
Jason Harris has worked in journalism for more than 20 years, including stints at daily newspapers and niche publications for oncology and cardiology. He is a senior editor for 

 and the annual Giants of Cancer Care® album. He also contributes to the OncLive On Air and OncFellows podcasts. Email: 

Treatment with the PD-1 inhibitor nivolumab (Opdivo) resulted in an overall response rate (ORR) of 24.3% in previously treated patients with squamous cell carcinoma of the anal canal (SCCA), according to findings from a single-arm phase II trial published in 

At a median follow-up of 10.1 months (95% CI, 9.4-12.2), 2 patients had a complete response and seven others had partial responses. Seventeen patients had stable disease and 8 patients experienced progressive disease. Three patients were not evaluable for response. The median overall survival (OS) was 11.5 months (95% CI, 7.1 to not estimable) and the estimated 1-year OS rate was 48% (95% CI, 32-74).

“These are previously-treated patients and there’s no established standard of care, so to have a single agent have activity with very few toxicities is quite exciting for this patient population,” co-author Cathy Eng, MD, professor of gastrointestinal medical oncology at MD Anderson Cancer Center, said in an interview with 

. “This patient population doesn’t get a lot of recognition. Rare cancers are often overlooked, not just this one.”

Eng said 10% to 20% of patients present with advanced SCAA and a similar number will progress to metastatic disease. Moreover, incidence is increasing by as much as 2% annually in Western countries.

 was willing to publish a small phase II trial in a rare cancer is recognition of the fact that there is an unmet need to find treatment options for these patients,” she added.

The phase II study (NCI9673) was conducted at 10 US academic centers. Eligible patients were immunotherapy-naïve, but had received prior treatment.

Four of the first 12 participants had partial response in the first stage of the of the study. That allowed researchers to recruit 25 additional patients for the second stage. Patients were assigned to 3 mg/kg IV of nivolumab every 2 weeks, and received a median of 6 doses. A total of 37 patients received at least one dose of nivolumab and were included in these findings.

median progression-free survival (PFS) was 4.1 months (95% CI, 3.0-7.9), up slightly from the 3.9 months reported initially. The 6-month PFS rate was 38% (95% CI, 24-60). Researchers noted that the longest duration of treatment was almost 1 year and was continuing as of the data cutoff date of May 2016.

Seven (78%) of the 9 responding patients had durable responses, with a median duration of 5.8 months (IQR, 3.9—8.1). As of the data cutoff, six responding patients remained on study. The longest ongoing duration of response of 10.4 months. Two patients were HIV-positive, one of whom had partial radiographic response. Among the responders, the median reduction from baseline in target lesions was 70% (IQR, 57-90).

By immunohistochemistry, responders had higher baseline percentages of T cells expressing CD8 and granzyme B than did nonresponders. Responding patients also had higher concentrations of PD-1 in immune cells in the tumor microenvironment compared with nonresponders. Furthermore, responders were more likely to express PD-1 in tumor cells.

Researchers observed grade 3 toxicities in 5 patients; 2 patients experienced anemia, and 1 patient each had grade 3 fatigue, rash, and hyperthyroidism. Researchers recorded a single incidence of grade 2 pneumonitis, and there were no unexpected serious adverse events in patients with HIV. There were no treatment-related deaths recorded in the study, but 43% of patients died due to progression.

Eng said this study is being amended to become a larger randomized study. Researchers hope to begin enrollment within 3 months.

Writing in an accompanying editorial, Stefano Cascinu, MD, PhD, with the Università di Modena e Reggio Emilia in Modena, Italy, praised the researchers for their results and said the study raises as many good questions as it answers.

“Much is unknown about using immunotherapy for the treatment of SCCA: how can we select patients who will benefit? How can other patients be made sensitive to these drugs? And what role might nivolumab have in the treatment of locoregional disease together [with] chemoradiotherapy?” he wrote. “Even so, Morris and colleagues have shown that nivolumab seems to benefit a quarter of patients. For the first time in 20 years, there is something new in the treatment of SCCA.”

Morris VK, Salem ME, Nimeiri H, et al. Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): a multicentre, single-arm, phase 2 study.

van der Zee RP, Richel O, de Vries HJC, Prins JM. The increasing incidence of anal cancer: can it be explained by trends in risk groups? 

