of big pharma) urothelial/bladder space. Its first potential approved indication is likely to be bladder, in which they could file for an accelerated approval based on data from the ongoing Phase II study, thus potentially beating Keytruda to the market in the urothelial space. It would certainly give physicians the chance to become familiar with the agent in the real-world setting so that by the time the agent is approved (if successful) in larger indications, it may ease the adoption process by clinicians; being approved on the market could also aid in off-label utilization following positive Phase III data in other tumor types, bypassing a delay for supplemental regulatory approval. In terms of its activity in metastatic RCC as monotherapy, data were presented from a Phase I expansion cohort that included 69 patients (McDermott, Abstract 809O). MPDL3280A was very well-tolerated in these patients with Grade 3 or higher fatigue reported in two patients; all other adverse events were Grade 1/2.  In 62 evaluable patients,  the ORR was 20% in patients with PD-L1 expression of IHC1+/2+/3+ (including one complete and six partial responses) and 10% in patients who were PD-L1 negative (IHC0).

While the inhibitors have been primarily tested as monotherapy, the next wave of trials will examine their efficacy in combination with other regimens, such as chemotherapy, targeted therapy and other immune modulators. Not surprisingly, Roche has already begun the clinical development of MPDL3280A in combination with Avastin® (bevacizumab) and reported preliminary data from a Phase Ib study (Lieu, Abstract 1049O). The study had two arms: Arm A (n=35) evaluated MPDL3280A IV every three weeks plus Avastin 15mg/kg IV every three weeks; Arm B (n=36) evaluated MPDL3280A IV every two weeks plus Avastin 10mg/kg every two weeks and FOLFOX. Dose expansion cohorts in Arm A included patients with colorectal cancer (CRC) and other solid tumors, including breast, melanoma, NSCLC and RCC; Arm B included oxaliplatin-naïve CRC (with or without liver lesions) as well as other solid tumors, including RCC and breast cancer. In Arm A, the combination with Avastin achieved 40% ORR in the first-line RCC cohort (n=10) and 8% ORR in CRC patients. In Arm B, the combination with Avastin plus chemotherapy achieved 36% ORR in CRC.

Avastin plus chemotherapy has been a blockbuster regimen in the treatment of CRC, so it is not surprising that Roche is pushing the combination with its PD-L1 inhibitor. Notably, initial data from Opdivo’s Phase I trial did not show activity in CRC (or prostate cancer), so CRC has not been on the forefront of pivotal studies for other PD-1 inhibitors. While the 36% ORR is certainly encouraging, one must question how much of it was contributed by Avastin plus chemotherapy alone. The response rate appears similar to that observed in pivotal trials for Avastin plus chemotherapy, so the early readout seemed perhaps a bit underwhelming.

But the response rate may not be the best endpoint to evaluate the efficacy of the combination regimen as immunotherapy does not always follow the standard response kinetics and can be associated with delayed responses. So it is still possible that longer follow-up might show improved survival, but will it produce truly stellar results as we have seen so far for the combination of two checkpoint inhibitors in melanoma (Sznol, Abstract LBA9003, ASCO 2014)? In the absence of randomized data, it is difficult to say whether this combination will pan out in CRC. The data in RCC, on the other hand, appear much more promising for the Avastin combination, although the number of patients was small. Avastin has shown efficacy as monotherapy in frontline RCC by achieving approximately 13% ORR, so the reported 40% ORR when combined with PD-L1 inhibitor provides encouraging evidence that the improved efficacy is driven by the addition of MPDL3280A. The activity of the combination regimen certainly appears higher compared to MPDL3280A alone, as discussed above, and might be the strategy going forward, although no such plans have been announced yet. It certainly would help Avastin garner greater utilization in RCC, where it is approved but not a key competitor. However, MPDL3280A plus Avastin will find itself competing with Opdivo, which is currently being studied in combination with Yervoy as first-line therapy for RCC in a head-to-head trial versus Sutent® (sunitinib, Pfizer).

The amount of data presented at ESMO on the role of immune checkpoint inhibitors was impressive and quite overwhelming. It has become very clear that PD-1 targeted drugs are considered a major breakthrough in oncology with the promise to make a meaningful impact in the lives of patients with various malignancies. To date, data has focused on their activity in solid tumors, but we expect to see the first sets of data for these agents in hemtatologic malignancies at the upcoming American Society of Hematology (ASH) conference. It is the beginning of exciting times in oncology and we can all sit back and enjoy the fight for the PD-1 space spanning multiple tumors.