Cascinu S. Anal cancer: from an orphan disease to a curable malignancy? 

doi: http://dx.doi.org/10.1016/S1470-2045(17)30091-8.

Articles

According to findings from a single-arm phase II trial, treatment with the PD-1 inhibitor nivolumab (Opdivo) resulted in an overall response rate of 24.3% in previously treated patients with squamous cell carcinoma of the anal canal.

Nivolumab Effective in Advanced Anal Cancer

Women with the HER2-enriched subtype of early-stage, HER2-positive breast cancer were more likely to have a pathological complete response (pCR) when treated with dual HER2-blockade, according to results from the PAMELA trial published in 

Among 151 women in the nonrandomized, open-label PAMELA study who had a pCR when treated with lapatinib (Tykerb) and trastuzumab (Herceptin), 41% (41/101) had the HER2-enriched subtype as compared with just 10% (5/50) who who had one of the other subtypes (odds ratio [OR] = 6.2; 95% CI, 2.3-16.8; 

 = .0004). The PAMELA findings were initially reported at the 2016 San Antonio Breast Cancer Symposium.

“This is one of the first studies to prospectively test the ability of a genomic biomarker to predict response to anti-HER2 therapy,” lead researcher Aleix Prat, MD, PhD, said in an interview with

. “Our results show that patients exquisitely sensitive to anti-HER2 therapies without chemotherapy can be identified.”

Prat, who is head of medical oncology at August Pi i Sunyer Biomedical Research Institute in Barcelona, Spain, added that the presence of the HER2-enriched subtype was not yet strong enough to guide treatment decisions, but could be effective when used in concert with other markers.

“Combining information such as subtype (HER2-enriched vs not), response at week 2 and response at surgery (pCR versus not), might help us identify these patients that are exquisitely sensitive to anti-HER2 therapies and do not need chemotherapy,” said Prat.

He went on to say that researchers are also trying to understand why most women with the HER2-enriched subtype (59%) did not respond strongly to the HER2 blockade. “We know there is still biological heterogeneity even within a subtype. For example, a subset of HER2-enriched tumors has 

 mutations, a potential biomarker of response. Thus, we are currently working on analyzing this biological heterogeneity within HER2-enriched to identify additional biomarkers of response beyond subtype.”

From October 2013 to November 2015, researchers for the PAMELA trial recruited 151 women at 19 hospitals in Spain. All patients were diagnosed with previously untreated, centrally confirmed HER2-positive, stage I to IIIA invasive breast cancer.

Patients were assigned to a loading dose of 8 mg/kg of IV trastuzumab followed by 6 mg/kg of IV trastuzumab every 3 weeks, along with 1000 mg daily oral lapatinib for 18 weeks, followed by surgery 1 to 3 weeks after last dose. Patients with HR-positive disease were also treated with letrozole or tamoxifen, depending on menopausal status and all patients were recommended to receive postoperative chemotherapy.

Using PAM50 gene expression profiling, researchers performed intrinsic subtyping at baseline and at week 2, and patients underwent a mandatory ultrasound at week 6. Patients who experienced any increase in tumor size were assigned to paclitaxel at 80 mg/m

 weekly for 12 weeks. Trastuzumab was maintained at the original dosage and lapatinib was reduced to 750 mg daily. Endocrine therapy was stopped before initiating chemotherapy in patients with progressive disease.

Tumors were classified as 1 of 5 intrinsic molecular subtypes—luminal A, luminal B, HER2-enriched, basal-like, and normal-like. About two-thirds of patients had the HER2-enriched subtype at baseline and a total of 101 women were positive for the subtype. Fifty women in the study were positive for 1 of the 4 other subtypes.

In multivariate analysis, OR was 4.0 (95% CI, 1.3-12.5;

 = .016) for pCR among patients with the HER2-enriched subtype compared with patients with non-HER2—enriched subtypes.

Researchers expected more women with the subtype to have pCR, but the absolute difference between the 2 groups (31%) was higher than the preplanned threshold (27%). Of 22 patients with luminal A subtype at baseline, none had a pCR. Only 11% of patients with basal-like disease at baseline achieved a pCR, though they also had HR-negative disease.