September 29, 2014 - 10:09 am Posted in ESMO / ECC Conference Coverage comments0 Comments

By: Len Kusdra, Analyst, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Senior Director, Clinical & Scientific Assessment, Kantar Health

The introduction of Herceptin® (trastuzumab, Roche/Genentech) over a decade ago turned HER2+ metastatic breast cancer (MBC) from what was once a patient population with poor prognosis to one with a vastly improved outlook and led the way for an influx of targeted therapies for this population. Now, the armamentarium against HER2+ MBC has expanded and includes several HER2-targeted agents: Tykerb® (lapatinib, GSK), Perjeta® (pertuzumab, Roche/Genentech) and Kadcyla® (ado-trastuzumab, Roche/Genentech). Updated overall survival (OS) data from the CLEOPATRA (NCT00567190) trial were presented at the Presidential Symposium at ESMO on September 28, 20141, and the results will serve to further solidify Roche as the dominant player in HER2-targeted treatment in MBC, if there was any doubt before now. The CLEOPATRA trial was designed to test whether the combination of Herceptin, Perjeta and docetaxel improved outcomes in first-line HER2+ MBC patients. The study randomized 808 patients to receive Hercpetin plus docetaxel plus either placebo or Perjeta. The primary endpoint was progression-free survival (PFS), and secondary endpoints included OS, PFS as assessed by the investigator, overall response rate and safety.

The initially published results2 in 2012 showed an improvement in PFS from 12.4 months in the control group to 18.5 months in the Perjeta group (HR=0.62; 95% confidence interval (CI), 0.51-0.75; P<0.001). The objective response rate was 69.3% in the control group and 80.2% in the Perjeta group (95% CI, 4.2-17.5; P = 0.001). These significant positive results led to FDA approval in 2012 and European approval in 2013 for Perjeta in combination with Herceptin and docetaxel as first-line treatment in HER2+ MBC. At the time, however, the data was not yet mature to determine OS, and many were left wondering whether the impressive improvement in the primary endpoint of PFS would translate into an equally significant improvement in OS.

Final results of CLEOPATRA did not disappoint. With a median follow-up of 50 months (range 0-70 months), addition of Perjeta to Herceptin plus docetaxel provided a 15.7-month improvement in OS compared with patients who received Herceptin, docetaxel and placebo (mOS: 56.5 months in the Perjeta arm vs. 40.8 months in the placebo arm; HR=0.68, 95% CI 0.56-0.84, p=0.0002). Updated PFS data were similar to what was published in 2012, with a slight increase in PFS in the Perjeta arm (18.7 months vs. 12.4 months, HR=0.68, p<0.0001). The toxicity profiles between the arms were similar and manageable, with the Perjeta arm experiencing a higher rate of Grade 3 febrile neutropenia (13.7% vs. 7.6%) and diarrhea (9.3% vs. 5.1%). The significant improvement in OS now solidifies Perjeta plus Herceptin and docetaxel as the new standard care in first-line MBC patients.

So what is next? According to Kantar Health’s CancerMPact® Treatment Architecture, Perjeta has already benefited from a significant penetration into the first line setting, with use in one-third of U.S. patients in the year after its launch.3 The question that arises is, can we improve even further on these results, and can we do it by eliminating chemotherapy altogether? One intriguing piece of data presented  was the duration of study treatment: While the number of cycles of docetaxel remained the same at eight cycles (range: 1-42 cycles for the placebo arm and 1-52 cycles for the Perjeta arm), the duration of study treatment was extended with the addition of Perjeta from 11.4 months (range: 0.1-66.3 months) in the placebo arm to 17.4 months (range: 0.1-67.7 months) in the Perjeta arm, raising the possibility of prolonged Perjeta and Herceptin combination even after ending the docetaxel portion of the study treatment. The possibility of removing chemotherapy and replacing it with targeted therapy alone has been the Holy Grail in the oncology field ever since Herceptin revolutionized the way MBC is treated. In that vein, the MARIANNE (NCT01120184) study is looking to do just that by examining whether Perjeta and Kadcyla are more efficacious than Herceptin plus Perjeta and a taxane (paclitaxel or docetaxel). In essence, Kadcyla would provide both the targeted therapy and the microtubule-disrupting activity provided by taxanes. Results from this study would certainly provide further impetus for a paradigm shift of complete elimination of chemotherapy in first-line MBC. Results from MARIANNE are expected before the end of this year. Until then, the results from the CLEOPATRA trial provide great hope for patients in a disease that had few options over a decade ago and opens the door for the development of novel and more potent combination therapies in what was once an intractable disease. These are exciting times indeed.


  1. Swain et al. Abstract 350O ESMO 2014
  2. Baselga et al. NEJM 2012
  3. Kantar Health, CancerMPact, Treatment Architecture United States, accessed September 28, 2014

September 29, 2014 - 09:09 am Posted in ESMO / ECC Conference Coverage comments0 Comments

By: Mara Jeffress, Associate Consultant, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Senior Director, Clinical & Scientific Assessment, Kantar Health

Head and neck cancer patients tend to receive chemotherapy doublets with or without the only approved targeted agent, the EGFR antibody Erbitux® (cetuximab, Bristol-Myers Squibb/Lilly/Merck Serono) as first-line therapy. Up to 90% of squamous cell carcinoma of the head and neck (SCCHN) patients have a tumor with EGFR aberrations, and according to Kantar Health’s CancerMPact® Treatment Architecture United States, in 2013 38% of chemotherapy-naïve SCCHN patients received Erbitux as part of their first-line therapy for advanced disease. Erbitux may also be used in second-line, with approximately one-fifth of patients receiving Erbitux monotherapy and another one-fifth receiving Erbitux in combination with chemotherapy.

The use of Erbitux in multiple lines belies the large unmet need for relapsed or refractory patients, whose median overall survival ranges from three to six months (Machiels, Abstract LBA29, ESMO 2014). In addition, less than half of patients who receive a first-line therapy go on to receive a second line of therapy.1 Several other EGFR-directed agents have been tested in SCCHN, including Vectibix® (panitumumab, Amgen), zalutumumab (Genmab), Iressa® (gefitinib, AstraZeneca), and Tykerb® (lapatinib, GlaxoSmithKline). All have failed to improve survival in Phase III trials. Gilotrif® (Giotrif® in Europe, afatinib, Boehringer Ingelheim), an oral small molecule that inhibits EGFR, HER2 and HER4, is currently approved in non-small cell lung cancer (NSCLC) and is vying for a spot in SCCHN.

The LUX-Head & Neck 1 trial of Gilotrif in 474 second-line SCCHN patients who had progressed on platinum treatment advanced the field at this year’s European Society for Medical Oncology (ESMO) meeting2 by being the first positive trial of a novel targeted agent since the pivotal Erbitux EXTREME trial.3 The LUX-Head & Neck 1 trial stratified patients 2:1 to receive either Gilotrif (40 mg daily, oral) or methotrexate (40 mg/m2, IV weekly), and patients were stratified by ECOG status (0 vs. 1) and prior EGFR inhibitor use. Median progression-free survival (PFS) was significantly improved in the Gilotrif arm (2.6 vs. 1.7 months, HR=0.80, p=0.030), as was overall response rate (ORR; 10.2 vs. 5.6%) and disease control rate (DCR; 49.1 vs. 38.5%). There was no significant difference in overall survival (median OS 6.8 vs. 6.0 months, HR=0.96, p=0.7). Patient-reported outcomes and quality-of-life measures favored Gilotrif. In addition, Gilotrif was less toxic with fewer dose reductions (32% vs. 42%), discontinuations (7% vs. 16%) and fatal events (0.6% vs. 3%). As expected, adverse events characteristic of EGFR inhibitors were higher in the Gilotrif arm (all grade rash 74% vs. 8%; Grade 3/4 rash 10% vs. 0%; all grade diarrhea 72% vs. 12%; Grade 3/4 diarrhea 10% vs. 2%). In the methotrexate arm stomatitis (39% vs. 43%), fatigue (25% vs. 32%) and neutropenia (<1% vs. 19%) were higher.

Subgroup analysis from LUX-Head & Neck 1 suggests that patients who are HPV p16-negative and who have not received prior Erbitux are more likely to respond to Gilotrif, and prior Erbitux in 60% of the enrolled patients may have negatively biased the trial. How much better would the efficacy outcomes have been if patients had been preselected to be HPV-negative? With such a high number of patients being treated with Erbitux in front-line, would it have been possible to quickly enroll such a trial? Perhaps, as was suggested by the discussant, Dr. Seiwert, there are other biomarkers that might help refine which patients benefit the most from Gilotrif?