Prat said that researchers in Barcelona are currently working with the Translational Breast Cancer Research Consortium group in the United States to design a prospective trial demonstrating that a subset of patients with HER2-positive disease can be cured following anti-HER2 therapies without the need of chemotherapy. In an accompanying editorial, Aju Mathew, MD, and Adam Brufsky, MD, PhD, wrote that the existing data is not yet strong enough to recommend eliminating chemotherapy for all patients with HER2-positive breast cancer, but deintensification of therapy is a goal worth pursuing.

“Results of the PAMELA trial provide valuable insights into how such a regimen can be used in patients who prefer a non-chemotherapeutic option or in those who are poor candidates for chemotherapy,” they wrote. “Results of the PAMELA trial shed light into the type of tumors that would need only HER2 blockade to achieve pathological complete response…Pathological complete response is an effective surrogate marker for improved survival outcomes, and further trials assessing intrinsic molecular subtypes are justified. These trials should contribute substantially to the study of treatment de-intensification in patients with early-stage HER2-positive breast cancer.”

Llombart-Cussac A, Cortés J, Paré L, et al. HER2-enriched subtype as a predictor of pathological complete response following trastuzumab and lapatinib without chemotherapy in early-stage HER2-positive breast cancer (PAMELA): an open-label, single-group, multicentre, phase 2 trial. 

Mathew A, Brufsky A. Less is more? De-intensification of therapy for early-stage HER2-positive breast cancer. 

According to results from the PAMELA trial, women with the HER2-enriched subtype of early-stage, HER2-positive breast cancer were more likely to have a pathological complete response when treated with dual HER2-blockade.

HER2-Enriched Subtype Predicts Response to Dual HER2 Blockade in Early Breast Cancer

Pembrolizumab (Keytruda) showed durable, clinically significant responses in patients with locally advanced head and neck cancer who were refractory to platinum-based chemotherapy and cetuximab (Erbitux), according to results from the single-arm, phase II KEYNOTE-055 study published online in the 

Across the study, the overall response rate (ORR) was 16% (95% CI, 11-23) with the PD-1 inhibitor, including 1 complete response, 27 (16%) partial responses, and 33 (19%) patients with stable disease. Eighty-seven patients (51%) had progressive disease. Compared with baseline, target lesions shrank in half of evaluable patients.

Response rates were also similar regardless of HPV status. The ORR was 16% in HPV-positive patients and 15% in HPV-negative patients.

, lead study author Joshua M. Bauml, MD, said that the prognosis is poor for patients with head and neck cancer who are refractory to both platinum-based chemotherapy and cetuximab. There are no FDA-approved treatments for this patient population and methotrexate, the most commonly used treatment, only has a response rate of around 5%.

“As such, a response rate of 16% is quite exciting,” said Bauml, an assistant professor of Hematology/Oncology and co-deputy director for the Lung/Head and Neck Medical Oncology Clinical Research Program in the Abramson Cancer Center at the University of Pennsylvania. “It is even more exciting when you consider the fact that this is a similar response rate to what was seen in KEYNOTE-012 and CHECKMATE-141, where patients were less heavily pretreated. For a select group of patients, we are seeing that pembrolizumab has activity, regardless of pretreatment status.”

KEYNOTE-012 showed an 18% response rate for pembrolizumab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck; however, no specific prior treatments were required for enrollment in KEYNOTE-012.

 Based on the KEYNOTE-012 data, the FDA approved pembrolizumab in August 2016 as a treatment for patients with recurrent or metastatic head and neck squamous cell carcinoma following progression on a platinum-based chemotherapy.

In CHECKMATE-141, the PD-1 inhibitor nivolumab (Opdivo) improved overall survival (OS) by 30% (HR, 0.70; 97.73% CI, 0.51-0.96; 

 = 0.01) versus investigator’s choice standard of care in patients with recurrent squamous-cell carcinoma of the head and neck whose disease had progressed within 6 months after platinum-based chemotherapy.

 The ORR in the nivolumab arm was 13.3%. Based on these findings the FDA approved nivolumab in this setting in August 2016.