The suggestion that prior treatment with Erbitux negatively biased overall survival outcomes in this trial may be a biologically sound rationale, but it is clinically irrelevant since Erbitux is an approved drug used in a large proportion of patients with advanced disease. This outcome may speak to acquired resistance to EGFR inhibition, which is an inherent risk to developing a drug with a similar mechanism of action in the relapsed/refractory setting. That PFS was significantly improved despite the majority of patients having received prior Erbitux suggests they were not completely resistant, that Gilotrif remains active in Erbitux-resistant clones, or that the mechanisms of action of these two drugs (monoclonal antibody vs. tyrosine kinase inhibitor) differ sufficiently to confer response when used in sequence.

Similar outcomes have been observed with other EGFR inhibitors studied in the platinum-pretreated advanced SCCHN setting: Zalutumumab significantly improved PFS but not overall survival compared with best supportive care,4 and Iressa improved response rate but not PFS or overall survival when compared with methotrexate.5 The lack of overall survival benefit in LUX-Head & Neck 1 is concerning since there are so few effective options in this disease; one would expect that an active agent could have an impact on overall survival. The FDA may take a similar stance, requiring an overall survival benefit for approval, although other regulatory authorities (such as the European Medicines Agency) may be more willing to approve a drug with a PFS benefit alone.

If approved, Gilotrif will compete directly with Erbitux in platinum-pretreated patients in the U.S., although ex-U.S. it will be largely unchallenged due to lack of approval of Erbitux in second-line. In the U.S., Erbitux will have nearly a decade head start over Gilotrif, although Gilotrif could have the advantage of being the first marketed drug to show a PFS benefit in a randomized trial in this setting (Erbitux was approved in the U.S. based on a single-arm study). A comparison of the available data suggests that Gilotrif has similar efficacy in second-line as Erbitux; in 103 platinum-resistant second-line patients, Erbitux demonstrated a 2.3-month time to progression and a 12.6% response rate.6 With physicians being so familiar with Erbitux, would they be willing to switch to Gilotrif given the available data? The fact that Gilotrif is an oral agent will help it differentiate itself. However, given the higher co-pays required for oral agents in the United States, patients’ pocketbooks may disagree. At this time, no head-to-head trials of Erbitux vs. Gilotrif are planned.

The LUX-Head & Neck 1 trial results are the first to report as part of the larger LUX-Head & Neck program, which includes a companion trial of similar design conducted in Asian patients (LUX-Head & Neck 3), as well as two studies evaluating Gilotrif as post-remission therapy in locally advanced SCCHN (LUX-Head & Neck 2 and 4). It’s encouraging that PFS was improved in this first trial to report, and confirmation of activity in these other trials could go a long way to establish the degree of clinical benefit that Gilotrif confers in SCCHN and form a foundation upon which it may become adopted into clinical practice for this disease.


  1. Kantar Health, CancerMPact® Treatment Architecture US, accessed September 28, 2014
  2. Machiels, Abstract LBA29, ESMO 2014
  3. Vermorken, NEJM, 2008
  4. Machiels, LBA5506, ASCO 2010
  5. Stuart, JCO, 2009
  6. Vermorken, JCO, 2007

September 18, 2014 - 08:09 am Posted in Featured comments0 Comments

SAN FRANCISO, CA – The 56th Annual Meeting of the American Society for Radiation Oncology (ASTRO) was in high gear this week. A record number of abstracts were submitted (n=2874); 2370 abstracts were presented, among these were 364 oral scientific sessions. More than 10,000 people from around the world attended the meeting, according to 2014 ASTRO President, Bruce T. Haffty, MD.

At the opening press conference, Dr. Haffty highlighted three important initiatives of ASTRO – participation in the ABIM’s Choosing Wisely® campaign, the Stereotactic Radiosurgery (SRS) patient registry, and the Radiation Oncology Incident Learning System (RO-ILS).

ASTRO unveiled its second list of 5 radiation treatments to question for routine use as part of Choosing Wisely®; these treatments/procedures should be thoroughly discussed by physicians with their patients to ensure appropriate use.

In 2013, ASTRO issued its first list of 5 such treatments, and the good news is that this effort is beginning to pay off in clinical practice, conserving resources for appropriate use, informed Dr. Haffty.

To find all 10 treatments that should be questioned before prescribing them go to:

The Stereotactic Radiosurgery (SRS) patient registry is a partnership between ASTRO and the American Association of Neurologic Surgeons (AANS). SRS purports to gather data from 30 diverse high-volume sites, with data specific to SRS, over the next 3 years. This national registry will define patterns of care in radiosurgery, and hopefully support informed decision-making to improve outcomes and possibly lower the costs of care for patients.