KEYNOTE-055 enrolled 228 patients between October 24, 2014, and September 23, 2015. Enrollees had been diagnosed with recurrent or metastatic head and neck cancer, and the majority had experienced disease progression within 6 months of treatment with platinum and cetuximab. Three-quarters of patients had received at least two prior lines of therapy in the metastatic setting.

Overall, 171 participants received at least 1 dose of pembrolizumab. The PD-1 inhibitor was administered at 200 mg every 3 weeks. Patients were assessed through imaging every 6 to 9 weeks. Patients received pembrolizumab for a median of 90 days (range, 1-401). The primary endpoints were ORR and safety.

Median progression-free survival (PFS) was 2.1 months (95% CI, 2.1-2.1) in all patients, regardless of HPV status. The overall 6-month PFS rate was 23%, including 25% in HPV-positive patients and 21% in HPV-negative patients.

Median OS was 8 months (95% CI, 6-11) in all patients. The overall 6-month OS rate was 59%, including 72% in HPV-positive patients and 55% in HPV-negative patients. The median duration of response was 8 months (range, 2+ to 12+);. At the April 2016 data cutoff 75% of responses were ongoing and 21% of patients were still receiving pembrolizumab treatment.

“It is particularly notable that patients in KEYNOTE-055 had prolonged responses, given that increasing lines of therapy are generally associated with worse outcomes in oncology,” the researchers wrote. “Pembrolizumab may therefore lead to significant improvements in outcomes for some patients, regardless of prior treatment with platinum and cetuximab.”

Researchers retrospectively evaluated the presence of PD-L1 using an investigational version of the PD-L1 IHC 22C3 pharmDx assay. Most patients (82%) were PD-L1 positive as determined by combined positive score (CPS) ≥1, and 28% of PD-L1-positive patients had a CPS ≥50%.

Response rates were similar regardless of PD-1 expression. Using the 1% CPS cutoff, the ORR was 18% (95% CI, 12-25) in PD-L1—positive patients and 12% (95% CI, 2-30) in PD-L1–negative patients. When the CPS was analyzed to 50% based on raw scores, the ORR was 27% (95% CI, 15-42) in patients with CPS ≥50% and 13% (95% CI, 7-20) in patients with CPS <50%. The 1 complete response recorded in the study occurred in a patient with a CPS of ≥50%.

Six-month PFS rates in PD-L1—positive patients were 24% (CPS ≥1%) and 31% (CPS ≥50%) compared with 20% for patients with either CPS <1% or CPS <50%. Six-month OS rates were 59% (CPS ≥1%) and 60% (CPS ≥50%) for PD-L1–positive patients compared with 56% (CPS <1%) and 58% (CPS <50%) for PD-L1–negative patients.

“Six- and 12-month progression-free and overall survival rates were relatively similar between PD-1 negative and positive patients, highlighting the clear limitation with this selection marker,” Amanda Psyrri, MD, PhD, chief of Medical Oncology and assistant professor of Medicine at National Kapodistrian University of Athens Medical School, said in an accompanying podcast. “Excluding such patients from potentially life-prolonging treatments on the basis of PD-1 expression remains a clinical and ethical dilemma.”

Bauml acknowledged that physicians need a better biomarker for this disease.

“The problem is that PD-L1, given its heterogeneous and dynamic nature, is simply not an ideal biomarker,” he said. “Current research efforts are underway to identify better ones, including mutational load and gene expression profiling.”

Two-thirds of patients reported treatment-related adverse events (AEs) of any grade. The most common all-grade AEs included fatigue (18%), hypothyroidism (9%), nausea (6%), AST increase (6%), and diarrhea (6%).

Bauml JM, Seiwert TY, Pfister DG, et al. Pembrolizumab for platinum- and cetuximab-refractory head and neck cancer: results from a single-arm, phase II study. 

Seiwert TY, Burtness B, Mehra R, et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. 

Ferris RL, Blumenschein G Jr, Fayette J, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. 

Twenty-six patients (15%) experienced a grade 3 or higher AE. The only immune-mediated AEs of any grade or treatment attribution reported in 2% or more of patients were hypothyroidism (16%), pneumonitis (4%), and hyperthyroidism (2%). Seven patients (4%) left the study due to treatment-related AEs, and 1 patient died of treatment-related pneumonitis.

Pembrolizumab has shown durable, clinically significant responses in patients with locally advanced head and neck cancer who are refractory to platinum-based chemotherapy and cetuximab, according to results from the single-arm, phase II KEYNOTE-055 study.

Pembrolizumab Impresses in Heavily Pretreated Head and Neck Cancer

 The FDA has accepted a supplemental new drug application (sNDA) for ibrutinib (Imbruvica) as a treatment for patients with chronic graft-versus-host-disease (cGVHD) after failure of 1 or more lines of systemic therapy, according to Janssen and AbbVie, the codevelopers of the BTK inhibitor.

The sNDA is based on data from the single-arm phase Ib/II PCYC-1129 trial, which were first presented during the 2016 ASH Annual Meeting. In the study, ibrutinib induced an overall response rate of 67% and showed clinically meaningful and durable responses in patients who failed at least 1 prior treatment for cGVHD. Twenty-one percent of responders had a complete response and 45% had a partial response. Additionally, most responders were able to reduce steroid doses to an acceptable minimal level.

The FDA granted a breakthrough therapy designation to ibrutinib as a potential treatment for cGVHD after failure of 1 or more lines of systemic therapy in June 2016. Under its standard review process, the FDA will issue its final decision on the ibrutinib sBLA within 12 months from the time of submission.

“Patients with chronic-graft-versus-host-disease are traditionally prescribed corticosteroids, which often do not produce an adequate response and may cause serious health complications for some patients,” Lori Styles, MD, senior medical director and GVHD program clinical lead at Pharmacyclics, an AbbVie company, said in a statement. “This regulatory filing is meaningful as it signifies the first potential indication for ibrutinib outside of hematological malignancies in a disease that severely impacts the patient's quality of life.”

In the PCYC-1129 trial, researchers evaluated 42 previously treated patients with cGVHD who continued on steroid-based regimens. Eligible patients had failed 3 or fewer prior therapies for cGVHD and had either more than 25% body surface area involving an erythematous rash or an NIH mouth score greater than 4. 

Patients received once-daily oral ibrutinib (420 mg) in combination with ongoing therapies, including corticosteroids and other immunosuppressants, until progression/worsening of cGVHD, recurrence of underlying malignancy, or unacceptable toxicity. The primary endpoint was cGVHD response based on the 2005 NIH consensus response criteria.

Seventy-one percent of  patients had a sustained cGVHD response of at least 5 months. Furthermore, cGVHD response was observed across multiple organs: 56% (20/25) of patients with 2 or more involved organs at baseline responded in at least 2 organs, and 42% of patients with 3 or more involved organs at baseline responded in at least 3 organs.

The most common adverse events (AEs) were fatigue (57%), diarrhea (36%), muscle spasms (29%), nausea (26%), and bruising (24%). Twenty-two (52%) patients experienced serious AEs, including pneumonia (6 patients ), septic shock (2 patients), and pyrexia (2 patients).

Based on these data, researchers initiated a phase III study to evaluate ibrutinib with corticosteroid versus placebo with corticosteroid as a first-line therapy for patients with new onset moderate or severe cGVHD. That trial is currently ongoing.

“Patients with chronic graft-versus-host-disease face an unpredictable, debilitating and sometimes life-threatening disease journey, which is further complicated by lack of FDA-approved medicines,” Sen Zhuang, MD, PhD, vice president of clinical development, hematology for Janssen Research & Development, said in a statement. "We continue to study the mechanism of action of Imbruvica, and are committed to exploring its potential to transform treatment paradigms and patient outcomes beyond its current indications in blood cancers.”

Ibrutinib was first approved in 2013 as a treatment for patients with mantle cell lymphoma, and has since gained further indications for chronic lymphocytic leukemia and Waldenström's macroglobulinemia.

Miklos D, Cutler CS, Arora M, et al. Multicenter open-label phase 2 study of ibrutinib in chronic graft versus host disease (cGVHD) after failure of corticosteroids. Presented at: 2016 ASH Annual Meeting; December 3-6, 2016; San Diego, California. Abstract LBA3.

The FDA has accepted a supplemental new drug application for ibrutinib as a treatment for patients with chronic graft-versus-host-disease after failure of 1 or more lines of systemic therapy.