The RO-ILS program sponsored jointly by ASTRO and the American Association of Physicists in Medicine (AAPM) is a patient-safety initiative that is the centerpiece of ASTRO’s Target Safely plan.  Radiologists are invited to submit data on radiation mishaps anonymously to give the radiation community a heads-up about potential problems and enable detection of patterns of safety.

“The anonymity provides confidentiality and creates a secure environment,” Dr. Haffty said. “Radiation is an extremely safe modality. Nonetheless, we want to strive for zero errors and review mistakes.”

Selected highlights from the Clinical Trials session include the following:

  • A study showing that radiation therapy was as effective as chemoradiation in reducing the incidence of dysphagia for patients with advanced esophageal cancer in the palliative setting (Abstract CT-03). This finding suggests that this patient population can avoid chemotherapy, its side effects and costs.
  • Convincing evidence showed that adding thoracic radiotherapy to prophylactic whole brain irradiation extends survival and reduces local recurrence in patients with advanced small-cell lung cancer (Abstract CT-05).
  • A very large study of more than 41,000 patients found that radiation improves 10-year survival by 50% in patients with early stage Hodgkin’s disease, yet radiation remains highly under utilized in this population in the U.S. (Abstract CT-08).  Medical oncologists are apparently not suggesting radiation because of perceived fears about long-term side effects.
  • Hypofractionated whole breast irradiation reduces acute toxicity and long-term fatigue compared with conventional fractionation in patients with stage 0-II breast cancer undergoing breast conserving therapy (Abstract LBA 3). Again, fears of side effects with a more concentrated dose of radiation delivered over a shorter time period have limited adoption of hypofractionated regimens.

Highlights of the Plenary Session

This included a talk centered on the ability of radiotherapy to induce antigen-specific immune responses when combined with anti-PD-1 blockade (Abstract PL-01). These preclinical data were selected for prime time presentation because of the intense interest in immunotherapy in the oncologic community with the recent successes in advanced melanoma.

Another Plenary Session talk showed that 28 months of androgen deprivation therapy (ADT) combined with high-dose radiation therapy improved biochemical control rates and survival compared with only 4 months of ADT plus high-dose radiation in patients with intermediate and high-risk localized prostate cancer. (Abstract PL-02). The benefit of prolonged ADT was seen mainly in high-risk patients.

This study adds to evidence that longer than 6 months or 1 year of ADT is needed to reap the survival benefits of this difficult-to-tolerate therapy.  A separate study, not presented at the plenary, showed that 18 months of ADT was just as effective as 36 months and improved quality of life when combined with radiation in this setting (Abstract 24). The optimal duration of ADT plus radiation remains to be established with certainty, but for now, longer than 12 months is better.

A separate Plenary Session presentation demonstrated that one high-dose of radiation therapy was as effective as more frequent lower doses of radiation in preserving mobility in patients with malignant spinal cord compression who cannot undergo decompression surgery (Abstract LBA 2). These patients have a miserable prognosis, with a neurological deterioration-free survival time of 1.4 months and an overall survival of just 4 months.

Other news of note is the development of a 10-gene signature to predict radiation sensitivity in a variety of solid tumors. This signature is treatment-specific rather than disease-specific, as distinct from genetic signatures for OncotypeDX or MammaPrint assays.

The signature was the subject of 10 presentations at ASTRO, and featured at a Panel Discussion (Abstracts 2463 2224, 2615, 1246, 2649, 2899, 3633, 3916, 1420, 1031, and 2873).

So far, the genetic signature has been tested and correlated with clinical outcomes in rectal, lung, esophageal, and brain cancer, as well as and metastatic colorectal and prostate cancers.

The signature is the brainchild of Javier Torres-Roca, MD, Moffitt Cancer Center in Tampa, FL, and it took 11 years to develop, he said. He believes the signature will be clinically actionable – showing that higher doses of radiation are needed in resistant patients (according to the signature) and reducing radiation doses in sensitive patients.

The signature is a joint venture with the NCI, Moffitt Cancer Center, and the Asan Medical Center in Korea. A company called CvergenX, founded by Dr. Torres-Roca and colleague Stephen Eschrish, PhD, has the license to market it, once it is CLIA or FDA approved.

By John McCleery

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