FDA Accepts Ibrutinib Application for GVHD

The European Union (EU) approved the combination of dabrafenib (Tafinlar) and trametinib (Mekinist) for patients with 

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

Novartis, maker of both drugs, reported in a statement that this is the first targeted treatment approved in all 28 EU member states for use in this specific patient population.

“Today's approval represents an important milestone for the lung cancer community, especially those patients living with the 

 mutation who previously had few options," Novartis Oncology CEO Bruno Strigini said in a press release.

The European Medicines Agency’s Committee for Medicinal Products for Human Use recommended approving the combination in February of this year. That recommendation was based on results from a 3-cohort, multicenter, nonrandomized, open-label study of patients with stage IV NSCLC.

In this phase II study, 36 treatment-naïve patients and 57 previously-treated patients were assigned to 150 mg twice daily of dabrafenib and 2 mg once daily of trametinib. Investigator-assessed objective response rate (ORR) was the primary endpoint. Previously treated patients had undergone at least 1 prior line of platinum-based chemotherapy, and one-third underwent at least 2 prior treatment cycles.

At a median follow-up of 9 months, the ORR was 61.1% (95% CI, 43.5-76.9) in the treatment-naïve group, and 68% of patients did not show progression. The group had not reached endpoints for median duration of response (DoR) or progression-free survival (PFS) at the time of approval. Novartis reported that researchers will present an in-depth analysis of the results for the treatment-naïve arm at an upcoming meeting.

The ORR was 66.7% (95% CI, 52.9-78.6) in the previously treated population. Researchers found that the response was durable, with a median DoR of 9.8 months (95% CI, 6.9-16.0).

These data for the previously treated arm are updated from results reported at the 2016 ASCO Annual Meeting and published in 

 The earlier findings showed an ORR with the combination of 63.2% (95% CI, 49.3-75.6), which lasted for a median duration of 9.0 months (95% CI, 6.9-18.3). The overall disease control rate was 79% (95% CI, 66-89) when patients who had stable disease for ≥12 weeks were included. Median PFS was 9.7 months (95% CI, 6.9-19.6).

After a median follow-up of 11.6 months, 2 patients (4%) assigned to the combination experienced a complete response, in the earlier findings. Overall, 9 patients had stable disease as their best response (16%). Half of confirmed responses remained ongoing at the October 2015 data cutoff.

In the third arm of the phase II trial, 78 previously treated patients with metastatic 

—mutant NSCLC received single-agent dabrafenib. The ORR in this cohort was 33% and the median PFS was 5.5 months.

In its release, Novartis reported that the most common all-grade adverse events (>20%) across the study included pyrexia, nausea, vomiting, peripheral edema, and diarrhea.

In 2015, the FDA gave the combination breakthrough designation for patients with 

The FDA first approved the combination of dabrafenib and trametinib for patients with metastatic melanoma in January 2014. The EU approved the dabrafenib/trametinib combination for adults with unresectable or metastatic melanoma with a 

, two different kinases within the serine/threonine kinase family in the RAS/RAF/MEK/ERK pathway The pathway plays a role in the development of multiple cancers, including NSCLC and melanoma.

Worldwide, there are roughly 1.8 million new cases of NSCLC diagnosed every year. About 36,000 patients, 1% to 3% of the total, are positive for the 

Planchard D, Besse B, Groen HJM, et al. An open-label phase II trial of dabrafenib (D) in combination with trametinib (T) in patients (pts) with previously treated BRAF V600E—mutant advanced non-small cell lung cancer (NSCLC; BRF113928). 

Dabrafenib plus trametinib in patients with previously treated BRAFV600E-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial [published online June 6, 2016]. 

The European Union (EU) approved the combination of dabrafenib and trametinib for patients with BRAF V600-positive advanced or metastatic non–small cell lung cancer.
 

Jason Harris

Articles

Nivolumab Effective in Advanced Anal Cancer

HER2-Enriched Subtype Predicts Response to Dual HER2 Blockade in Early Breast Cancer

Pembrolizumab Impresses in Heavily Pretreated Head and Neck Cancer

FDA Accepts Ibrutinib Application for GVHD

Dabrafenib/Trametinib Combo Wins EU Approval for BRAF+ NSCLC